The Evidence Regarding the Drugs Used for Ventricular Rate Control

Two studies evaluating digoxin during exercise did not find a significant heart rate reduction.^14,22 In one trial that suggested a difference, no measure of statistical significance was provided.²⁸ Four of the studies of digoxin and placebo evaluated exercise tolerance.^14,22,28,29 In one14 the cardiac output was higher for patients taking digoxin, and in another²² the time on the treadmill was longer with digoxin although the maximal attainable heart rate blood pressure product was higher with placebo.

Calcium-Channel Blockers Versus Digoxin for Rate Control. Three trials compared diltiazem with digoxin,^14,19,40 and 3 compared verapamil with digoxin^14,41,42 with the outcomes reported in [Table 3] and in [Figure 4]. The scatter plot is most useful for noting the trend toward improved control with calcium-channel blockers both at rest and with exercise. Notably, the cardiac output on digoxin during exercise was greater than in the 2 diltiazem groups (12.6 L/min vs 10.9 L/min and 9.1 L/min for 60 mg and 120 mg, respectively).¹⁴ Conversely, the group receiving verapamil was able to exercise longer on the treadmill than the digoxin group.⁴³ This latter study, however, had methodologic flaws, including little description of the participants.

b-Blockers Versus Digoxin for Rate Control. Four trials compared b-blockers with digoxin for rate control in atrial fibrillation, and the outcomes are reported in [Table 3] and in Figure 5.^22,28,42,43 Similar to the results of the trials of b-blockers compared with placebo, the efficacy of b-blockers was most convincing in the trials that evaluated their use during exercise. There appeared to be little difference between the efficacy of b-blockers and digoxin at rest.

Other Drugs and Combinations Versus Placebo and Digoxin. [Table 4] summarizes the outcomes for the few trials of other agents. Not surprisingly, of the 8 trials that compared digoxin with a combination of digoxin with a calcium-channel blocker,^{14,19,22,38,40,41,45,46} only one study did not find a significant decrease in mean resting heart rate with the addition of the calcium-channel blocker.⁴⁰ In 5 of the 6 studies with an exercise evaluation,^{14,19,38,41,45} the combination of a calcium-channel blocker and digoxin controlled the heart rate better than digoxin alone, while the sixth trial did not report the statistical significance of this outcome.¹⁴ Of the trials of a b}-blocker combined with digoxin, all were more effective than placebo, and all were more effective than digoxin alone except for the combination of digoxin and labetolol.²⁸ During exercise, however, this combination was more effective than either comparison arm.

Other Drugs Evaluated for Rate Control. There were 9 other randomized controlled trials of drugs for rate control in atrial fibrillation.^50-58 Two studies compared intravenous magnesium sulfate with intravenous verapamil for acute control.^50,51 In both studies, a higher percentage of subjects reached a heart rate of less than 100 beats per minute with verapamil than with magnesium sulfate.

Two studies evaluated rate control with propafenone or flecainide, both at 2 mg per kg intravenously for 1 hour; both significantly reduced the heart rate from baseline.^52,53 In both studies, subjects were allowed to continue on digoxin, calcium-channel blockers, and b-blockers. The side effects of flecainide were of more concern than those of propafenone, with conduction abnormalities in the flecainide group. Another study compared propafenone with quinidine for rate control.⁵⁴ Propafenone significantly slowed the heart rate at rest compared with quinidine. Either drug effectively slowed the heart rate compared with baseline.

Disopyramide did not reduce the mean resting heart rate from baseline.⁵⁵ The combination of diltiazem and digoxin reduced the mean resting heart rate to a greater degree than the combination of propranolol and digoxin, but all 3 drugs together were even more effective.⁵⁶ That study also demonstrated that with exercise the combination of propranolol and digoxin was more efficacious for heart rate control than diltiazem and digoxin and that the 3-drug combination was not better than just propranolol and digoxin. The combination of pindolol and digoxin reduced the maximum area under the heart rate curve significantly more than verapamil and digoxin.⁵⁷ Finally, the combination of amiodarone and digoxin slowed the resting heart rate when compared with baseline, while the combination of quinidine, verapamil, and digoxin did not; this was a small trial, however, and the baseline resting heart rates were not rapid.⁵⁸

Discussion

The randomized controlled trials of diltiazem and verapamil used by patients with atrial fibrillation provide strong evidence for their efficacy in reducing heart rate both at rest and with exercise when compared with placebo. In all of the studies that evaluated calcium-channel blockers compared with placebo during exercise, the calcium-channel blockers produced either an increase in cardiac output, oxygen consumption, or distance walked. There was also moderate evidence that diltiazem or verapamil was more effective at heart rate control both at rest and during exercise in the direct comparisons with digoxin, with a more rapid onset of action. Although digoxin appeared to increase cardiac output, verapamil prolonged time on the treadmill and increased oxygen consumption. Thus, the evidence strongly supports the use of diltiazem or verapamil for ventricular rate control in atrial fibrillation. Although they have a negative inotropic effect, reflex responses to vasodilatation usually result in a small increase in cardiac output. Therefore, except in moderate to severe heart failure, the negative inotropic effect is often not clinically apparent.⁶⁰