Review Article
Illusions of truths in the Symplicity HTN-3 trial: generic design strengths but neuroscience failings

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Abstract

The Achilles heel in catheter-based studies of renal denervation for severe hypertension is the almost universal failure to apply a confirmatory test for renal denervation. When renal denervation efficacy was assessed, using measurements of the spillover of norepinephrine from the renal sympathetic nerves to plasma, the only test validated to this point, denervation was found to be incomplete and nonuniform between patients. It is probable that the degree of denervation has typically been suboptimal in renal denervation trials. This criticism applies with special force to the Symplicity HTN-3 trial, where the proceduralists, although expert interventional cardiologists, had no prior experience with the renal denervation technique. Their learning curve fell during the trial, a shortcoming accentuated by the fact that one-third of operators performed one procedure only. Recently presented results from the Symplicity HTN-3 trialists confirm that renal denervation was not effectively or consistently achieved in the trial.

Section snippets

Testing for Achieved Renal Denervation

The belief that renal denervation has been achieved in clinical trials of catheter-based renal denervation is almost invariably based on hope and trust, rather than testing. This contrasts with the studies of surgical renal denervation in experimental hypertension, where good experimental design necessitates that the effectiveness of denervation is always confirmed, typically by documenting 90–95% reduction in the kidney content of norepinephrine.

Among clinical studies of renal denervation,

Renal Denervation “Armageddon”: The Symplicity HTN-3 Trial

A challenge to the percutaneous renal denervation treatment of resistant hypertension came with the 9 January 2014 press release concerning the Simplicity HTN-3 trial in drug-resistant hypertension, the pivotal study for US Food and Drug Administration licensure, and in the subsequent New England Journal of Medicine publication on 29 March,23 indicating that the primary efficacy endpoint had not been reached in the trial.

A lot was expected of the Symplicity HTN-3 study. Five times larger than

Development of a More Generally Accessible Method for Testing Efferent Sympathetic Nerve Ablation?

There is a pressing need to incorporate valid testing for renal sympathetic denervation into all clinical trials of the procedure. Growing acceptance has emerged for this important principle, but some of the planned testing for denervation, such as using measurements of heart rate variability, are fanciful. In truth, it is difficult to know how to proceed, as the only validated test for renal denervation, measurement of renal norepinephrine spillover,4, 6 has very limited availability and could

Afferent Renal Nerves and Their Ablation

Sensory nerves running from the kidneys to the central nervous system contribute to activation of the sympathetic nervous system in patients with drug-resistant hypertension, through their projection to the hypothalamus.29 Ablation of these nerves during the renal denervation procedure contributes to BP lowering by causing central inhibition of central sympathetic outflow.30 The nociceptive receptors within the kidney, which are responding to a renal injury signal,29 can be targeted with

The Future of Renal Denervation in Treating Severe Hypertension

The Symplicity HTN-3 trial has inflicted a “flesh wound” on the renal denervation field, but this is not fatal; the trial is now seen to have failed in its neuroscience execution, not effectively and consistently achieving renal denervation.24 In the pause that this trial created world-wide, it is now time to reflect on what future science is needed (Table 3). Failure to test for renal denervation, as an intrinsic component of all trials but one, represents the Achilles heel of the field. It is

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    The author is a Senior Director of the Baker IDI Heart and Diabetes Institute Melbourne, and Conjoint Professor of Medicine Monash University, Melbourne. His primary funding is in the form of a Senior Principal Research Fellowship from the Australian National Health and Medical Research Council [ID586601]. He discloses research funding and receipt of consultancy fees, travel expenses, and honoraria from Medtronic, which funded the research from which some of the presented results are drawn, but the author holds no shares in the company or patent rights for renal denervation. In the preparation of this article no financial or other support was provided by Medtronic.

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