Clinical trials of antiarrhythmic therapies and optimizing health care resource deployment: the need for a paradigm shift

Abstract

Randomized clinical trials (RCTs) of antiarrhythmic therapies have proliferated since they replaced observational clinical reports over two decades ago. Challenged initially at almost every step, from ethics to endpoints, RCTs have formed the bedrock of evidence-based medicine and practice guidelines in cardiac arrhythmias. Yet the implementation of evidence-based diagnostic or therapeutic guidelines suitable for clinical practice has not been without difficulty. Some have evoked an uneasy acceptance in many quarters and others even more difficult execution in medical practice. Examples abound. The rate versus rhythm debate in atrial fibrillation (AF) management is a prominent one. Clinical trial outcomes were more readily accepted by generalists than specialists, with the latter perplexed by the unexpected outcome that ran counter to physiologic principles and lacked a robust and complete explanation [1, 2]. Prophylaxis of sudden death events in clinical practice using implantable defibrillator devices in high-risk patients resulted in unused device therapy in a very large proportion of all recipients [3]. These non-uniform outcomes are also seen in cardiac resynchronization therapy and ablation of an increasingly broad spectrum of the AF population [4, 5]. Recently, these foundational clinical trials have been revisited in part or in great measure [6, 7]. These reports have been both enlightening and concerning. They enlighten us by revealing common underlying threads of behavior in arrhythmia disorders. They evoke concern in two areas. Firstly, by revealing serious adverse effects of long established and widely employed therapeutic interventions; and secondly, that our current paradigms of clinical trial design and patient enrollment result in highly variable benefits with a serious proportion of patients receiving little or no longterm benefit from the intervention. Statisticians remind us regularly of the perils and pitfalls of both retrospective visits to clinical trial data and subgroup analyses. To paraphrase a distinguished editor of this Journal, there should be due caution around “relying on subgroup analyses or declaring a difference when there is none and vice versa.” This concern arises mostly due to lack of statistical power in the original trial design for the subgroup analysis, which may actually mask potential benefit or harm. At best, we accept the premise that these subgroup analyses can be construed as hypothesis generating. We do appear to be better at selecting subgroups that achieve significant harm in clinical trials with safety monitoring. However, the implications of looking away from highly visible patterns of behavior in clinical outcomes have enormous implications for both patients subjected to unnecessary care and wasted resources in a resource-limited global health care environment. For example, with direct and indirect cardiac resynchronization defibrillator expenditures exceeding three billion US dollars in this year past, nonresponders to this therapy contributed over one billion dollars in cost. Some of these individuals could be simply identified by baseline characteristics at implant, according to trial subgroup analyses. In this authors’ view, it is time for a paradigm shift in health care resource deployment that does take into account important subgroup data. What are common threads of behavior in arrhythmia outcomes? They appear to lie in three different areas. Firstly, a clear understanding of important baseline variables in recruited populations that will impact outcomes. Managing S. Saksena (*) UMDNJ-Robert Wood Johnson School of Medicine, 161 Washington Valley Road, Suite 201, Warren, NJ 07059, USA e-mail: DRSSEPNJ@aol.com