Status of Renal Denervation Therapy for Hypertension: Still in Search of the Magic Bullet

C. Venkata S. Ram, MD, MACP

Disclosures

Circulation. 2019;139(5):601-603. 

Systemic hypertension remains a major perpetuating cardiovascular disorder globally accounting for substantial mortality and morbidity.[1] Elevated blood pressure from any cause is a precursor for the onset and progression of coronary artery disease, heart failure, cerebrovascular disease (including dementia), peripheral vascular disease, chronic kidney disease, and end-stage kidney disease. Despite significant advances in our understanding and management of hypertension, a large number of patients continue to have blood pressure levels above the recommended goals. Reasons for uncontrolled hypertension, despite effective therapy, are multifactorial, complex, and not fully understood. Several factors contribute to so-called resistant hypertension, one of which is poor compliance with medical therapy, and complementary therapeutic pathways for effective blood pressure control are needed.

The seeming complexity of controlling hypertension despite optimal therapy has triggered much research and consideration of device-based interventional therapies, such as catheter-based renal denervation (RDN) and baro-receptor activation. To date, research interest and progress in the potential utility of RDN to treat hypertension has been phenomenal.[2] A pathophysiological role of the sympathetic nervous system in the genesis of hypertension is well established.[3,4] Before the current era of pharmacological inhibition of sympathetic nervous system, surgical ympathectomy was used to treat severe hypertension.[5] However, surgical sympathectomy was fraught with intolerable adverse consequences such as postural hypotension and was therefore abandoned. The pathophysiological concept underlying surgical sympathectomy remained intact and has been revived by the development of RDN therapy directed at ablation of renal (efferent and afferent) nerves penetrating the renal artery. Stimulation of renal afferent and efferent nerves raises blood pressure by vasoconstrictor and volume/sodium mechanisms.[6] Hence, blunting the activity of renal nerves by RDN has been shown to lower blood pressure levels. Catheter-based renal endovascular approaches using radiofrequency, ultrasound, or chemical agents to disrupt renal nerve traffic have been developed and assessed in several clinical trials.[7–9]

The initial proof-of-concept clinical studies with RDN demonstrated dramatic therapeutic results.[10,11] RDN was hailed as a possible panacea to resolve the puzzle of uncontrolled hypertension. These initial observations showed that RDN therapy lowered systolic and diastolic blood pressure levels by as much as 32 mm Hg and 20 mm Hg, respectively. It is interesting to note that, in these earlier nonrandomized trials, the blood pressure–lowering effect of RDN endured up to 36 months. The enthusiasm for RDN evaporated quickly when a sham-controlled randomized trial, Simplicity HTN-3 (Renal Denervation in Patients With Uncontrolled Hypertension), showed that RDN was not superior to drug therapy.[12] A number of reasons have been proposed to explain the lack of benefit from RDN in Simplicity HTN-3, such as incomplete denervation, the inexperience of the operators, improper selection of patients, and faulty design of the study itself. The failure of RDN therapy subsequently led to the improvement and redesign of the ablation catheters to provide (comprehensive) 4-quadrant bilateral renal nerve ablation of the main plus accessory renal arteries.[13,14] These second-generation RDN catheters have yielded blood pressure effects with expectations reset to more realistic modest goals (single-digit blood pressure reduction as opposed to the originally observed double digits).

In the study reported by Fengler and coworkers[15] in this issue of Circulation, the investigators compared 3 different techniques of RDN in patients with resistant hypertension. The Radiosound-HTN comparative trial (Randomized Comparison of Ultrasound Versus Radiofrequency Denervation in Patients With Therapy Resistant Hypertension) showed that, in patients with resistant hypertension, RDN using endovascular ultrasound afforded superior reduction in ambulatory systolic blood pressure (SBP) in comparison with radiofrequency ablation of the renal arteries. As discussed in the publication, endovascular ultrasound–based RDN was the winner over radiofrequency ablation of the main arteries with or without ablation of the side branches. This first randomized head-to-head comparison of 3 RDN methods reveals novel findings and raises new questions about the procedural mechanics of RDN therapy. A total of 120 patients were assigned to 1 of the 3 study groups: radiofrequency ablation of the main renal arteries RDN, versus radiofrequency ablation of the main renal arteries and branches RDN, versus endovascular ultrasound ablation of the main renal arteries RDN. The primary outcome (ambulatory SBP) at 3 months was superior in the endovascular ultrasound ablation of the main renal arteries RDN group (13.2 mm Hg) in comparison with radiofrequency ablation of the main renal arteries RDN (6.5 mm Hg), with intermediate effects observed with radiofrequency ablation of the main renal arteries and branches RDN (8.3 mm Hg). Although the average blood pressure (BP) reductions were modest and the number of patients was small, head-to-head comparison showed an advantage for endovascular ultrasound ablation of the main renal arteries RDN perhaps because of the deeper penetration of ultrasound energy and more complete renal nerve ablation. It should be noted that the actual proportion of patients demonstrating at least a 5 mm Hg drop in SBP did not differ in the treatment groups.

Even with the publication of these new data, it is difficult to predict whether RDN is firmly back on track as a viable option to treat hypertension. Some caveats should be mentioned, including that only patients with large renal arteries were chosen for the study; the findings may not be replicable in patients with small-caliber renal arteries. Patient enrollment in the study was very selective; of 1884 patients screened, only 120 patients met the inclusion criteria, a reflection of how rigorous and complex the patient selection was for a condition so common as hypertension. This raises the question of practical applicability of RDN in the real world. In a few patients, the reduction in SBP was impressive (close to 40 mm Hg), but in a majority of responders, the effect was more modest, and in ≈30% there was no change in SBP. So, we have a basket filled with good responders, marginal responders, and nonresponders who all met the same entry criteria. How can we reconcile these disparate or even divergent results? It is curious how the responder nomenclature has changed lately in the RDN clinical trials. In the earlier studies,[10,11] SBP reductions of 30 to 40 mm Hg were touted as the usual responders, and now exactly similar reductions in BP are heralded as hyperresponders. That means the earlier acclaim for RDN efficacy was unrealistic, and a more reasonable 5- to 6-mm Hg change in SBP is now acknowledged as the expected norm. The earlier ballyhoo has given way to more sober and prudent expectations.

The ultimate litmus test is to identify hyperresponders and nonresponders to RDN therapy. And this is not going to be easy without a clear definition of the parameters that might predict therapeutic response to RDN. Otherwise, we will be left with average reductions in BP. The law of averages will not work in the clinical setting just as mixing passing grades in an examination with failing grades misses the successful candidates. The quest in RDN science is how to separate the winners from the losers. Selection of suitable patients for RDN therapy, therefore, is of paramount importance that will make or break the promise of RDN. Which is the best technology to offer a critical degree of renal denervation? What are the biological, humoral, and physical characteristics of a responder versus nonresponder? And which level of hypertension best responds to RDN? Is the delayed BP response to RDN at 3 or 6 months realistic in clinical practice? And what do you do during this hopeful waiting period of 3 to 6 months? Obviously, this is not the conventional standard to monitor BP response to any therapy. Procedures such as baro-receptor activation and removal of a sympathetic nervous system mass by sympathectomy or pheochromocytoma excision yield an immediate blood pressure response (hours to days), whereas response to RDN may take weeks to months. The undue delay in response raises the question of mechanism(s) by which RDN influences blood pressure regulation in patients with hypertension.

At the moment, what is known is outweighed by what is unknown. And furthermore, if the therapeutic outcome is operator dependent, the scope of RDN will be very narrow. Is it possible that in responders RDN intercepted only the pressor renal nerve traffic? And in nonresponders, only the (vaso) depressor renal nerves are intercepted? The alluring possibility of selectively denervating only (vaso) pressor renal nerves should be explored. Any procedure or drug is ultimately defined by the ratio of responders to nonresponders. Even with direct (visual) surgical sympathectomy in only 27% of patients, a diastolic BP reduction of 20 mm Hg was achieved.[5] It should not be a bombshell then that BP response to an imperceptive and imperfect procedure such as RDN is at best modest. The results shown by Fengler et al are encouraging and pave the way for a possible revival of RDN as a conceivable option to complement antihypertensive drug therapy. The results of Radiosound-HTN leave the door open for continued procedural refinements and precision in accomplishing optimal RDN. Is the glass half-full or half-empty? It is in the eye of the beholder. Given the highly variable therapeutic responses in a heterogeneous conglomerate of patients with systemic hypertension, RDN therapy is still in search of the magic bullet.

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