Renal Denervation for the Treatment of Hypertension: Making a New Start, Getting It Right

Abstract

The renal nerves contribute to hypertension through effects in the kidney that enhance sodium retention and renin secretion, and by effects in the central nervous system that increase systemic sympathetic activity. Therefore, targeting the renal nerves provides a logical basis for treating hypertension. Several trials of renal denervation-achieved by applying radiofrequency energy through catheters placed in the renal arteries-have been completed. Clinical results have been incon-sistent, however, partly because of factors related to the ablation technique and partly because these studies have been performed in patients with the inadequately defined clinical condition of ''treatmentresistant hyper-tension.'' This statement now explains our conclusion that future studies of renal denervation should be guided by the established randomized, controlled clinical trial designs used for studying antihypertensive drugs and other treatments for hypertension. BackgroundEven before the treatment of hypertension became routine, it was understood that high levels of blood pressure (BP) were associated with premature death, stroke, cardiovascular events, and renal failure. One of the early and effective interventions for severe or symptomatic hypertension was the use of surgical sympathectomy. 1 Although this technique was useful in reducing BP and improving survival, major side effects such as disabling postural hypotension and sexual dysfunction were important limiting factors. Later, many of the early drugs developed for treating hypertension were also based on interrupting the sym-pathetic nervous system, but, again, their side effects-although not as severe as those associated with surgical intervention-made these drugs difficult to use.

Raising the Bar in Renal Sympathetic Denervation Research and Reporting

“…The major difference between three of the four papers discussed 30,57,58 and the paper by Mahfoud and colleagues, 59 ie, their respective views on the inclusion of sham controls, reflects a potential ongoing regulatory discrepancy between US and European health authorities. Various European regulators have already given marketing approval to RDN for RH based on clinical studies that did not employ a sham-control group.…”

“…Several recent publications have discussed options for accelerated pathways for future RDN development in the post-Symplicity HTN-3 era, with a continued focus on unmet needs in hypertensive patients. Lobo and colleagues 57 presented the Joint United Kingdom (UK) Societies' 2014 consensus statement on RDN for RH; White and colleagues 58 presented the American Society of Hypertension's (ASH's) scientific statement on pathways for moving forward the development of RDN for hypertension; Weber and a group of colleagues actively involved in the next generation of RDN clinical trials 30 presented their thoughts in an editorial; and Mahfoud and fellow members of a multidisciplinary European Expert Group 59 presented their recommendations in a European clinical consensus conference proceedings paper.…”

“…58 Importantly, all expert opinions advocated the employment of ambulatory BP monitoring (ABPM) [60][61][62][63][64] as an informative methodology likely to mitigate the impact of white-coat hypertension. Interestingly, three of the papers advocated the use of a sham-control treatment arm, 30,57,58 while Mahfoud and colleagues 59 did not, as discussed below.…”

“…In the case of the Symplicity RDN system, the sponsor's decision to now pursue the SPYRAL HTN Global Clinical Trial Program, 65 a program employing the SPYRAL catheter and modified study designs very much in line with those discussed in three of the four expert opinion papers just reviewed, 30,57,58 leaves open the question of whether RDN by another method may be proven to be effective (perhaps in a more precisely defined patient population) or whether early studies simply benefitted from unrecognized confounders. In addition, one wonders whether more rigorous methods applied in earlier studies, such as sham-control groups and/or ABPM, would have enabled an earlier "no-go" decision, saving hundreds of participants in clinical trials from risk of invasive procedures and millions of dollars spent on a doomed phase 3 study.…”

“…Turner and O'Brien 44 noted that, by writing in the voice of his beloved character Sherlock Holmes, Sir Arthur Conan Doyle was able to wryly observe that it is a huge mistake to theorize before one has acquired the data, since to do so inevitably leads one to twist facts to suit theories rather than developing theories to suit facts. With the recent guidance from leading US and European investigators, 30,[57][58][59] it now appears that we have good road maps to guide the acquisition of appropriately informative data and more authoritatively determine whether RDN is likely to be a useful clinical intervention for certain prospectively identifiable individuals with RH. Since RDN is also being explored in a multitude of other indications, researchers in those fields are encouraged to read the guidance documents pertaining to hypertension and transfer suggestions therein to their respective areas of investigation.…”