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Abstract & Commentary
By Michael H. Crawford, MD, Editor
Source: Ulimoen SR, et al. Calcium channel blockers improve exercise capacity and reduce N-terminal Pro-B-type natriuretic peptide levels compared with beta-blockers in patients with permanent atrial fibrillation. Eur Heart J 2014;35:517-524.
Current guidelines recommend monotherapy with either beta-blockers or rate lowering calcium blockers for heart rate control in patients with permanent atrial fibrillation (AF). However, few comparative data exist on these therapies. Thus, this group of investigators from Norway report on a prespecified substudy of the RATe control in Atrial Fibrillation (RATAF) study of four different once-daily drug regimens for rate control in permanent AF. They included 80 patients with non-valvular, non-ischemic AF without heart failure who after a 2-week drug washout were started on metoprolol succinate 100 mg, diltiazem SR 360 mg, verapamil SR 240 mg, or carvedilol 25 mg once daily in randomly determined 3-week intervals in a blinded fashion. Cardiopulmonary exercise testing and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels were done at baseline and on the last day of each treatment period.
One-quarter of the patients dropped out of the study, half because of adverse effects of the drugs, leaving 60 analyzable patients. All four treatments significantly decreased resting and maximum exercise heart rates compared to baseline. At peak exercise, carvedilol resulted in the lowest heart rate. The mean peak oxygen uptake (peak VO2) was significantly lower during metoprolol and carvedilol compared to baseline (21 and 20 vs 23 mL/kg/min, P < 0.001), whereas diltiazem (24) and verapamil (23) were unchanged. Diltiazem and verapamil treatment significantly reduced NT-proBNP at rest and peak exercise (831 and 897 pg/mL at rest vs 1039) and (985 and 1063 at peak vs 1262 pg/mL). Metoprolol and carvedilol increased these levels (1332 and 1205 at rest vs 1039 pg/mL) and (1634 and 1440 at peak vs 1262 pg/mL). The authors concluded that when diltiazem and verapamil are used for heart rate control in permanent AF, they preserve exercise capacity and reduce NT-proBNP levels, whereas beta-blockers do the opposite.
Beta-blockers are often considered first-line therapy for heart rate control in AF. In hospitalized patients, especially those with ischemic heart disease or heart failure, this approach makes sense and this study appropriately excluded such patients. Also, in patients with paroxysmal AF, which may be triggered by increases in adrenergic tone, beta-blockers would be a logical first pick. In this study of outpatients with permanent AF, calcium antagonists were equally efficacious as beta-blockers in controlling rest and exercise heart rate, but unlike beta-blockers, they increased exercise performance and reduced NT-proBNP.
Patients with permanent AF may be particularly vulnerable to the negative lusitropic effects of beta-blockers. Since beta-blockers impair early diastolic left ventricular (LV) relaxation, lack of atrial contraction to compensate may explain the raised BNP and reduced exercise tolerance on beta-blockers despite similar heart rate control as calcium blockers. Also, calcium blockers decrease isovolumic LV relaxation time and improve diastolic filling.
There are some limitations to this study. It is small and one-quarter of the enrolled patients dropped out. About half dropped out for reasons unrelated to the study and the rest experienced adverse drug effects, mostly when on beta-blockers. Also, it is unclear whether the drug doses chosen were equivalent. In addition, we have no LV function data to help understand the mechanism of the differences in responses to treatments. Finally, the resting heart rate targets in this study were an aggressive 60-80 beats/minute, whereas the newest studies suggest that heart rates up to 110 beats/minute are acceptable. Whether this more lenient heart rate target would have changed the results of the study is unknown. However, many patients have symptoms with heart rates over 90 beats/minute, so symptom relief has to be considered in treatment goals. At this time, my take away from this study is that unless there are other indications for beta-blockers, calcium antagonists should be tried first in patients with permanent AF who need heart rate control.