The effect of rate versus rhythm control in patients with atrial fibrillation who have undergone previous pacemaker (PM) implantation is unknown. We evaluated the mortality in patients with atrial fibrillation and a PM randomized to rate or rhythm control treatment strategies. The Atrial Fibrillation Follow-up Investigation of Rhythm Management data set was stratified by the presence (n = 250) or absence (n = 3,810) of a PM at randomization into the rate or rhythm control arm. Kaplan-Meier curves were used for univariate analysis, and proportional hazards were used for multivariate analysis. The subjects with a PM (n = 250) were older (73 vs 69 years, p <0.01) and had a greater prevalence of coronary artery disease (53% vs 37%, p <0.01) and congestive heart failure (33% vs 23%, p <0.01). All-cause mortality was significantly greater in the PM patients who were randomized to the rhythm control arm (n = 128) than in the patients enrolled in the rate control arm with or without a PM (n = 2,027, p <0.01) and those in the rhythm control arm without a PM (n = 1,905, p <0.01). Multivariate analysis revealed that predictors of all-cause mortality included PM patients randomized to the rhythm control arm (hazard ratio 2.59, 95% confidence interval 1.46 to 4.58, p <0.01) and the presence of congestive heart failure (hazard ratio 2.42, 95% confidence interval 1.40 to 4.16, p <0.01). In conclusion, all-cause mortality was greater among patients with atrial fibrillation with a PM, who were randomized to the rhythm control arm of the Atrial Fibrillation Follow-up Investigation of Rhythm Management study compared with all other patients enrolled in the Atrial Fibrillation Follow-up Investigation of Rhythm Management study. The rhythm control strategy in patients with a PM was an independent predictor of mortality.
The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study is 1 of the largest multicenter trials investigating mortality. A total of 4,060 subjects with atrial fibrillation (AF) were randomized to a rhythm control or rate control treatment strategy. The study revealed that no survival benefit was present for patients treated with the rhythm control strategy compared with the rate control strategy. In their evaluation of the clinical factors associated with abandonment of either treatment strategy, Curtis et al found that the presence of a pacemaker (PM) at randomization was significantly associated with the maintenance of the rate control strategy. This finding was not surprising, given that having a PM allowed for more aggressive uptitration of rate controlling medications, such as β blockers, without the side effect of bradycardia. Similarly, the presence of a PM might allow for more aggressive uptitration of rhythm control medications by preventing symptomatic bradyarrhythmias that can be associated with drugs such as amiodarone and sotalol, the 2 most commonly used drugs in the AFFIRM study. Of the total AFFIRM cohort, 250 subjects had received a PM before randomization. Although the patients with a PM were included in the AFFIRM mortality analysis, no subgroup analysis was performed evaluating the mortality in this specific population of patients. The goal of the present study was to evaluate the AFFIRM data set to assess all-cause mortality in those patients with AF who had received a PM before randomization to the rhythm control or rate control arms. The secondary goals were to evaluate the data for the possible predictors of mortality in patients with a PM and AF.
Methods
The institutional review board of the University of Miami Miller School of Medicine (Miami, Florida) approved the present study. The AFFIRM trial public-use, limited-access data set (devoid of personal identifiers) was subsequently obtained from the National Heart, Lung, and Blood Institute (National Institutes of Health, Bethesda, Maryland).
AFFIRM was a randomized, multicenter trial that enrolled 4,060 patients with AF who were aged ≥65 years or had risk factors for stroke and death. These patients were then randomized to a rate control strategy (n = 2,027) in which the treating physician used β blockers, calcium channel blockers, and digoxin (alone or combined) to target a heart rate of <100 beats/min both at rest and with activity (tested using the 6-minute walk test). Alternatively, the patients were randomized to the rhythm control arm (n = 2,033), in which the goal was to maintain sinus rhythm using pharmacologic therapy and cardioversion, as necessary. Acceptable pharmacologic interventions for rhythm control included amiodarone, disopyramide, flecainide, moricizine, procainamide, propafenone, quinidine, and sotalol (alone or combined). All patients were treated with warfarin to a goal international normalized ratio of 2.0 to 3.0. However, in the rhythm control arm, this could be discontinued by the treating physician if the patient was maintained in sinus rhythm for 4 to 12 weeks. The patients in the rate control arm were required to continue anticoagulation therapy for the duration of the study. The follow-up period was 5 years, at which time the primary end point of mortality was evaluated. We performed a post hoc analysis of patients with AF (n = 4,060) who had had a PM at randomization (n = 250) versus those patients without a PM at randomization (n = 3,810). These subjects were further stratified by the treatment arm, resulting in 4 groups: with a PM in the rhythm control arm (n = 128), without a PM in the rhythm control arm (n = 1,905), with a PM in the rate control arm (n = 122), and without a PM in the rate control arm (n = 1,905).
We included the end points of all-cause mortality and cardiovascular mortality and the combined end point of death, ventricular tachycardia, ventricular fibrillation, cardiac arrest, ischemic stroke, major bleeding, pulmonary embolism, and myocardial infarction. We were unable to separate the outcomes into individual end points, because only the combined end point was available from the public-access data set.
For the categorical variables, the Rao-Scott chi-square test was used to evaluate the group differences. For continuous variables, analysis of variance and the independent samples t test were used to evaluate the group differences. Kaplan-Meier curves were then used for univariate analysis of cardiac and all-cause mortality, and the Cox proportional hazard regression model was used to calculate the hazard ratio (HR), 95% confidence intervals, and p values of cardiac mortality and all-cause mortality for possible predictors of death. HRs were reported after multivariate adjustment for age, coronary artery disease (CAD), diabetes, hypertension, β-blocker use, digoxin use, first episode of AF, rhythm at randomization, smoking, gender, stroke, lipid-lowering therapy, and angiotensin-converting enzyme inhibitor therapy. The mean follow-up period was 3.5 years. The subjects were excluded if the mortality data were missing. The analyses were performed using Statistical Analysis Systems, version 9.2 (SAS Institute, Cary, North Carolina), and all tests were 2-tailed, with p ≤0.05 considered statistically significant.
Results
The patients with a PM were significantly older (73 vs 69 years, p <0.01), with a greater prevalence of CAD (53% vs 37%, p <0.01) and congestive heart failure (CHF) (33% vs 23%, p <0.01). More patients with a PM were men in the rhythm control group than were the patients in the same treatment group without a PM; however, the percentage of men did not differ compared with the patients with a PM in the rate control group. The patients with a PM randomized to the rate control arm had significantly lower mortality than those randomized to the rhythm control arm ( Table 1 and Figure 1 ). Otherwise, no significant differences were found in the baseline characteristics among the patients with a PM assigned to the rate or rhythm control arm ( Table 1 ). Fewer patients with a PM were in nonsinus rhythm at randomization into the rhythm control group than were those without a PM in the same treatment group. Among the patients with a PM, no difference was found in the rhythm status at initiation for the patients assigned to the rhythm or rate control strategy. The subjects with a PM randomized to the rhythm control arm had a mortality of 32.8%, which was greater than that for the subjects with a PM in the rate control arm (19.7%) or those without a PM in the rhythm control (15.0%) or rate control (16.5%) arms (p <0.01 for all groups; Table 1 and Figure 2 ) Multivariate analysis (HR, 95% confidence interval, p value) revealed that the predictors of all-cause mortality for the subjects with a PM included randomization to the rhythm control arm, the presence of CHF, and the duration of AF. Warfarin was protective ( Table 2 ).
| Characteristic | Rate Control Arm | Rhythm Control Arm | ||
|---|---|---|---|---|
| PM Implantation (n = 122) | No PM Implantation (n = 1,905) | PM Implantation (n = 128) | No PM Implantation (n = 1,905) | |
| Age (yrs) | 72 ± 7.1 | 69 ± 8% ∗ | 74 ± 7.2 | 69 ± 8.2 † |
| CAD (%) | 48.3 | 36.6 ∗ | 57.8 | 37.8 † |
| First episode of AF (%) | 21.1 | 36.7 ∗ | 30.6 | 35.6 |
| Sinus rhythm at randomization (%) | 47.6 | 54.8 | 41.8 | 54.5 † |
| Smoker (%) | 13.1 | 11.8 | 7.0 | 12.9 † |
| Warfarin therapy (%) | 80.3 | 84.4 | 85.9 | 84.9 |
| Men (%) | 40.2 | 40.6 | 47.6 | 37.3 † |
| Stroke (%) | 14.8 | 13.2 | 18.0 | 13.1 |
| Diabetes mellitus (%) | 22.9 | 20.8 | 17.2 | 19.3 |
| CHF (%) | 36.1 | 22.6 ∗ | 30.5 | 22.3 † |
| Hypertension (%) | 71.3 | 70.7 | 64.1 | 71.4 |
| Lipid-lowering therapy (%) | 18.0 | 22.1 | 18.7 | 23.4 |
| β-Blocker therapy (%) | 38.9 | 42.0 | 39.8 | 43.7 |
| Digoxin therapy (%) | 57.4 | 52.7 | 46.8 | 53.5 |
| All-cause mortality (%) | 19.7 | 15.0 (p = 0.16) | 32.8 ‡ | 16.5 † (p <0.01) |
∗ p <0.05 for PM group versus no PM group in the rate control arm.
† p <0.05 for PM group versus no PM group in the rhythm control arm.
‡ p = 0.02 for rate versus rhythm control arm for all patients with a PM; p <0.01 for difference in deaths for PM vs no PM group in patients in the rhythm control arm.
| Variable | HR | 95% Confidence Interval | p Value |
|---|---|---|---|
| CHF | 2.419 | 1.404–4.165 | <0.01 |
| Rhythm control arm | 2.590 | 1.463–4.586 | <0.01 |
| Duration of AF | 1.334 | 1.046–1.701 | 0.02 |
| Warfarin therapy | 0.339 | 0.172–0.670 | <0.01 |
The predictors of all-cause mortality for patients without a PM included CAD, diabetes mellitus, smoking, history of stroke, and CHF ( Table 3 ). Warfarin therapy, female gender, and lipid-lowering therapy were protective ( Table 3 ).
| Variable | HR | 95% Confidence Interval | p Value |
|---|---|---|---|
| Age | 1.063 | 1.050–1.077 | <0.01 |
| CAD | 1.646 | 1.376–1.970 | <0.01 |
| Diabetes mellitus | 1.509 | 1.251–1.821 | <0.01 |
| First episode of AF | 1.26 | 1.065–1.498 | <0.01 |
| Sinus rhythm at randomization | 0.822 | 0.693–0.974 | 0.02 |
| Smoking | 1.718 | 1.363–2.165 | <0.01 |
| Warfarin therapy | 0.659 | 0.532–0.816 | <0.01 |
| Female gender | 0.795 | 0.665–0.951 | 0.01 |
| Stroke | 1.615 | 1.305–1.998 | <0.01 |
| CHF | 2.087 | 1.747–2.492 | <0.01 |
| Lipid-lowering therapy | 0.756 | 0.608–0.941 | 0.01 |
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