Renal Denervation: A Look Back While Driving Ahead

Endovascular renal sympathetic denervation (RDN), a minimally invasive, catheter-based endovascular procedure to treat resistant hypertension (HTN) generated exceptional excitement in the medical community. Multiple pre-clinical and clinical trials using different technology in phase 1 to 4 studies had shown significant blood pressure reduction. One of the major reasons for the enthusiasm was the dearth of options for treating this very difficult to treat patient population suffering from resistant HTN. The science of RDN had made noteworthy progress and yet with Medtronic’s announcement that its SYMPLICITY-3 (S-3) trial did not meet the predefined effectiveness endpoint dampened enthusiasm and, rightfully so, put a pause on the sprint of RDN. The unusual breaking of this news ahead of its expected scientific presentation led some of us to get ahead of ourselves with a negative conclusion, similar to some of us who rushed into optimism as a result of the positive data from the previous trials.

Effectiveness of renal denervation

Long-term follow-up data from SYMPLICITY 1 (S-1), SYMPLICITY 2 (S-2), the Global SYMPLICITY Registry (Medtronic RDN), REDUCE HTN (Boston Scientific, Vessix), ENLIGHTN (St. Jude), WAVE II (Kona Medical ultrasound) and RAPID (OneShot, Covidien) studies were presented at different conferences in 2013.¹ All these trials, using different technology for renal denervation, at long-term follow-up (up to 36 months) showed consistent, statistically significant reduction in office blood pressure in patients treated with RDN. But the data supporting significant ambulatory blood pressure (ABPM) reduction was scant and the size of blood pressure reduction on ABPM was not as robust as in the office blood pressure. All these trials were observational studies limited by bias, except one: S-2 was a randomized, controlled trial. 

On January 9, 2014, Medtronic announced that the S-3 trial did not meet the effectiveness endpoint at 6 months, but met the safety endpoint. S-3 is a prospective, randomized, controlled, double-blinded (both clinicians and patients) trial with a sham control, and included high ambulatory blood pressure (ABPM) (not just high office BP) as an inclusion criterion. The sample size for SYMPLICITY-3 was much larger and adequately powered for safety and effectiveness evaluation.² The primary efficacy endpoint was the comparison of systolic BP (SPB) change from baseline to 6 months in the RDN arm compared to the change from baseline to 6 months in the control arm (SBP_{RDN 6 month} – SBP_{RDN baseline}) – (SBP_{Control: 6 month} – SBP_{Control baseline}).² Reduction of office blood pressure by 5 mm Hg is considered a meaningful reduction as it translates into a 14% reduction in stroke, 9% reduction in cardiovascular disease and 7% reduction in mortality.³ 

All we know so far is that the S-3 trial did not meet the effectiveness endpoint, which can result from different numerical scenarios, some of which are described in the figure based on the S-3 trial design (Figure 1).² With that said, the SYMPLICITY-3 Committee, investigators and Medtronic officials have shown great restraint, professionalism, and incredible respect to the scientific peer review process under complex circumstances. We all await the full release of the data on Saturday, March 29th at 9:35 am EST at the American College of Cardiology Scientific Sessions in Washington, D.C., and should hold on to any speculations until then. 

Safety and limitation of renal denervation treatment 

S-3 met the safety endpoint at 6 months. At long-term follow-up, all clinical trials using different technologies showed no deterioration in renal function, i.e., renal sympathetic denervation does not deteriorate renal function. 

Optical coherence tomography (OCT) of the renal arteries immediately after performing renal denervation with a non-irrigation radiofrequency technology showed charring, edema and thrombus formation at the intima. There were no clinical sequelae from these findings. From all the trials of endovascular renal denervation, there were three incidences of renal artery stenosis on follow-up. Two of the three renal artery stenoses involved the progression of the pre-existing renal artery disease. There were a few acute procedural-related complications from the femoral artery access.

In the WAVE II trial involving Kona Medical’s ultrasound renal denervation system, intra-procedure and 72-hour post procedure pain in the lower back remains a major concern. It will be intriguing to see the results of WAVE III, which promises to use a completely non-invasive RDN with lesser duration of ultrasound energy.  

The major limitation of endovascular renal denervation is that approximately 2 in 10 patients will have non-suitable renal artery anatomy for endovascular RDN.

A look at some of the other debates on renal denervation: Responders vs. non-responders

A responder is defined as a 10 mm Hg blood pressure reduction in response to renal denervation. Irrespective of the technology used, about 1 in 5 patients did not respond to RDN in previous trials. The numbers of ablations per artery or the heart rate response are not a predictor of BP response. The only strong predictor of the treatment response is higher baseline blood pressure. The debate continues on:

• Who should we define as responder vs. non-responder? Is 10 mm Hg acceptable or should 5 mm Hg reductions be considered as a responder?
• Some of the patients in the SYMPLICITY Registry did not experience even a 10 mm Hg drop, but have reduced their HBA1C or had reduced left ventricular (LV) mass (LV hypertrophy). Is that patient considered a non-responder?
• Twenty-nine percent (29%) of the patients in S-1 did not respond until the 6-month mark, but at 36 months, 100% of patients responded with at least a 10 mm Hg BP reduction. Why was there such a late response?

Regeneration of sympathetic nerves

One of the major theoretical concerns was that the renal nerve might regenerate. At the end of 36-month follow-up in SYMPLICITY 1 and 2, there was persistent, statistically significant lowering of blood pressure. This may imply that there is no clinically relevant regeneration of sympathetic nerves at the end of 3 years.

Is renal denervation effective only for a single ethnicity?

The majority of the patients enrolled in the different clinical trials (Reduce HTN, EnligHTN, and SYMPLICITY) were predominantly male Caucasian patients. Is it possible that the blood pressure lowering effect of renal denervation may be specific to ethnicity? 

Successful RDN is simple: use any energy to ablate the renal nerves and treatment effects will be the same?

Currently available data indicate that irrespective of the type of energy used for renal denervation, a significant reduction in blood pressure was achieved in observational studies. Each technology has its own theoretical and practical advantages and disadvantages. Safety may be an issue with some of the approaches and one may be safer than the others. 

Is ablation precision essential? 

The notion that the renal nerve distribution in the adventitia is predictable and the renal nerves travel at predictable distance from the intima circumferentially may be right for the healthy animal model, but not in patients. The two-dimensional angiography showing a normal renal artery does not rule out the presence of atherosclerosis in these patients with resistant hypertension. Therefore, the distance from the contact of the electrode at the intima to the nerves in the adventitia may not be predictable. Also, the energy dissipation through normal tissues versus atherosclerotic tissue may be different. Therefore, the optimal contact to intima itself may not predict adequate nerve ablation. The local temperature at the point of contact in the intima would be affected by the blood flow. Renal blood flow is auto-regulated, and can vary significantly from patient to patient and in different physiologic conditions. Similarly, a complete circumferential nerve ablation is crucial. 

 Ambulatory blood pressure response to renal denervation

Do we need ABPM? Does ABPM have to be gold standard? Certainly, a clinical trial looking at the effectiveness of RDN has to include ABPM as an endpoint. But what if ABPM reduction is only 5 mm Hg and the office BP reduction is 12 mm Hg? We have substantial data from multiple, different clinical trials where office blood pressure predicted morbidity and mortality. 

Use of renal denervation beyond resistant hypertension

While S-4 is halted, the Global SYMPLICITY Registry and heart failure studies continue. Intriguing data from small trials have shown the effectiveness of RDN for atrial fibrillation, ventricular arrhythmia, heart failure, ventricular hypertrophy and metabolic syndrome. 

Renal denervation going forward

I believe the announcement by Medtronic regarding the S-3 results provided us with a valuable pause, the ability to slow down and reassess where we are going. It is an opportunity to better understand the pathophysiology, technique, devices, and most appropriate patients (including non-HTN indications) for the RDN procedure. 

Historically, we live in very different times than just a few decades ago. Our scientific curiosity, attention to details, and regulatory processes have all evolved to a point where sometimes I question what would have happened if angioplasty had been invented by Andreas Gruentzig in our current era of treatment evaluation. The initial plain old balloon angioplasty (POBA) had a 50% rate of restenosis, 33% rate of acute/sub-acute thrombosis, and a very high procedure-related complication rate, including the need for emergency bypass surgery. Would angioplasty ever have evolved into what it is today if it had been studied in the current era of intervention evaluation? If the POBA trial were conducted with the same rigor and oversight currently required by U.S. IDE trials, angioplasty might have died a premature death. If OCT (optical coherence tomography) had been performed after the coronary POBA (as with the trial using OCT to image after renal denervation), many experts probably would have fought against angioplasty. The evolution from POBA to second-generation drug-eluting stents would never have taken place. 

To date, there have been substantial animal studies using different technologies that have supplied the pathological evidence for disabling renal sympathetic nerves. Ten patients in SYMPLICITY 1 had reduced renal vein norepinephrine (NE) spillover, reduced total body NE spillover, reduced plasma renin flow, and improved renal plasma flow, along with improved blood pressure. These markers were an objective dataset, unlike the systolic BP reading. Prior to understanding, debating and discussing the S-3 data after its release, it is clearly too early to just give up on a potentially promising therapy with the scope for helping many patients.

Definitive conclusions and a verdict regarding the future of renal denervation would be premature. I am hopeful that the science will continue to drive forward.

Disclosure: Dr. Kintur Sangvhi reports no conflicts of interest regarding the content herein.

Dr. Sanghvi is the founder of the website RDNWorld.org. He can be contacted at sanghvik@deborah.org

References

1. RDNWorld.org. Abstracts from different conferences on RDN world. Available online at https://www.renaldenervationworld.org/clinical-trials- question/?category_id=10. Accessed February 14, 2014.
2. Kandzari DE, Bhatt DL, Sobotka PA et al. Catheter-based renal denervation for resistant hypertension: rationale and design of the SYMPLICITY HTN-3 Trial. Clin Cardiol. 2012 Sep: 35(9): 528-535.
3. Whelton PK, He J, Appel LJ et al. Primary prevention of hypertension: clinical and public health advisory from the Nation High Blood Pressure Education Program. JAMA. 2002 Oct 16; 288(15): 18882-18888.

Read more on the current state of renal denervation: 

Resurrecting Renal Denervation Research After the Device Industry Gold Rush