Prof. Dr. Sundeep Mishra writes about major trials that tested the effectiveness of Renal Denervation (RDN) in patients with resistant hypertension.

Worldwide, one among three adults faces the risk of developing hypertension in their lifetime. Hypertension is really the 'first' among the fatal diseases which could be prevented, alongside the most common health issue in humans. Many a time, it is a silent killer because it can present without any symptoms, develop ‘deceitfully’ and be diagnosed when it causes a health complication, although in most cases it presents indirectly as a heart attack, stroke, loss of sight, heart failure, renal failure and arteriosclerosis.

It has been estimated that even in the west, nearly 50% of hypertensives are not diagnosed, but of those diagnosed, 50% don’t receive any treatment and out of those receiving treatment at least 50% are inadequately controlled.

However, the picture is much more dismal in developing countries including India where it has been estimated that less than one in ten have adequate blood pressure control. Many of these individuals are uncontrolled despite sincere efforts by physicians and caretakers because they have a kind of hypertension called resistant hypertension.

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Resistant hypertension

It has been estimated that prevalence across the world is >10% and it is associated with high morbidity and mortality.

It is to these patients that renal denervation (RDN), a minimally invasive, endovascular catheter-based procedure using radiofrequency ablation or ultrasound ablation aimed at treating resistant hypertension can be applied.

In reality, the nerves in the wall of the renal artery are ablated by applying radiofrequency pulses or ultrasound to the renal arteries. This causes reduction of sympathetic afferent and efferent activity to the kidney, and blood pressure can be decreased.

However, the field of RDN for the treatment of hypertension has witnessed a lot of turmoil. Early uncontrolled, physician unblended studies reported stunning reductions in clinic blood pressure (BP) following RDN in patients with uncontrolled and/or treatment-resistant hypertension.

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SYMPLICITY HTN-3 trial

All the supposed benefits of RDN were put to proof when the results of the first large, randomised, observer-blinded, and sham-controlled trial SYMPLICITY HTN-3 (Renal Denervation in Patients With Uncontrolled Hypertension) came to fore. This trial did not reveal any BP-lowering effect of RDN compared to sham-operator treatment. However, proponents of this concept remained unfazed.

“Post-mortem” of SYMPLICITY trial revealed that a variety of factors that could have led to the failure of RDN; inappropriate patient selection, variability in adherence to antihypertensive medications, incomplete RDN, technical failure of RDN or even relative inexperience of operators.

This led to a series of controlled early-phase studies by entrepreneurs and device manufacturers in patients not only of resistant hypertension but also other kinds of hypertension. 

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SPYRAL HTN-OFF MED trial

First of the studies, the SPYRAL HTN-OFF MED (Catheter-Based Renal Denervation in Patients With Uncontrolled Hypertension in the Absence of Antihypertensive Medications) trial, published in the Lancet reported an analysis that revealed a significant effect of RDN on both clinic BP and ambulatory BP (ABP) in patients with stages 1 to 2 hypertension who were not using antihypertensive medications.

The SPYRAL HTN-OFF MED was a randomised, sham-controlled, proof-of-concept trial evaluating the effects of RDN on BP in the absence of antihypertensive medications. There were 80 patients randomly assigned: 38 to the RDN group and 42 to the sham-control group.

Although the trial had few numbers and a short follow-up, the RDN therapy was found to lower clinic BP and ABP by approximately 8/5 mm Hg and 6/4 mm Hg, respectively, in patients with stages 1 to 2 hypertension. This moderate reduction in BP after RDN was apparent as early as 3 months. Importantly, the rate of procedural complications was low.

The SPYRAL HTN-OFF MED trial differs substantially from previous RDN in terms of population enrolled (stage 1-2 hypertension), treatment naïve status, and denervation technique.

1. Patient population: The trial was carried out on stage 1-2 hypertension (both systolic and diastolic) rather than resistant hypertension, as in earlier trials.
2. Drug therapy status: The patients were not on any anti-hypertensive therapy unlike other studies wherein patients were on 3 or more anti-hypertensives.

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SYMPLICITY vs SPYRAL HTN-OFF MED trials

The technique of denervation was different:

1. Earlier SYMPLICITY trials used a single-node renal denervation catheter in the main renal arteries (i.e. before any bifurcation or in branch renal arteries), while SPYRAL HTN-OFF MED trial used a multinodal catheter that delivered 4 simultaneous radiofrequency ablations in a helical pattern and included branch vessels. The delivery in branch vessels may have contributed to efficacy because it is the distal portion of the artery, where nerve density has been found to be substantially greater than in the proximal renal artery.
2. More intense denervation was carried out in SPYRAL HTN-OFF MED trial; an average of 18 ablations was performed in the main renal arteries, and 26, in branch vessels, vs. only 11 ablation attempts and none in branch vessels in the SYMPLICITY HTN-3 trial.

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RADIANCE-HTN SOLO trial

Recently, RADIANCE-HTN SOLO was also published in Lancet. It was a multicentre, international, single-blind, randomized, sham-controlled trial undertaken at 39 centres in the US and Europe. Patients with combined systolic-diastolic hypertension with ABP ≥135/85 mm Hg and <170/105 mm Hg (after 4-week discontinuation of up to two antihypertensive medications) and had suitable renal artery anatomy were included in the study.

Patients randomised to RDN (1:1) underwent this procedure with the Paradise system (ReCor Medical, Palo Alto, CA, USA); the controls underwent a sham procedure consisting of renal angiography only. The primary effectiveness endpoint was the change in daytime ABP systolic blood pressure at 2 months in the intention-to-treat population.

Patients remained off antihypertensive medications throughout the 2 months of follow-up unless specified blood pressure criteria were exceeded. Major adverse events included all-cause mortality, renal failure, an embolic event with end-organ damage, renal artery or other major vascular complications requiring intervention, or admission to hospital for a hypertensive crisis within 30 days and new renal artery stenosis within 6 months.

This study revealed that in patients undergoing RDN (n=74) vs. a sham procedure (n=72), the reduction in daytime ABP was greater with RDN (−8.5 mm Hg) vs. sham procedure (−2·2 mm Hg), p=0·0001. No major adverse events were reported in either group.

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Thus, it can be concluded that vis a vis a sham procedure, endovascular ultrasound RDN reduced ABP at 2 months in patients with combined systolic-diastolic hypertension in the absence of medications. These 2 trials reveal that there is still hope for RDN in at least select patients of hypertension.

Disclaimer-The information and views set out in this article are those of the author(s) and do not necessarily reflect the official opinion of M3 India. Neither M3 India nor any person acting on their behalf may be held responsible for the use which may be made of the information contained therein. 

The writer, Dr. Sundeep Mishra is a Professor of Cardiology.