Correspondence
Dofetilide for Atrial Fibrillation
N Engl J Med 2000; 342:289-290January 27, 2000
- Article
To the Editor:
Contemporary pharmacotherapy for patients with advanced congestive heart failure (New York Heart Association functional class III or IV) typically involves the concomitant use of digoxin, loop diuretics, angiotensin-converting–enzyme inhibitors, and increasingly, beta-blockers. In the September 16 issue of the Journal, Torp-Pedersen and coworkers1 reported that dofetilide had a neutral effect on the risk of death from any cause, reduced the risk of hospitalization for worsening congestive heart failure, and was effective in restoring (and maintaining) sinus rhythm in patients with atrial fibrillation. However, it is unclear whether therapy with digoxin was an exclusion criterion, according to the design of study, since there was no specific mention of outcomes with respect to digoxin, either as combination therapy or as one of the predefined treatment subgroups. Clearly, digoxin is still widely prescribed for patients with congestive heart failure who have atrial fibrillation, yet the trial results provide little, if any, insight with respect to whether the authors view dofetilide as an alternative to digoxin, or whether these two agents can be used safely together.
Similarly, there appeared to be a potentially adverse, negative interaction between dofetilide and beta-blockers with respect to the primary end point of death from any cause (hazard ratio for the comparison with the receipt of placebo plus a beta-blocker, 1.55; 95 percent confidence interval, 0.89 to 2.70). Although, strictly speaking, this finding was not statistically significant, the trend toward a higher risk of death among patients with congestive heart failure who received dofetilide plus a beta-blocker (55 percent higher than in the group that received placebo and a beta-blocker) raises serious concern about whether these two agents should be used together.
In the light of these considerations, could the authors clarify whether they believe it is safe and appropriate to recommend dofetilide for patients with congestive heart failure, whether or not they have atrial fibrillation, who are concomitantly taking digoxin, beta-blockers, or both?
1 ReferencesPablo Ferraro, M.D.
Abbas Khawari, M.D.
William E. Boden, M.D.
SUNY Health Science Center, Syracuse, NY 132101
Torp-Pedersen C ,Moller M ,Bloch-Thomsen PE , et al. Dofetilide in patients with congestive heart failure and left ventricular dysfunction. N Engl J Med 1999;341:857-865
Full Text | Web of Science | Medline
To the Editor:
The abstract is a widely read and frequently cited part of an article. Therefore, its fidelity to the body of the article is of paramount importance. In that regard, I have great concern about the abstract of the article by Torp-Pedersen et al., which concludes that “in patients with congestive heart failure and reduced left ventricular function, dofetilide was effective in converting atrial fibrillation, preventing its recurrence, and reducing the risk of hospitalization for worsening heart failure. Dofetilide had no effect on mortality.”
The following is a summary and analysis of the data in the body of the article that are relevant to the conclusions. First, at one month, only 12 percent of patients with atrial fibrillation who were treated with dofetilide had conversion to sinus rhythm. Second, at the end of 12 months, only 36 percent of the patients in the dofetilide group with successful conversion from atrial fibrillation to si-nus rhythm by either pharmacologic or electrical means remained in sinus rhythm. Third, each of the 762 patients in the dofetilide group required hospitalization at the initiation of the study in order to start dofetilide thera-py safely, because of the risk of life-threatening arrhythmia. This large number of hospitalizations stands in contrast to the much smaller number of hospitalizations (70) that were avoided in the dofetilide group, compared with the placebo group, during the 36 months of the study. Finally, female patients and patients in New York Heart Association class III or IV at base line were at significant risk for torsade de pointes despite very careful titration of the dose of dofetilide by experienced investigators.
Stanley A. Rubin, M.D.
UCLA School of Medicine, Los Angeles, CA 90073Author/Editor Response
The authors reply:
To the Editor: Ferraro et al. raise important questions about the concomitant treatment of patients with dofetilide and digoxin or beta-blockers. Digoxin and beta-blockers were allowed in the study. In the dofetilide group, 481 patients (63.1 percent) received digoxin, as compared with 463 (61.2 percent) in the placebo group. There was no interaction between treatment with dofetilide and digoxin with respect to survival (P=0.6). Approximately 10 percent of patients in the trial received beta-blocker treatment, and the trend toward a poorer prognosis among patients who received beta-blockers as well as dofetilide was not significant (P for interaction, 0.07). In a companion study (unpublished data), in which patients with severe left ventricular dysfunction after acute myocardial infarction were randomly assigned to receive dofetilide or placebo, over 45 percent of patients in each group were treated with beta-blockers. The trend was in the opposite direction, with a favorable outcome of treatment with dofetilide plus a beta-blocker; again, this interaction was not statistically significant (P=0.12).
Dr. Rubin criticizes the validity of our conclusions but does not cite our results correctly. After one year, the total rate of cardioversion was 61 percent in the dofetilide group and 33 percent in the placebo group. The probability of remaining in sinus rhythm at one year after conversion from atrial fibrillation was 78 percent in the dofetilide group and 43 percent in the placebo group. Dr. Rubin quotes only one-month figures for spontaneous conversion, but dofetilide was associated with spontaneous cardioversion over a very long period of time. Our conclusions regarding atrial fibrillation were based on these figures.
Dr. Rubin's calculations regarding the benefit of hospitalization are not relevant. Our patients were not hospitalized specifically to receive dofetilide but were recruited for the study during a hospitalization in which they had congestive heart failure. However, we have shown that dofetilide is effective in reducing hospitalizations among patients with heart failure and in restoring and maintaining sinus rhythm. Dofetilide therapy is therefore an alternative to rate control in these patients.
With respect to the issue of proarrhythmia, our findings would have been equally neutral with respect to survival if all patients who had torsade de pointes, cardiac arrest, or both during the three days of monitoring had died. The rate of proarrhythmia is small as compared with the mortality rate in patients with congestive heart failure. Understanding this point is important with respect to the comparison of dofetilide with other class III drugs and with class I drugs, for which the benefits of monitoring the initiation of therapy have not been proved, but have also never been assessed.
Christian Torp-Pedersen, M.D.
Lars Køber, M.D.
Gentofte Hospital, DK-2900 Hellerup, DenmarkMogens Møller, M.D.
Odense University Hospital, DK-5000 Odense, Denmark
