Design Considerations for Clinical Trials of Autonomic Modulation Therapies Targeting Hypertension and Heart Failure

Several device-based approaches to autonomic nervous system modulation are under investigation for the treatment of resistant hypertension and heart failure (Table 1).1 This line of research has evolved from the recognition that these diseases originate or are worsened by excess sympathetic activity and loss of parasympathetic tone.9–13 Drug therapies, including β-blockers, α-blockers, and centrally acting antihypertensive drugs, can modulate these neurohormonal systems, but they are often insufficient to control blood pressure (BP) or are limited by side effects or nonadherence. Technological innovations have produced devices that modulate the autonomic nervous system, including renal denervation, carotid baroreceptor stimulation, vagal nerve stimulation, and spinal cord stimulation. View this table: Table 1. Select Completed and Ongoing Clinical Trials of Autonomic Modulation Therapies in Hypertension and Heart Failure In Europe, several autonomic modulation therapy devices have received the Conformite Europeenne mark.14 US Food and Drug Administration evaluation of these devices is ongoing. The need for adequately powered, randomized, controlled studies with longer follow-up to capture definitive evidence of safety and effectiveness has been noted.14–17 The 9th and 10th Global Cardiovascular Clinical Trialists Forum (Paris, France, December 2012 and December 2013) convened a panel of primary investigators of ongoing trials, along with biostatisticians, National Institutes of Health scientists, European, and United States regulators, and medical device and pharmaceutical industry scientists to discuss the strengths and limitations of current clinical trials, optimal designs for future trials, approvability of new devices, and considerations for integrating these technologies into practice. This article summarizes the key discussion points and identifies knowledge gaps in this field that need to be addressed by additional research. The mechanisms of autonomic modulation are complex, and a comprehensive review of these mechanisms is outside the scope of this article. Briefly, all existing strategies aim to decrease central sympathetic outflow. Renal …