The Evidence Regarding the Drugs Used for Ventricular Rate Control
Another notable feature of these trials was the permissibility of other agents during the trial, as detailed in the evidence table. Permitting the use of digoxin in trials testing other medications, without reporting the number of participants in each arm receiving digoxin, can potentially confound the results.
Although not shown in the evidence table, most trials had explicit inclusion criteria. Some required atrial fibrillation lasting longer than 1 month or longer than 6 months, and several specified a ventricular rate required for entry, such as more than 120 beats per minute or “rapid rate.” Exclusion criteria varied from none to stringent; it was particularly stringent in those studies that involved exercise, from which subjects with angina or significant congestive heart failure were often excluded. None of the trials used echocardiographic data as inclusion or exclusion criteria.
Quality Scores
Many studies were weakest in their description of the participants in the study arms, so it was not always possible to tell if the groups were similar. This can be seen in the exceptionally low scores in the “representativeness” category. The potential for bias and confounding varied markedly across the trials, as did the description of the therapies. It was often unclear which other therapies the patients may have been receiving. Generally, the investigators described the outcomes completely and objectively measured them with Holter monitoring or telemetry. The completeness of statistical reporting was variable, with many studies only reporting a P value without reporting a measure of variability in the outcomes.
The studies published more recently had slightly higher total quality scores. Total quality scores were strongly associated with the size of the study, with the larger studies receiving higher scores (P < .001).
Outcomes
As shown in [Table 3], all of the trials reported either the heart rate reduction [on] for the active drug compared with the comparative drug or the proportion of patients who reached the target heart rate. Many of the trials also evaluated the efficacy of the drugs during exercise. The exercise test itself varied among the trials and included measurement of distance walked on a treadmill, measurement of oxygen consumption, and workload tolerated on a stationary bicycle.
On the basis of our qualitative assessment of the trials, we felt that any mathematical pooling of the results would result in invalid estimates of treatment effects. This was because of the markedly different treatment regimens within each drug class and the differing goals of treatment (acute or chronic management). The mixed quality of the trials also argued against pooling.
Study Results
Calcium-Channel Blockers Versus Placebo for Rate Control. All comparisons of calcium-channel blockers with placebo demonstrated that the calcium-channel blocker was more efficacious than placebo at reducing heart rate both at rest and during exercise. Five of the trials used diltiazem, 4 used verapamil, and 1 evaluated both drugs. An improvement in exercise tolerance was almost always seen, although different measures of tolerance were used. All but 2 of the trials allowed the participants to use digoxin but did not report what percentage of subjects in each treatment group received the drug. Despite different rates in the placebo arms, there was uniformity in treatment effects across the trials [Figure 1].
b-Blockers Versus Placebo for Rate Control. Seven different b-blockers were tested. Only 7 of the 12 comparisons demonstrated efficacy of the b-blocker at rest, although all were efficacious during exercise. The efficacy appears to be medication dependent. Atenolol (at 50 mg daily28 or twice daily20 or 100 mg daily28) performed significantly better than placebo. Timolol (1 mg intravenously) allowed more subjects to reach the target heart rate compared with placebo.24 Pindolol28 (5 mg or 15 mg twice daily) and nadolol25 (titrated dose) significantly reduced mean resting heart rate. The data regarding xamoterol were mixed.20-23 Celiprolol26 and labetalol were no more efficacious than placebo at rest.
All of the tested b-blockers demonstrated a significant reduction in heart rate with exercise compared with placebo; this included atenolol, labetalol, nadolol, celiprolol, and xamoterol.19,20,22,24,25 [Figure 2] shows that the effect of b-blockers on heart rate during exercise was more uniform than their impact on heart rate control at rest. However, these trials suggest that exercise tolerance in patients with atrial fibrillation may be reduced with b-blockers.
As in the calcium-channel blocker studies, most of the trials allowed subjects to continue on digoxin.Digoxin Versus Placebo. The outcomes with digoxin were mixed, as shown in [Table 3] and [Figure 3]. Two of the trials of digoxin versus placebo did not demonstrate a reduction in mean resting heart rate;28,30 in 5 trials, however, there was a reduction.14,22,31,32,38 Two of these studies included patients on verapamil in both arms, so we could not attribute all of the rate reduction to digoxin alone.31,32
