Off-label, but on-target: use of regadenoson with exercise.

Pharmacologic stress testing has evolved considerably during the past 25 years, providing an extension of the benefits of physiologic imaging to those who are unable to undergo maximal exercise testing. Vasodilator stress myocardial perfusion imaging now compromises more than half of nuclear cardiology procedures in the United States, as multiple procedural advances and additional clinical evidence support this procedure as a mainstay in cardiac testing. The clinical use of pharmacologic testing began with oral and intravenous dipyridamole and later with intravenous adenosine, which provided a more reliable hyperemic response with regards to coronary blood flow, a short half-life, and an outstanding safety profile. More recently, we have seen the introduction of selective A2a agonists, with regadenoson presently available for clinical use. This agent offers not only the potential for an improved side effect profile but also a unique dosing strategy. With a fixed dose administration via an intravenous bolus, regadenoson may be administered easily and rapidly at any give time, even when patients are actively exercising on a treadmill or bicycle. The need for terminating the exercise protocol, drawing up the appropriate weight-based dose, and preparing the infusion pump is obviated; regadenoson may be administered ‘‘on demand’’ while the patient is still performing exercise. Why is the adjunctive use of exercise with vasodilator stress important? Multiple publications with dipyridamole and adenosine have clearly demonstrated improved image quality, reduced bothersome side effects such as flushing and abdominal discomfort, and enhanced safety, mostly due to reduced conduction disturbances. Regadenoson has now been in clinical use for approximately 5 years and virtually from its day of approval, laboratories have been using adjunctive exercise with this agent to improve side effect profile and image quality. Yet, to date, only limited data has been published using combined exercise and regadenoson stress; none of these trials have been multicenter in nature and few have had the rigor of a pivotal clinical trial, such as ADVANCE MPI. However, image quality, safety, and adverse effects are all favorably impacted by the additional of exercise with regadenoson administration. In this issue of the Journal, Parker et al report the findings of a randomized trial comparing dipyridamole with exercise to regadenoson with exercise. This study is unique in that the administration of the vasodilator was ‘‘conditional’’ and not necessarily administered to all patients who were exercising. The results demonstrate that half of the patients did not require regadenoson administration, thereby reducing potential side effects and cost. This study also confirmed the benefits of adjunctive exercise, impacting on image quality, safety, and adverse effects. If exercise is so beneficial for most patients undergoing vasodilator stress, why is this not part of promotion materials that accompany regadenoson? The unfortunate reality is that combining exercise with regadenoson is considered an ‘‘off-label’’ use of this agent, designed for pharmacologic stress testing in patients ‘‘unable to undergo adequate exercise stress’’. In the past 3 years, more than $9 billion in penalties have been levied against pharmaceutical manufactures for the marketing of off-label use of prescription medications. Regadenoson’s manufacturer (Astellas Pharma US, Inc) has therefore been appropriately concerned about promoting an off-label use of this agent. Although there may be a theoretical risk of reduced safety, unacceptable side effects, or a change in the diagnostic accuracy when exercise is added to vasodilator stress imaging, there is no evidence for such concern. However, rigorous trial data, such as with a phase 3 study, are lacking. To provide such pivotal clinical data to support off-label medication use, such as the when combining regadenoson with exercise, is exorbinently expensive and time consuming, often exceeding the potential supplemental revenue. From the Cardiovascular Division, University of Miami Miller School of Medicine, Miami, FL. Reprint requests: Robert C. Hendel, MD, Cardiovascular Division, University of Miami Miller School of Medicine, 1120 NW 14th Street, Suite 1123, CRB, Miami, FL 33136; rhendel@med. miami.edu. J Nucl Cardiol 2013;20:179–81. 1071-3581/$34.00 Copyright 2012 American Society of Nuclear Cardiology. doi:10.1007/s12350-012-9643-5