The Evidence Regarding the Drugs Used for Ventricular Rate Control

Data Abstraction

A form was developed to extract information from the eligible articles regarding study quality, characteristics, and findings. The section on study quality was created after our review of forms used in meta-analytic studies^8,9 and a literature review^10,11 and with the assistance of The Cochrane Collaboration. The resultant form incorporated⁶ key questions used by The Cochrane Collaboration in its reviews and¹⁴ key questions identified by Detsky and colleagues.¹⁰ Our form was pilot-tested for clarity and reproducibility and revised as needed. The final version contained 22 questions assessing quality in the following 5 areas: representativeness (how well the study population was described); potential for bias and confounding; description of therapy (eg, how similarly the groups were treated); outcomes and follow-up; and statistical reporting and interpretation [Table 1]. Each question was worth a maximum of 2 points, and the score in each category was the percentage of points received out of the total available. The overall quality score was calculated as the average of the scores for the 5 categories.

The portion of the form for quantitative data abstraction included sections for subject inclusion and exclusion criteria, baseline subject characteristics, therapeutic protocols, and outcomes. We recorded the mean heart rate at rest, the mean maximum heart rate during exercise or immediately after exercise, the proportion of subjects who reached the goal heart rate reduction in each treatment arm, and any measure of exercise tolerance.

The review of study quality was done independently by 2 reviewers, and differences were resolved by consensus. Quantitative data were abstracted by one primary reviewer and then checked for accuracy by a secondary reviewer. The reviewers were not blinded to the author, institution, or journal, since it seemed unlikely that this information would make a significant difference in the results.¹²

Presentation of the Data

We constructed 3 evidence tables with the trials grouped according to the regimens being compared. [Table 2a][Table 2b] displays the quality scores and key design elements of each trial. [Table 3] contains a listing of the trials of the most frequent comparisons and the absolute differences in heart rates of patients using those therapies. [Table 4] shows the results from the trials for which there were few, if any, given comparisons.

Data was synthesized by creating scatter plots of mean heart rates at rest and with exercise for each of the main drug comparisons (Figures 1-5). The data were not amenable to formal mathematical pooling (ie, meta-analysis) because of significant qualitative heterogeneity among the studies.*

Results

Literature Yield

We retrieved 74 abstracts. Of these, 8 were abstracts of articles from non–English-language literature. Forty-five trials were eligible for inclusion in our review; the authors of those studies evaluated 17 different drugs and several combinations of drugs. Some of the included trials were not designed as rate-control studies; they were studies of pharmacologic conversion that included heart rate data.

Qualitative Synthesis

The following comparisons were made in the trials: calcium-channel blockers,¹⁴-²¹ b-blockers,^19-28 digoxin,^{14,22,28,30-32,38} or other drugs and combinations compared with placebo;^{14,28,29,33-38} calcium-channel blockers,^14,39-42 b-blockers,^23,29,43,44 or other drugs and combinations compared with digoxin;^{14,27,40,44-49} and other drug comparison trials.^{18-20,27,42,50-58} Many of the trials involved more than 2 treatment arms. Nearly all of the trials of calcium-channel blockers, b-blockers, and digoxin were designed to evaluate rate control. The studies of the other drugs were principally trials evaluating atrial fibrillation conversion that also reported heart rate data. Two of the digoxin trials were also aimed at evaluating conversion to sinus rhythm.

Study Design

As shown in [Table 2a][Table 2b], there were important similarities and differences among the trials evaluating the same therapies. The duration of the trials and route of administration of the drug are presented to aid in interpretation of the results.

Notably, all of the trials of any given comparison were done within 10 years of each other. This should reduce the likelihood of secular trends affecting the outcomes of the trials. The range in study sizes is extreme, although most of the trials enrolled fewer than 50 patients. Several trials had fewer than 10 participants, and it was anticipated that these small trials would have little power to detect differences between treatments.

The regimens differed among the trials of the same medication. The intravenous diltiazem and verapamil doses were fairly uniform, although the oral dosages and frequency of administration differed. Some of the b-blocker trials involved titration of the medication to effectiveness, and digoxin was often dosed to a target blood level. All these differences may have had an impact on the outcomes. The followup times ranged from minutes to 6 weeks. Short trials may be appropriate for intravenous agents; however, several of the trials assessed the outcome a very short time after a single oral dose of medication, before a therapeutic blood level could be expected.