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Renal denervation: What happened, and why?

Cleveland Clinic Journal of Medicine. 2017 September;84(9):681-686 | 10.3949/ccjm.84a.14129
September 1, 2017|Cleveland Clinic Journal of Medicine
Mehdi H. Shishehbor, DO, MPH, PhD;Tarek A. Hammad, MD;George Thomas, MD, MPH
Author and Disclosure Information

Mehdi H. Shishehbor, DO, MPH, PhD
Professor of Medicine, Case Western Reserve University, Cleveland, OH; Co-Chair, Harring Heart and Vascular Institute; Director, Cardiovascular Interventional Center; Co-Director, Vascular Center, University Hospitals of Cleveland, OH; Site Principal Investigator, SYMPLICITY HTN-3 trial

Tarek A. Hammad, MD
Department of Medicine, Division of Cardiology, The University of Texas Health Center at San Antonio

George Thomas, MD, MPH
Director, Center for Blood Pressure Disorders, Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute, Cleveland Clinic; Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH; Investigator, SYMPLICITY HTN-3 trial

Address: Mehdi H. Shishehbor, DO, MPH, PhD, University Hospitals of Cleveland, 11100 Euclid Avenue, Lakeside, 3rd Floor, Cleveland, OH 44107; shishem@gmail.com

ABSTRACT

Despite promising results in initial trials, renal denervation failed to achieve its efficacy end points as a treatment for resistant hypertension in the SYMPLICITY HTN-3 trial, the largest trial of this treatment to date (N Engl J Med 2014; 370:1393–1401). Is renal denervation dead, or will future trials and newer technology revive it?

KEY POINTS

  • Renal denervation consists of passing a catheter into the renal arteries and ablating their sympathetic nerves using radiofrequency energy. In theory, it should lower blood pressure and be an attractive option for treating resistant hypertension.
  • SYMPLICITY HTN-3 was a blinded trial in which patients with resistant hypertension were randomized to undergo real or sham renal denervation.
  • At 6 months, office systolic blood pressure had failed to fall more in the renal denervation group than in the sham denervation group by a margin of at least 5 mm Hg, the primary efficacy end point of the trial.
  • Methodologic and technical shortcomings may explain the negative results of the SYMPLICITY HTN-3 trial, but most device manufacturers have put the brakes on future research into this novel therapy.
  • Today, renal denervation is not available in the United States but is available for routine care in Europe and Australia.

Better technology is coming

Figure 1. Distribution and density of renal sympathetic nerves. Distribution of nerves stratified according to total number (each green dot represents 10 nerves), relative number as percent per segment, and distance from the lumen in the proximal (A), middle (B), and distal (C) location.
Sakakura et al and Mahfoud et al showed that the concentration of sympathetic periarterial renal nerves is higher in the proximal and ventral areas but closer to the lumen in the distal segment (Figure 1).13,14 Moreover, Id et al15 found that ablating nerves in the renal arteries without addressing accessory arteries resulted in less-optimal blood pressure reduction. Thus, the technical aspects of the procedure are highly important.

Advanced renal denervation catheters are needed that are multielectrode, smaller, easier to manipulate, and capable of providing simultaneous, circumferential, more-intense, and deeper ablations. The ongoing Investigator-Steered Project on Intravascular Renal Denervation for Management of Drug-Resistant Hypertension (INSPIRED)16 and Renal Denervation Using the Vessix Renal Denervation System for the Treatment of Hypertension (REDUCE-HTN: REINFORCE)17 trials are using contemporary innovative ablation catheters to address the limitations of the first-generation Symplicity catheter.

Further, Fischell et al18 reported encouraging results of renal denervation performed by injecting ethanol into the adventitial space of the renal arteries. This is still an invasive procedure; however, ethanol can spread out in all directions and reach all targeted nerves, potentially resulting in a more complete renal artery sympathetic ablation.

As technology advances, the WAVE IV trial19 is examining renal denervation performed from the outside through the skin using high-intensity focused ultrasound, which eliminates the need for femoral arterial catheterization, a promising noninvasive approach.

Proposals for future trials

The European Clinical Consensus Conference for Renal Denervation20 proposed that future trials of renal denervation include patients with moderate rather than resistant hypertension, reflecting the pathogenic importance of sympathetic activity in earlier stages of hypertension. The conference also proposed excluding patients with stiff large arteries, a cause of isolated systolic hypertension. Other proposals included standardizing concomitant antihypertensive therapy, preferably treating all patients with the combination of a renin-angiotensin system blocker, calcium channel blocker, and diuretic in the run-in period; monitoring drug adherence through the use of pill counts, electronic pill dispensers, and drug blood tests; and using change in ambulatory blood pressure as the primary efficacy end point and change in office blood pressure as a secondary end point.

Trials ongoing

To possibly address the limitations posed by the SYMPLICITY HTN-3 trial and to answer other important questions, several sham-controlled clinical trials of renal denervation are currently being conducted:

  • INSPiRED16
  • REDUCE-HTN: REINFORCE17
  • Spyral HTN-Off Med21
  • Spyral HTN-On Med21
  • Study of the ReCor Medical Paradise System in Clinical Hypertension (RADIANCE-HTN).22

We hope these new studies can more clearly identify subsets of patients who would benefit from this technology, determine predictors of blood pressure reduction in such patients, and lead to newer devices that may provide more complete ablation.

Obviously, we also need better ways to identify the exact location of these sympathetic nerves within the renal artery and have a clearer sense of procedural success.

Until then, our colleagues in Europe and Australia continue to treat patients with this technology as we appropriately and patiently wait for level 1 clinical evidence of its efficacy.

Acknowledgments: We thank Kathryn Brock, BA, Editorial Services Manager, Heart and Vascular Institute, Cleveland Clinic, for her assistance in the preparation of this paper.

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