More Data Needed on Renal Denervation

MIAMI BEACH, FLA.—Current data are promising, but SYMPLICITY HTN-3 and other trials are expected to provide more answers.

Recent results show exciting promise for renal denervation and hypertension, but many questions remain, according to Deepak L. Bhatt, MD, MPH, co-principal investigator of the SYMPLICITY HTN-3 trial.

More work is needed to understand the mechanism of action along with effect size and durability. In addition, there are patients who do not respond initially, he said during a presentation at TCT 2012.

“There is a lot of work to be done to determine if it is the afferent or efferent nerves that are the predominant players and the clinical benefits that seem to derive from renal denervation,” Bhatt, of Harvard Medical School, Boston, said.

However, parallel results of the SYMPLICITY HTN-2 and ARSENAL trials appear promising, despite the small number of patients. In the ARSENAL trial, presented at EuroPCR 2012, patients were enrolled with an average baseline blood pressure of 176/96 mm Hg. The responder rate was 78% of patients who had at least a 10 mm or more drop in the systolic BP measured in the office, with 41% of patients achieving a systolic BP of less than 140 mm Hg. In SYMPLICITY HTN-2, the primary endpoint of office-based BP measurement was reduced by 32/12 mm Hg from 178/96 mm Hg at baseline in patients who received denervation (n = 49; P<.0001 for systolic and diastolic BP).

The SYMPLICITY HTN-3 trial is expected to provide additional support for renal denervation, overcoming the limitations of previous studies and serving as the basis for FDA approval. The study will enroll 530 patients at 90 U.S. sites. The primary efficacy endpoint is change in office systolic BP from baseline to 6 months and the secondary endpoint is change in 24-hour ambulatory systolic BP. The primary safety endpoint is mortality, end-stage renal disease or procedural complications within 1 month or new renal artery stenosis within 6 months.

Anatomy and pathophysiology

In another presentation, Michael Böhm, MD, PhD, of the University Hospital of Saarland, Homburg/Saar, Germany, explained that sympathetic nervous system activation affects cardiometabolic and renal diseases, including hypertension, obesity, chronic HF and renal failure.

The first indication that sympathetic activation is involved in development of hypertension came from studies of younger patients who were followed for about 40 years, said Böhm, adding that sympathetic activation is associated with the development of sustained hypertension.

“Therefore, tachycardia and increase in BP go hand in hand,” Böhm said. “Futhermore, activation of the sympathetic nervous system in an 18-year follow-up study after a stress test is associated with elevation of BP. The third tercile of norepinephrine concentration after mental stress is associated with higher BP levels.”

The kidneys generate a great deal of sympathetic activation, he said, adding that studies have shown that when the kidneys are removed, there is a strong reduction of sympathetic activation. When the kidneys are under stress such as from ischemia, there is an efferent signaling to the brain, further enhancing sympathetic efferent activation.

“So there is a vicious cycle in the activation between the brain and the kidney to produce and enhance sympathetic activation,” Böhm said.

Interrupting this process was achieved in the early 1950s through surgery and resulted in a response rate of 30%, a rate that is higher than with the current technology. Early attempts also resulted in an increase in survival. Böhm said that new technology not yet approved for use in the United States may gain access to the nerves in the adventitia by providing high-frequency energy with a catheter that is located in the renal artery. High frequency is employed by applying heat into the adventitia and cooling the internal part of the renal artery.