Unnerving Results from the Symplicity HTN-3 Renal Denervation Trial

Bradley P. Knight, MD, FACC, FHRS, Editor-in-Chief
Bradley P. Knight, MD, FACC, FHRS, Editor-in-Chief

Renal denervation (RDN), achieved by endovascular radiofrequency ablation of the nerves lining the renal arteries, has been shown in several studies to be an effective therapy for medically-refractory hypertension by lowering sympathetic tone. Treatments for resistant hypertension may not be a big concern for the heart rhythm community, but RDN has also shown promise as a treatment for atrial fibrillation (AF) and heart failure; some electrophysiologists are already in hot pursuit of RDN. There has been so much enthusiasm for this therapy, and promising early data, both in clinical trials and from basic physiology observations, that companies have invested hundreds of millions of dollars in research and development, acquisitions, and the pursuit of FDA approval. Medtronic, for example, acquired Ardian and its technology – the Symplicity Renal Denervation System. This system is already approved in Europe, as are five other RDN devices.1 

To the surprise of many, Medtronic announced in January 2014 that the results of their pivotal RDN trial, Symplicity HTN-3, did not reach its primary efficacy endpoint.2 Although the details are not clear and the study has not been published, this was a big dissappointment to many. The full results are expected at the American College of Cardiology Meeting in March. 

The primary efficacy endpoint in the study that was not reached was the reduction in systolic blood pressure at six months. What was perhaps the most interesting aspect of the trial was that the control group underwent an actual sham procedure. This is rare in medical device research. There was, however, a recent trial involving sham surgery published in December 2012, where patients undergoing meniscal repair arthroscopic knee surgery were randomized to sham surgery. The real surgery was found to be of no benefit. It is possible, therefore, that Symplicity HTN-3 was negative because the placebo effect of the procedure was controlled for in this strict trial design. Patients who undergo an invasive procedure, such as RDN, may be more compliant with their medical therapy after the procedure.

Are there other potential reasons for the trial to have been negative? Some have argued that it could be due to the use of early-generation technology. This seems unlikely given that earlier trials using a similar approach without a sham control did show a benefit. Another potential reason for the negative results of the Symplicity HTN-3 trial is the possible lack of durability of the RND procedure. It is conceivable that the response to RND diminishes over time, either due to progression of the hypertension, activation or accommodation of other mechanisms that govern blood pressure, or reinnervation of the kidneys. The regrowth or recovery of previously ablated tissue is something that electrophysiologists are all too familiar with, having dealt with patients who have recurrent AF and undergo a repeat pulmonary vein ablation procedure only to be found to have pulmonary vein reconnection months or years after an initially successful procedure.

With the negative results of Symplicity HTN-3, stoppage of several other RDN trials by Medtronic, and termination of the pivotal trial for St. Jude Medical’s renal denervation system, EnligHTN IV, due to low enrollment, has the RDN procedure hit just a snag or a nail in its coffin? Unfortunately for patients with AF, if there is little prospect for a hypertension indication for RND, it seems unlikely that industry will pursue the technology as a treatment for AF.

References

  1. Renal sympathetic denervation. Wikipedia. Published Jan 13, 2014. Available online at http://en.wikipedia.org/wiki/Renal_sympathetic_denervation. Accessed January 17, 2014. 
  2. Medtronic’s Renal Denervation System Fails. MedPage Today. Published Jan 9, 2014. Available online at http://www.medpagetoday.com/Cardiology/Hypertension/43715. Accessed January 17, 2014.