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Executive Summary

Programmed electrical stimulation (PES) is a "relevant" investigational technique for the evaluation of drug efficacy in certain arrhythmias, FDA Office of Drug Research & Review Director Robert Temple, MD, said during a Sept. 6 workshop on the role of the procedure in antiarrhythmic drug testing. "It seems to me that we've been moving toward the idea that such a large fraction of the treating community thinks that PES is relevant for the treatment of certain arrhythmias that to launch an antiarrhythmic without any experience in that is an inadequate work-up," Temple said. He noted that "there are probably other kinds of things one could do that we would say -- 'well, that's still optional, its not so widely accepted that its absolutely necessary.'" Because of the prevalence of PES use in the research community, Temple said it seems "by now some experience in electrical stimulation is something one wants to know about" in assessing antiarrhythmics. The workshop, co-sponsored by Vanderbilt University, FDA, and the Natl. Institutes of Health, sought feedback from the academic community on the viability of requiring PES testing for investigational antiarrhythmic drugs. Temple has suggested PES be incorporated into antiarrhythmic testing guidelines. Joel Morganroth, MD, Hahnemann University, commented: "From a regulatory point of view . . . if I were the FDA, I would not demand that a new antiarrhythmic drug undergo electrophysiological testing . . . if there were sufficient data to give the proper dose and proper guidelines towards the use in benign or potentially lethal arrhythmias." However, he said a black box in the labeling should state that electrophysiological testing in lethal arrhythmias was not conducted and that use of the drug in patients with lethal arrhythmias is not part of the approved indications. Temple remarked that "its a bit ostrich-like . . . to try to label around the essentials." Study To Assess Comparative Accuracy Of PES v. Holter Monitoring Urged By Vanderbilt's Woosley Summarizing the consensus of workshop participants, Raymond Woosley, MD/PhD, Vanderbit University, co-director of the program with FDA Cardio-Renal Div. Deputy Director Stewart Ehrreich, PhD, stated that PES is "one of many ways to evaluate" most antiarrhythmic drugs. He said a "standard protocol would be desirable and is probably feasible," and particularly "a graded increase in degree of stimulation protocol would be very feasible." He added that many participants felt studies "should be comparisons to active controls." With respect to patient population, Woosley stated that "patients with coronary artery disease and recurrent sustained ventricular tachycardia are probably good candidates" for the studies while patients with non-sustained ventricular tachycardia are not. Phillip Podrid, MD, Harvard, compared the use of holter monitoring with PES. He said holter monitoring is "a standard, useful, regulatory, applicable method of finding new antiarrhythmic drug efficacy in patients with benign and potentially lethal arrhythmias" and "appears to be potentially useful as a model to predict sudden cardiac death prevention in potentially lethal ventricular arrhythmias." Podrid said, in his opinion, electrophysiological testing is "the standard for new drug efficacy testing in lethal ventricular arrhythmias" and would probably be his model of choice "to fight sudden death prevention in the lethal ventricular arrhythmia group." He added that ambulatory monitoring is probably an alternate and equally effective means of determining whether a new drug is or is not effective. In a presentation on the safety and cost of PES, Leonard Horowitz, MD, Hahnemann University, assessed the results of 4,015 initial and 4,530 follow-up electrophysiologic procedures conducted from January 1979 to December 1983. Complications in these studies included five deaths, 19 cardiac perforations, four hemorrhages requiring transfusion, eight arterial injuries requiring repair, and 20 cases of major venous thrombosis. Horowitz noted that three of the deaths "occurred unexpectedly and were clearly precipitated by the procedure," while two deaths occurred in patients who were "in extremis and death was imminent." By comparison, he reported that among 53,581 cardiac catherization studies there were 51 unexpected deaths. Horowitz said the estimated hospital cost is $1,000-$2,200 for initial electrophysiological studies and $400-$947 for follow-up drug evaluation studies. In addition, he said "most people find that the technical cost of electrophysiologic studies is greather than the technical cost for angiographic cardiocatheterization." Woosley noted that several issues have not yet been resolved, including the endpoint best suited for PES testing. "I think a study to define . . . the endpoint which gives the best predictability for clinical outcome would be the best test for the future," Woosley stated. In addition, he said studies to assess the comparative accuracy of PES versus holter monitoring and to define the standards for PES protocol design are necessary.

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