Response to Letter Regarding Article, “Acute Pharmacological Conversion of Atrial Fibrillation to Sinus Rhythm”
We appreciate the comments by Dr Reiffel about our report1 from the Food and Drug Administration (FDA) Cardiovascular and Renal Drugs Advisory Committee Meeting, December 2007, which reviewed 2 development programs for the acute pharmacological conversion of atrial fibrillation. On the basis of his letter, we would like to clarify several points.
The deliberations and recommendations of FDA advisory panels are focused on the development program under review and therefore do not serve as a comprehensive assessment of the overall management or treatment options of a particular disorder. Furthermore, the context of the advisory committee meeting is based on formal presentations and documents prepared by the sponsor, as well as an independent analysis of the data under consideration by the FDA. Importantly, not all the evidence may be in the public domain before the advisory committee meets. In the case of acute pharmacological conversion of atrial fibrillation, 2 new agents (vernakalant and tedisamil) were reviewed on separate days. Our assessment of these agents focused on the fact that the primary clinical benefit of acute conversion was symptomatic relief of atrial fibrillation because the development programs were not designed to determine any long-term benefits of such conversion. Therefore, the context of reviewing therapies for symptomatic benefit requires that the benefits and associated risks be clearly understood.
In the particular case of vernakalant and tedisamil, the clinical benefits were acknowledged by the committee as a shortened time (by a few hours) in symptomatic atrial fibrillation and avoidance of electrical cardioversion. It is interesting to note that in both programs, at the end of the 24-hour observation period, a similar proportion of patients on drug and placebo were in sinus rhythm. Thus, at 24 hours, “watchful waiting” in the placebo groups resulted in similar outcomes as observed in the drug groups based on the inherent rates of spontaneous conversion and the use of electrical cardioversion. The safety of the development programs was also reviewed, and serious concerns were raised. These included drug-induced ventricular arrhythmias, torsade-like arrhythmias, hypotension, and death. On the basis of the overall review, the committee believed that the risk–benefit relationship was favorable for vernakalant and unfavorable for tedisamil. We hope that these comments further clarify the nature and content of the advisory committee meeting.
Hiatt WR, Lincoff AM, Harrington RA. Acute pharmacological conversion of atrial fibrillation to sinus rhythm: is short-term symptomatic therapy worth it? A report from the December 2007 meeting of the Cardiovascular and Renal Drugs Advisory Committee of the Food and Drug Administration. Circulation. 2008; 117: 2956–2957.