From the Department of Medicine, Mayo Clinic Foundation, Rochester Minnesota; and the Department of Medicine, Montreal Heart Institute and the University
of Montreal, Quebec, Canada
Antiarrhythmic drug therapy is needed in patients with atrial fibrillation who find its symptoms disturbing, even with good rate control, and in those who require effective atrial contraction to maintain their exercise tolerance or prevent congestive heart failure. Three drugs, propafenone, sotalol, and low-dose amiodarone (a maintenance dose of 200 mg daily) are frequently used to prevent atrial fibrillation. The Canadian Trial of Atrial Fibrillation (CTAF) was the first controlled, multicenter clinical trial to compare sotalol, propafenone, and low-dose amiodarone. The results showed that the recurrence of atrial fi-brillation was significantly less likely with amiodarone.1 We used detailed data on utilization and costs collected during the CTAF study to determine if low-dose amiodarone also has a significant effect on medical costs.
Patients and methods
The analysis included 403 patients with atrial fibrillation who were enrolled at 19 centers in Canada. All had had an episode of symptomatic atrial fibrillation within the previous 6 months, for which chronic antiarrhythmic drug therapy was planned. Patients were also required to have had at least one episode of atrial fibrillation lasting longer than 10 minutes and electrocardiographic documentation of the arrhythmia. Patients who had continuous atrial fibrillation for more than 6 months, a myocardial infarction within the past 6 months, cardiac surgery during the previous 30 days, New York Heart Association (NYHA) functional class III or IV, or Wolff-Parkinson-White syndrome were excluded.
Patients were randomized to treatment with amiodarone, sotalol, or propafenone. If atrial fibrillation persisted after 14 days of loading doses of amiodarone or 4 days of treatment with sotalol or propafenone, cardioversion was recommended. If the first drug given to a patient in the sotalol or propafenone arm was unsuccessful, the second agent was given and cardioversion was attempted. All analyses were done on an intention-to-treat basis.
Information on hospitalizations, including diagnosis, length of stay, and time in the intensive care unit (ICU), were taken from hospital discharge summaries. We used estimates of the average total costs at Ontario hospitals broken down by discharge diagnosis to estimate inpatient costs. The cost of outpatient procedures was estimated using accounting data from the Montreal Heart Institute. For Quebec patients, we estimated the cost of physician services using data from the Quebec Health Insurance Board. This data is similar to Medicare data in the United States; it records all payments made by the government to physicians on a per patient basis. These data also provided a record of how many times each Quebec patient was seen in an emergency department.
Because of concerns that amiodarone can harm the thyroid and cause pulmonary fibrosis, all patients on amiodarone had chest radiographs at 6 and 12 months. Thyrotropin was measured every
6 months. Using accounting data from the Montreal Heart Institute, we estimated the total cost of these tests to be $61.60 (Canadian).
Chi-square tests were used to assess differences between categorical (noncontinuous) variables. Although our data were not normally distributed, we had enough patients to use analysis of variance for data analysis. We verified the statistical results with a Kruskal-Wallis test. This test is independent of the distribution of the underlying data. To control for variables reflecting the patients’ health at randomization, we used a multiple regression analysis to determine the effect of treatment assignment.
Of the 403 patients, 201 were randomized to amiodarone, 101 to sotalol, and 101 to propafenone. The groups were well balanced with the exception that 13% of the amiodarone patients had left ventricular hypertrophy, whereas 21% of patients given sotalol or propafenone had left ventricular hypertrophy. Follow-up data were available for 392 patients at 1 year.
Patients taking amiodarone used fewer services for atrial fibrillation than those on sotalol and propafenone during the year after randomization. Twenty-five percent of patients receiving sotalol or propafenone were admitted for atrial fibrillation versus 14% of patients taking amiodarone. As a result, the average patient taking amiodarone spent half as much time in the hospital for atrial fibrillation as did the average patient taking sotalol or propafenone (figure 1). We also found that the frequency of electrical cardioversion was 40% lower in the patients taking amiodarone. Fewer pacemakers were implanted in the patients in the amiodarone group. Most patients spent no time in the ICU during hospitalizations for atrial fibrillation. There was no significant difference between the groups regarding number of days spent in the ICU.
Figure 2 depicts costs per patient during the year after randomization. The cost calculations shown are
based on the costs in the Canadian hospitals participating in the trial, but are presented in US dollars. The costs of hospitalization and procedures related to atrial fibrillation were significantly lower for patients taking amiodarone compared with those taking sotalol or propafenone. A statistically significant difference was found with both the analysis
of variance and Kruskal-Wallis tests
(P < .03). When we added costs associated with stroke, amiodarone’s cost advantage increased to 43% and remained statistically significant
(P = .02). No statistically significant difference between the groups was found when looking at hospitalizations for all diagnoses. This finding reflected the substantial hospital costs that were not related to atrial fibrillation in this population. Thirty-one percent of amiodarone patients and 36% of patients taking sotalol or propafenone were admitted to the hospital at least once. Patients in each group had approximately the same number of hospital and emergency department visits and days in the hospital and the ICU. Costs for all hospitalizations and combined hospital and physician costs were also similar for both groups. When we compared total costs controlled for patients’ health status at enrollment using a multivariate regression, we found that amiodarone reduced total costs by 7%; however, this finding was not statistically significant.
The CTAF study showed that low-dose amiodarone is more effective than sotalol or propafenone in preventing recurrence of atrial fibrillation.1 Recently, the antiarrhythmic drug substudy of the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) reached a similar conclusion, finding amiodarone superior to sotalol and class I agents in maintaining sinus rhythm and drug tolerance at
1 year.2 Our results show that low-dose amiodarone reduces the costs associated with atrial fibrillation. Costs for atrial fibrillation hospitalizations—by far the most common type of hospitalization—were significantly lower with amiodarone. Cardioversion, a procedure that is expensive and unpleasant, was 40% less frequent. Our results are consistent with a previous retrospective study by Catherwood and colleagues and a study by Eckman and colleagues who also found that amiodarone reduces costs.3,4
We were surprised that the low-er frequency of atrial fibrillation
in patients taking amiodarone did not manifest itself in fewer emergency department visits. The effect of amiodarone may have been obscured by variations in emergency department visits that were not related to atrial fibrillation. We did not find that there was an increase in utilization of services related to amiodarone use that would have offset the reduced utilization related to atrial fibrillation.
After adjusting for patient health at randomization, we still found no significant difference in total hospital costs or combined hospital and physician costs. We considered the possibility that the cost of treating the side effects of amiodarone, particularly the most feared side effect, pulmonary fibrosis, might have canceled out the savings that amiodarone generated in atrial fibrillation-related costs. We found no evidence for this in the data.
In most studies that documented amiodarone-related side effects, patients were treated with high doses of up to 800 mg daily. In our study, the dose was 200 mg daily. A meta-analysis of trials comparing low-dose amiodarone (150 to 330 mg
daily) with placebo found the incidence of pulmonary toxicity over 1 year with amiodarone was 1.9% versus 0.7% with placebo.5 This difference was not statistically significant, and no fatalities were related to pulmonary toxicity. In the Congestive Heart Failure-Survival Trial of Antiarrhythmic Therapy (CHF-STAT), pulmonary fibrosis was diagnosed in only 1.1% of patients during 45 months of amiodarone therapy versus 0.8% of those receiving placebo.6
We probably did not find a significant difference in total costs because of the many other health problems in our patient population. Almost one half of the costs for the group taking sotalol or propafenone and more than two thirds of the costs for the group taking amiodarone were not related to atrial fibrillation treatment. The costs from these other health problems likely conceal the relatively smaller differences in costs related to atrial fibrillation.
Although our data reflect costs in Canadian hospitals, our results probably apply in the United States as well, because we found the same results for hospital days and procedures—the most expensive health care resources in the United States—as we did for costs. We did not explicitly take the cost of drugs into account because prices change rapidly as these drugs come off patent and vary greatly in different markets. Amiodarone, propafenone, and sotalol are all presently available in generic forms, however, and are all relatively inexpensive.
Our study showed that amiodarone reduces atrial fibrillation-related medical procedures and costs compared with propafenone and sotalol. We were not able to show an overall reduction in total medical costs in this relatively sick population. If a decision is made to maintain sinus rhythm in a patient with atrial fibrillation, the superior efficacy and potential cost advantage of amiodarone should be considered in drug selection. The decision must also be weighed with the risk of adverse events and other therapeutic considerations.