ACC 2009: Catheter-Based Renal Denervation Reduces Resistant Hypertension

Susan Jeffrey

March 30, 2009

March 30, 2009 (Orlando, Florida) — A new proof-of-concept study in 45 patients with resistant hypertension suggests that a brief catheter-based procedure can safely ablate renal sympathetic nerves and may provide persistent blood-pressure reduction.

In this open first-in-human trial, renal denervation caused "substantial and sustained" blood-pressure reduction without serious adverse events, specifically renal artery aneurysm or stenosis, or any change in kidney function.

"We saw an immediate and sustained reduction in blood pressure, which at the 6- to 12-month end of the study was around a 25-mm-Hg systolic reduction," lead author Henry Krum, MD, from the Center of Cardiovascular Research and Education in Therapeutics at Monash University, in Melbourne, Australia, told Medscape Neurology & Neurosurgery.

Substudies looking at norepinephrine spillover and ambulatory monitoring "confirm, I think, that what we're seeing is real, supporting the concept that 1, we really are lowering blood pressure, and 2, we're doing it via denervation of sympathetics," he said. "And it's simple and safe."

The results are published online March 30 in the Lancet, to coincide with their presentation here at the American College of Cardiology 58th Annual Scientific Session.

Renal Sympathetic Nerves Crucial to Hypertension

Renal sympathetic efferent and afferent nerves are crucial for the initiation and maintenance of systemic hypertension, the authors write. The nerves lie within and immediately adjacent to the wall of the renal artery. The company sponsoring the trial has developed a catheter-based system using radiofrequency (RF) ablation to disrupt renal sympathetic nerves without affecting other abdominal, pelvic, or lower-extremity innervation (Symplicity, Ardian, Palo Alto, California).

During the procedure, the tip of the catheter is directed into the distal renal artery and 2 minutes of RF energy is applied, Dr. Krum said. "The tip is withdrawn, circumferentially rotated within the artery, and a further 2 minutes of energy is applied, and so on all the way back through the renal artery, so in the end there's usually about 4 to 6 applications of the RF energy," he said. The first 10 patients in this open trial had staged procedures, but the remaining patients had bilateral ablations.

They enrolled 50 patients from 5 Australian and European centers. All had resistant hypertension, defined as a systolic blood pressure of > 160 mm Hg on 3 or more antihypertensive medications including a diuretic. Five patients were subsequently excluded for anatomical reasons, mainly the presence of dual renal artery systems.

Patients received treatment between June 2007 and November 2008, with follow-up to 1 year. The primary end points were office blood pressure and safety data, taken prior to and then at 1, 3, 6, 9, and 12 months after the procedure. Renal angiography was done before, immediately after, and 14 to 30 days after the procedure, as well as magnetic resonance imaging (MRI) at 6 months. Blood-pressure lowering was assessed using repeated-measures analysis of variance (ANOVA). A subgroup of patients was studied using renal noradrenaline spillover to assess the effectiveness of the renal sympathetic denervation achieved.

Among the treated patients, the baseline mean office blood pressure was 177/101 mm Hg (standard deviation, 20/15 mm Hg) while on a mean of 4 to 7 antihypertensive medications. The estimated glomerular filtration rate was 81 mL/min/1.73m2, and mean reduction in renal noradrenaline spillover was 47% (95% CI, 28% – 65%).

In terms of safety, there was 1 intraprocedural renal artery dissection that occurred prior to the delivery of the RF energy, which was successfully stented with no further sequelae. There were no other renovascular complications.

Blood-pressure reductions were seen among the treated patients at all time points, beginning as soon as 1 month after the procedure. By comparison, blood pressure continued to rise among the 5 patients who were excluded from the procedure.

Blood-Pressure Changes (mm Hg) in Resistant Hypertension Patients With and Without Renal Denervation

Time Point, Mo Renal Denervation (n = 45) Nontreated Patients (n = 5)
1 -14 / -10 +3 / -2
3 -21 / -10 +2 / +3
6 -22 / -11 +14 / +9
9 -24 / -11 +26 / +17
12 -27 / -17

 

Individually, however, not all patients responded to therapy. If response was defined as a blood-pressure reduction of 10 mm Hg systolic or greater, 83% of patients responded, Dr. Krum noted. For the other 17% of patients, it is possible that either they were not adequately denervated, that renal sympathetic activation was not part of their hypertension process, "or potentially both," he said. However, they were not able to find any baseline predictors of response vs nonresponse in this small trial.

Medications were stable over the course of the trial, but 3 patients required reduction in medications after normalization of blood pressure for symptomatic hypotension, he noted. Nine patients had their medications increased; 5 were responders by the 10-mm-Hg criteria, and 4 were nonresponders.

Ambulatory blood-pressure monitoring provided similar results and suggested a return of normal drops in night-time blood pressure, or "dipping." "The majority of patients on ambulatory monitoring were non- or reverse dippers preprocedure, and this relationship changed postprocedure so that most patients became dippers following the RF ablation," Dr. Krum noted.

Importantly, renal function was not affected by the procedure.

The next step will be a randomized trial, he said, although it is not clear at this point whether the comparator would be a sham procedure or simply randomizing these patients to usual care. There are plans to investigate the procedure in the setting of chronic kidney disease, and also potentially in systolic heart failure, he said.

Providing Hope

In a Comment accompanying the paper, Michael Doumas, MD, from the Hypertension and Cardiovascular Research Clinic at the Veterans Affairs Medical Center and George Washington University, in Washington, DC, and Stella Douma, MD, from the Hippokration Hospital and Aristotle University of Thessaloniki, in Greece, call the study by Krum and colleagues a "breakthrough study that opens up new avenues in the treatment of resistant hypertension."

The blood-pressure reduction was "impressive," and no adverse events were observed, they write. "Renal denervation itself does not seem to raise safety flags, because it occurs in kidney transplantation and seems to be of minor importance."

They give credit to the investigators for doing such a study "and the elegant and demanding techniques they used (noradrenaline spillover) to support their findings," they write. However, not all studied patients responded to treatment, they point out, "which underlines the need to identify predictors of blood-pressure reduction."

The procedure is minimally invasive, though, and interventional radiologists and cardiologists are already familiar with accessing the renal artery and using RF ablation, so that "we could rationally assume that the new technique might be widely used, if proven effective and safe in large randomized trials."

They conclude that this approach, although promising, cannot be considered a first-line option for treatment but should be reserved for those who have hypertension that is truly resistant to drug therapy. Further research is also required to better identify those who may benefit from this intervention, they add.

"However, we feel that our questions will soon be answered and our concerns eliminated," Drs. Doumas and Douma conclude. "Therefore, we strongly believe that Krum and colleagues provide hope for the management of a difficult clinical condition."

Wider Application?

However, Dr. Krum was uncertain why, if it is found to be safe and effective in randomized investigation, it should not be considered at some point first-line treatment as an alternative to lifelong medical therapy.

"Certainly that would be a starting point, but I think there might be great potential even in patients who have less severe forms of hypertension," he said in an interview. "We have no data on that, but I think we would be remiss if we didn't explore that area, because we're talking about something that's very simple — it's a 40-minute-odd procedure that produces these sustained reductions and could get patients off polypharmacy potentially."

After Dr. Krum's presentation, this question came up during the panel discussion, posed by Marvin A. Konstam, MD, from Tufts University School of Medicine, in Boston, Massachusetts. Dr. Konstam asked whether, provided that it is eventually proven to be safe and effective, "an expanded approach like this could in fact be applied much more broadly than just the most severe refractory patients, when you think about a lifetime of multiple medications."

"I think initially this will be driven by considerations such as ethics committees and regulatory authorities," Dr. Krum replied, "but I completely agree with the premise of your statement, that this is a simple application and in comparison with or as an adjunct to lifelong polypharmacy, I think this really does have tremendous potential."

Douglas L. Mann, MD, from Baylor College of Medicine, in Houston, Texas, also on the panel, expressed concern that denervating the renal artery might have functional consequences. However, Dr. Krum pointed out that in renal transplantation, denervated kidneys are transplanted into recipients and appear to function completely normally.

Dr. Mann also asked about the potential for nerve recovery after the procedure that might necessitate repeat procedures to maintain the effect. Some recovery of nerve fibers does occur, Dr. Krum acknowledged, to the efferent, not the afferent, renal sympathetics. "The reinnervation is anatomical," he said. "The real issue is whether it is functional, and as you saw, out to 12 months at least, we saw no functional evidence of reinnervation, but I completely agree we need to follow these patients for longer."

The study was funded by Ardian. Dr. Krum reports no conflict of interest. Disclosures for coauthors appear in the paper. Drs. Doumas and Douma declare no conflict of interest.

Lancet. Published online March 30, 2009.

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