After the initial success of catheter-based renal artery sympathetic nerve ablation, many questions remained: Are the findings reproducible? Are they durable? Will they translate into “real-world” practice? In a series of papers at ACC.12, investigators looked for answers with new study results as well as updates to key trials of renal denervation (RD).

One such trial: SYMPLICITY HTN-2, which included 106 patients with resistant hypertension. Murray Esler, MD, Melbourne, Australia, said 52 study participants underwent four to six 2-minute treatments per artery with an investigational, radiofrequency generator (Medtronic, Inc.), while another 54 patients were randomized to no further treatment beyond stable doses of three or more antihypertensive agents per patient. All had on-treatment baseline office systolic BP ≥160 mm Hg (or ≥150 mm Hg with type II diabetes mellitus). The primary endpoint was 6-month office BP.

Six months after randomization, active treatment was associated with a mean reduction of 32 mm Hg systolic and 12 mm Hg diastolic BP. In the control group, BP increased by 7 mm Hg systolic and 1 mm Hg diastolic (p < 0.0001 vs. RD).

Subsequently, 35 individuals in the control group crossed-over to RD. Six months later (12-months post randomization), BP in this group decreased by a mean of 24/8 mm Hg (p < 0.001), similar to the 12-month decrease of 28 mm Hg systolic BP in the immediate-treatment group.

In an interview, Dr. Esler said, “The natural tendency toward an increase in BP from baseline to 6 months shows the potential cost in delaying treatment with renal denervation.”

Thus, RD provides safe and sustained BP reduction up to 1 year and the crossover findings indicate that the primary endpoint results are reproducible.

Non-responders Responded Over Time

Despite receiving a mean of 5.1 antihypertensive medications at baseline, the 153 subjects in the expanded SYMPLICITY HTN-1 cohort had a mean office systolic BP of 175.98 mm Hg at baseline. Paul A. Sobotka, MD, professor of medicine and cardiology at Ohio State University, Columbus, reported that between 1 and 24 months postprocedure, mean systolic BP decreased steadily (-19 mm Hg at 1 month, -33 mm Hg at 24 months) as did mean diastolic BP (-9 mm Hg at 1 month, -15 mm Hg at 24 months).

(At the time of the trial, Dr. Sobotka was a medical advisor to Medtronic, Inc. He is currently a Medtronic employee in addition to being a professor at OSU.)

Systolic BP decreases plateaued, remaining at 33 mm Hg below baseline through 36 months. Diastolic BP decreased further, plateauing at 19 mm Hg below baseline at 36 months. These decreases were statistically significant for all time points (p < 0.01).

Patients were classified as non-responders if they did not achieve at least a 10 mm Hg reduction in systolic BP. The non-responder rate was 31% at 1 month post-procedure, 10% at 24 months, and 0% at 36 months. While slightly delayed, Dr. Sobotka emphasized that when patients became responders, the magnitude of response was similar to early responders.

The data suggest that response time is not related to RD failure or operator error. In all likelihood, it is some physiological response that makes some patients capable of manifesting a BP response early and others not. Whether it is vascular in nature, cardiac remodeling, change of volume status, or correction of baroreceptor function is unclear, but “immediate BP readings alone are not up to the task of identifying successful or failed denervation,” said Dr. Sobotka. Treatment effects were consistent across subgroups stratified by age, diabetes status, and baseline renal function.

Real-World Data

Darren Mylotte, MD, from the Institut Cardiovasculaire in Paris, presented 6-month results of a registry including 35 patients with baseline office systolic BP ≥160 mm Hg (mean 181.1± 21.9 mm Hg) while on three or more antihypertensive agents (mean 4.6± 1.0). Unlike the SYMPLICITY trials, the registry included individuals with renal artery duplication and estimated glomerular filtration rates (eGFR) <45 mL/min. “We included patients with eGFRs <45 because this patient population with severe hypertension is at extremely high risk of adverse events,” Dr. Mylotte said.

Office/ambulatory systolic BP reductions at 6 months were 28.2/21.2 mm Hg; office/ambulatory diastolic reductions were 13.5/9.3 mm Hg (p < 0.001 for both). “The results are very similar to those of SIMPLICITY HTN-2,” he said. Two of three patients with duplex renal arteries responded. Target BP was achieved in 26.5% of patients. “This is somewhat disappointing, but these were patients with severe hypertension,” said Dr. Mylotte. Importantly, he added, “there is no hard evidence of significant decline in renal function, though more data are required.”

Axel Bauer, MD, of Eberhard-Karls-University in Tubingen, Germany, noted recent data indicating that excessive BP variability contributes to end-organ damage independently of mean BP. Sympathetic over-activity and blunted arterial baroreflex function are likely culprits, he said.

Testing the hypothesis that RD would reduce 24-hour BP variability and instability independently of BP effects, Dr. Bauer and colleagues assessed 11 consecutive patients fulfilling SYMPLICITY trial criteria with 24-hour ambulatory BP monitoring before and 6 months after RD. They evaluated the maximum difference of BP between two consecutive readings and other related measures and found significant reductions for both systolic (p = 0.006) and diastolic variability (p = 0.011).

Renal denervation led to a pronounced effect on 24-hour BP variability and instability. Thus, it might confer beneficial effects on end-organ damage beyond reduced BP.

Calling the finding “spectacular,” Dr. Sobotka noted in an interview that the mechanism by which BP variability causes morbidity is speculative. Frequent spikes in BP confer hemorrhagic stroke risk, while low BPs may lead to lacunar strokes or renal ischemia.

He said, “What’s so exciting about the story line for renal denervation is this: The reduction of drive to the kidney, or the ability to singularly and selectively remove drive from the kidney to the brain, can impact multiple systems in a very desirable way. It’s as if the kidneys are a ‘neurologic Chernobyl,’ generating signaling that can be systemically catastrophic. If you can attenuate that signal by interfering with the renal sympathetic afferents, you reduce central sympathetic tone. That should have desirable effects at cardiac and vascular levels, with insulin resistance, sleep disorders, and very likely also chronic kidney disease.

All of this is testable, and we will learn about it in the next few years.”
Before RD can be applied to patients with milder hypertension, Dr. Sobotka said further, “we must prove to our deep satisfaction that there are no late complications associated with the procedure.”

SYMPLICITY HTN-3, the pivotal US trial in recruitment stage, adds a sham control and a larger sampling of African-Americans who often suffer from the ravages of untreated hypertension. “The potential is extremely interesting,” said William C. Cushman, MD, chief of the Preventive Medicine Section at the Veterans Affairs Medical Center in Memphis, in an interview.

“If a single procedure can substantially improve or cure hypertension for many years, that’s a huge advantage. But we need more data. Many of these so-called resistant patients in these studies—I’m not convinced they really had adequate medical therapy. And, ultimately, what is most important are the long-term effects on cardiovascular outcomes and mortality. We need a study looking at that.”

Editor’s note: To read more, see the recent State-of-the-Art paper on renal denervation in JACC Cardiovascular Interventions. 2012;5:249-58.

Keywords: Stroke, Lacunar, Denervation, Baroreflex, Sleep Wake Disorders, Insulin Resistance, Systole, Registries, Pressoreceptors, Renal Artery, Eye Abnormalities, Veterans, Glomerular Filtration Rate, Diastole, Reaction Time, Hypertension, Diabetes Mellitus, Renal Insufficiency, Chronic, Brain

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