The Evidence Regarding the Drugs Used for Ventricular Rate Control
All of the tested b-blockers successfully reduced heart rate with exercise when compared with placebo, and most of them reduced resting heart rate. The effect on exercise tolerance was variable and may be due to the different receptor specificities of the tested drugs and the varying treatment times before testing.
When administered acutely, b-blocking agents depress myocardial function secondary to the withdrawal of adrenergically mediated inotropic and chronotropic support. However, in patients with congestive heart failure treated for longer than 1 month, b-blockers may improve myocardial function by improving intrinsic systolic function.59,61-63 Extrapolating to patients with atrial fibrillation, b-blocker therapy may increase left ventricular ejection fraction compared with placebo if administered for longer than 1 month. None of the trials in this review lasted for longer than 4 weeks, so it is conceivable that the worsening exercise tolerance was a transient effect of the drug.
When compared with digoxin, the trials favored the use of b-blockers, as digoxin was less efficacious than metoprolol in resting heart rate reduction and less efficacious than labetalol at rate reduction during exercise. Furthermore, time on the treadmill was longer with both labetalol and metoprolol than with digoxin.
It will be interesting to see the effect of the third-generation b-blockers, such as carvedilol, on heart rate control in atrial fibrillation. We anticipate that they will be effective at ventricular rate control, with an improvement in exercise tolerance. Celiprolol and xameterol are not available in the United States and are no longer being evaluated for approval by the Food and Drug Administration.
Although several of the studies comparing digoxin with placebo were limited by subtherapeutic serum levels of digoxin at the time of evaluation, the others did show a resting heart rate reduction. There is little evidence to support the efficacy of digoxin for heart rate control with exercise. However, in the 2 trials that evaluated exercise tolerance on digoxin compared with placebo, cardiac output and time on the treadmill were greater with digoxin.
The trials evaluating other drugs, including propafenone, clonidine, and amiodarone yielded insufficient evidence to support their use for rate control at this time. These drugs appear promising and may prove efficacious when more evidence becomes available.
The optimal degree of heart rate control for patients with atrial fibrillation is unclear, particularly during exercise. Certainly an excessively rapid rate impairs ventricular filling and decreases cardiac output. However, severely limiting the heart rate acceleration that is needed to maintain cardiac output can also limit exercise tolerance.63 There are few empirical trials of this. One recent study found that ventricular rate control in atrial fibrillation had no impact on cardiovascular performance as measured by endurance on a treadmill.63 The studies in our review that report only on heart rate control during exercise without mention of exercise tolerance may be of less value to clinicians.
It is important to recognize that both heart rate control and exercise tolerance are surrogate outcomes for what is truly important to clinicians and their patients: their well-being, ability to conduct their daily activities, and mortality. Although several of the studies did inquire about symptoms such as palpitations or breathlessness, the use of validated quality-of-life questionnaires was rare. A study comparing pharmacologic treatment of atrial fibrillation with atrioventricular junction ablation and pacing demonstrated the use of several different quality-of-life measures: a Quality-of-Life Questionnaire, Specific Symptoms Scale, New York Heart Association Classification, and a Specific Activity Scale.64 The authors of that study commented that they were uncertain whether the sensitivities of these scales were high enough to use as they did.
Our study is the first comprehensive evidence-based review that focused on this aspect of the management of atrial fibrillation. Several recent reviews described ventricular rate control trials in the context of other pharmacologic therapies for managing atrial fibrillation,65,2-4 but those studies did not comprehensively review all the rate control trials. Furthermore, they contained recommendations for drugs that have never been evaluated in controlled trials of patients with atrial fibrillation exclusively (such as intravenous esmolol and intravenous propranolol).2
Limitations
Our systematic review was subject to the same limitations that are common to most reviews. The important differences among the trials preclude mathematical pooling and have to be taken into account when drawing conclusions using these studies. As in most assessments of study quality, our assessment tool was tailored to fit the topic, so the scores cannot be directly compared with quality assessments of studies on other topics. Our intent was to be able to compare the trials.
Few of the studies evaluated adverse effects in any systematic way. This inconsistent reporting of adverse effects limited our ability to comment on them. Many of the trials incompletely described the enrolled participants, so applying these results to all patients with atrial fibrillation should be done cautiously. Also, since results were seldom stratified by the clinical features of the enrolled patients, we could not report on the evidence supporting the use of these drugs in different patient populations.
