The announcement from Medtronic in January has apparently brought down the curtain on the much-heralded approach to the treatment of refractory hypertension using radio-frequency renal artery sympathetic nerve ablation (RASNA) applied through the tip of the Symplicity catheter.
This technology is being used widely around the world for the treatment of refractory hypertensive patients. The enthusiasm for RASNA was generated by a series of reports suggesting that an amazing decrease in systolic blood pressure of more than 30 mm Hg can be obtained in patients with resistant hypertension taking three or more antihypertensive drugs. However, the SYMPLICITY HTN-3 trial (Clin. Cardiol. 2012;35:528-35), which enrolled 535 patients with refractory hypertension, failed to achieve the primary endpoint of a significant decrease in systolic pressure in the radio-frequency (RF)-treated patients compared with the sham-operated patients. In the study, blinding was rigorously managed by renal artery catheterization of all 535 patients, with RF ablation instituted in two-thirds of the patients, and a sham operation conducted in one-third.
As a result of the observations in SYMPLICITY HTN-3, Medtronic is suspending enrollment in current trials using the Symplicity device throughout the world, and will "continue to ensure patients access to the Symplicity technology at the discretion of their physicians in countries where the device is approved," according to its statement.
Enthusiasm for RF ablation of the sympathetic nerves accompanying the renal artery was generated by a series of publications describing the physiologic and therapeutic effects. The first publications in this series described the metabolic changes that occurred after RF ablation carried out in one patient who experienced a decrease in systolic pressure of 20 mm Hg associated with modulation of sympathetic activity 30 days and 12 months after the procedure (N. Engl. J. Med. 2009;361:932-4). This study was followed by two subsequent reports of patients in whom RASNA was carried out. A proof-of-concept trial (SYMPLICITY HTN-1) in 153 patients reported a substantial decrease in blood pressure over a 2-year period (Hypertension 2011;57:911-7). A second trial (SYMPLICITY HTN-2) randomized 106 patients to either RASNA or standard therapy. That trial reported that 84% of the patients receiving RASNA had a reduction of blood pressure greater than 10 mm Hg within 6 months, compared with 35% of the control group (Lancet 2010;376:1903-9). Both studies reported a profound decrease in blood pressure that ensued over a 6-month period in 80%-90% of patients undergoing the therapy. In light of these reports, it is difficult to explain the fact that SYMPLICITY HTN-3 was a negative study.
Modulation of the sympathetic nervous system for the treatment of hypertension is not new. More than 60 years ago, Smithwick and colleagues carried out both surgical lumbar and sympathetic splanchnicectomy for its treatment with uncertain results (JAMA 1952;153:1501-4). In an era when all that we could offer hypertensive patients was a low-salt diet, the procedure became rather popular. However, the surgical risks, adverse side effects, and uncertainty of benefit led to both procedures being discontinued. Recently, there have been studies of the effect of stimulation of the carotid sinus nerve for the treatment of hypertension.
The potential benefit of modulation of the arterial sympathetic nerves, and particularly those located in the renal artery, became the focus of this recent interest. Nevertheless, a number of questions have arisen in regard to the mechanism of RASNA. And why does it take 6 months to achieve the blood pressure response? In addition, there is very little published data in regard to the changes in the renal artery and its adjacent tissue as a result of the RF ablation.
At the present, Medtronic has not provided any information beyond its indicating the lack of benefit. Further information will be reported at the upcoming American College of Cardiology scientific sessions. In the meantime, speculation is rampant as to whether the initial reports were purely placebo effects or if there is something intrinsically flawed in the SYMPLICITY HTN -3 trial.
Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.