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A viewpoint on drugs that prolong the QTc interval

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A viewpoint on drugs that prolong the QTc interval
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  A Viewpoint on Drugs That Prolong the QTc interval Raymond John Lipicky, MD ir rufRcient evidence exists to suggest that pro- iongation of the QT interval corrected for heart rate (QTJ is -flly be&k&i. in ail but life- threatening situations, Qr, proiongation resulting from pharmacoiogic agents must be wmsWred a risk. Decause vnse relations for tor- sades ds poities cannot be established and be- cause prolongation of the QT, interval is th&jht to precede the deveiopment of torsades, it is rea- sonabie to assume that the QT, proiongation it- self constitutes the marker of risk. An assess. mentofthereiationbetweenthedoseofagiven drug and its effect on the QT, interval will aid in making the judgment that the potential be&R ouhmighs the risk. ideally, a drug should demon- strateaswideasafetymarginaspossBie,as reflected in a large separation between the EDso value associated with therapeutic benefit and that assoc&ted with QT, prokngation. (Am J Cardioi 1993;72536-54B) From the Division of Cardio-Renal Drug Products Office of Drug Evaluation I Center for Drug Evaluation and Research U.S. Food and Drug Administration Rockville Maryland. Address for reprints: Raymond Lipicky MD Director Cardio- Renal Division HFD-110 U.S. Food and Drug Administration 5600 Fishers Lane Rockville Maryland 20857. T e decision to institute any type of therapeu- tic intervention should be based on an assessment of the known (or anticipated) potential benefits versus the known (or antici- pated) potential risks to an individual patient. Drug approval generally depends dn the conclu- sion that a patient population studied in controlled clinical trials gained a measurable benefit from the drug that was not outweighed by the measured risks for that population. Our current state of knowledge is such that prolongation of the QT interval corrected for heart rate (QT,) cannot be considered beneficial, since it is not known to make patients feel better or live longer. TORSADES VERSUS QT, PROLONGATION Torsades de pointes is a potentially life-threat- ening arrhythmia that is known to be associated with drugs that prolong the QT, interval. The incidence of torsades is also increased among individuals who have a longer than normal QT, for unknown reasons. Superficially, then, it appears that a longer-than-normal QT, increases the prob- ability of one’s developing torsades, Thus, pro- longed QT, should be viewed as an adverse effect. In the presence of a prolonged QT,, the absence of documented torsades in some patient popula- tions studied does not establish an absence of risk. Rather, the longer-than-normal QT, should be taken as documentation that the risk of torsades is increased in these populations but that the popula- tion is too small or the duration of observation too short to obtain a reliable point estimate of the incidence (or increased risk). Prolongation of QT, is a surrogate for torsades. The ideal way to evaluate the dose-dependent risk of torsades is by studying the incidence of torsades as a function of dose. However, it is not reasonable to expect that such a data base could be developed. The current policy of the Food and Drug Administration, Center for Drug Evaluation and Research, Office of Drug Evaluation I, Divi- sion of Cardio-Renal Drug Products is to ask for documentation of the relation between dose admin- A SYMPOSIUM: PROLONGED QT INTERVAL 538  istered and prolongation of QT, in both normoka- lemic and hypokalemic states. The intention is to provide a quantitative estimate of the relation between dose of drug and increase in risk in the “normal” state and in a state in which the risk of torsades is thought to be increased. The ultimate purpose is to assess the safety margin of the drug by comparing the dose needed to obtain the desired benefit (probably measured in other clinical trials) and the dose that increases the risk of an adverse outcome. DOSE-RESPONSE RELATION The most favorable profile would reflect a large separation (2 1 order of magnitude) between the dose-response relation on the benefit side and the dose-response relation on the risk side. If the 2 EDj0 values were close-for example, differing by a factor of only 1.25-most clinicians would judge the safety margin too small to warrant use of the drug, unless the nature of the benefit far out- weighed the risk, for instance, if the drug were indicated for the treatment of life-threatening ventricular arrhythmias, the net gain would likely outweigh the risk. On the other hand, if the potential benefit were less than lifesaving (e.g., to reduce sniffles), any risk of death would likely be considered unacceptable. Thus, if the ‘safety mar- gin’ (defined by the respective EDS0 values) was < lo-loo-fold, and the benefit could be regarded as trivial, evaluation of merit would be a matter of judgment. If one accepts that the primary goal during drug development is, in the present context, to establish a safety margin (by determining the separation between the ED50 for beneficial effects and the EDS0 for QT, prolongation), a clinical trial started today would best be served by collecting data via a Holter monitor. The QT, may not be the best predictor of torsades, but without a continuous analogue record of the electrocardiogram tracing, which would enable one to determine what and when (in relation to dosing) to measure, the opportunity to make the relevant observation may be lost. i4B THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 72 AUGUST 26 1993
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