Resurrecting Renal Denervation Research After the Device Industry Gold Rush

Renal denervation therapy is a novel form of minimally invasive catheter-based, percutaneous treatment where selective nerve ablation is administered through the renal arteries with the aim of lowering blood pressure in patients with resistant hypertension. Resistant hypertension is a condition defined by a blood pressure that stays above the goal, despite treatment with three or more antihypertensive agents, including at least one diuretic therapy.

In the past year alone, the number of renal denervation trials registered on ClinicalTrials.gov (U.S. National Institutes of Health) has more than doubled in the wake of extremely promising early results, and at least 6 devices are currently CE marked in Europe. The device industry entered into an unbridled gold rush for market share in the approximately $32 billion-dollar resistant hypertension therapy industry.

In light of recent technological developments and surprising pivotal clinical trial results, the future of renal denervation took a surprisingly tenuous turn in early 2014. Most notably, the January 2014 announcements that the pioneer Symplicity (Ardian/Medtronic) renal denervation system failed to meet its primary efficacy endpoint in its pivotal HTN-3 trial and Covidien’s announcement that it will be exiting its OneShot renal denervation program for market reasons have stymied the field. These announcements came as a shock to many members of the clinical community following the promising results of a number of earlier European trials.

The fault for the recent high-profile failures of renal denervation trials lies, in part, with the design of research, but also stem from disequilibrium between standardized treatments employed in clinical trials and practical clinical implementation — both of which are likely to improve as technology and technique for renal denervation improves. Several additional considerations are important in moving forward successfully with renal denervation research and clinical implementations.

1. Additional mechanisms. It is possible, and even likely, that inhibition of the sympathetic nervous system is not the sole mechanism by which renal denervation exerts antihypertensive effects, as indicated by norepinephrine spillover in SYMPLICITY HTN-1 trials.  Nervous and hemodynamic effects may also be present, and should be assessed by future studies using controlled assessments of circulating or urinary catecholamines, microneurography, renal catecholamine spillover, or by assessing heart rate variability.
2. Penetration depth. The largest concentration of renal nerves is found approximately 2 to 4 mm from the renal artery lumen in humans, and the majority of these nerves are located in the proximal renal artery (lesser amounts of nerves are also found in the middle and distal renal artery). A fundamental issue with renal denervation therapies is the limited depth of nerve kill, which, when too shallow, can produce limited nerve kill with only modest hypertension alleviation effects. Furthermore, improper delivery of renal denervation radiofrequency energy pulses could damage the renal artery, producing pain while ablating only a minority of targeted sympathetic nerve fibers. If large-scale clinical procedures were performed with only partial denervation, potentially as a result of inexperience or improper device technique, efficacy results could be artificially low compared to properly performed procedures.
3. Novel devices and technology. As evidenced in Cardiosonic’s TIVUS I and II studies as well as other recent device trials, next-generation multidirectional catheters have the ability to improve outcomes of targeted renal denervation. The original Ardian 8 French (F) compatible catheters used in the early hypertension trials are significantly different than modern 6F devices, meriting consideration of important differences in design characteristics among catheters, including guiding sheath versus balloon-steered designs; radiofrequency or ultrasound energy use; number of radiofrequency electrodes; number and adjustability of energy shot delivery; stabilization techniques (such as balloon inflation), and temperature control. 
4. Physician training and experience. The unparalleled rapid development of renal denervation devices over the past several years, particularly in Europe, has exceeded the ability of regulatory agencies to and other authorities to develop guidelines for experienced interventionists top select and treat patients with truly resistant hypertension, which may contribute to poor results in large-scale studies that do not closely match the promising early results in smaller cohorts at more specialized tertiary care centers. As these devices and their regulation mature, training and experience coupled with improved patient selection undoubtedly will improve clinical outcomes.
5. Other novel approaches. While the renal denervation devices available are pioneer devices in the field, devices that are currently in infantile stages are likely to maximize the potential of this therapeutic strategy. For instance, promising preclinical results have been achieved using in vivo animal models with ethanol-mediated perivascular renal sympathetic denervation, resulting in renal denervation of 54-88% with no detectable stenoses at 45 days post-procedure. Such next-generation devices that employ highly differentiated approaches have the potential to garner better results than first generation and even second-generation devices that are currently on the market.

Conclusions and summary

The end of the renal denervation gold rush does not represent the failure of renal denervation therapy. Quite the opposite: the surprising recent results from large-scale clinical trials and the exit of major players from the market signal the end of an era of poorly conceived and non-standardized patient selection, and exploratory device design and implementation. These events should be viewed as an inevitable step and learning experience critical to the maturation of the promising field of renal denervation therapy devices that, unlike their drug therapy predecessors, offer an opportunity to achieve a sustainable solution to the global treatment-resistant hypertension epidemic.

Disclosure: Dr. Raghotham Patlola reports he is a shareholder of ASI (Ablative Solutions Inc.) Dr. Louis Salvaggio reports no conflicts of interest regarding the content herein. 

The authors can be contacted via Dr. Raghotham Patlola at rpatlola@aol.com

Read more on the current state of renal denervation: Renal Denervation: A Look Back While Driving Ahead