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Renal denervation for resistant hypertension gaining momentum in United States
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Research into renal denervation continues to grow at a fast pace, with recent data demonstrating that the procedure may be a nonpharmacologic alternative for the treatment of patients with resistant hypertension.
The role that the renal sympathetic system plays in controlling BP was first demonstrated in the 1930s. At that time, surgical interruption of the sympathetic nervous system was found to result in significant reductions in BP. Today, what is known as renal denervation is a minimally invasive, endovascular, catheter-based procedure that uses controlled, low-power radiofrequency ablation aimed at treating resistant hypertension. Applying radiofrequency pulses to the renal arteries causes reduction of renal sympathetic afferent and efferent activity, thus decreasing BP levels.
Currently, no renal denervation device is FDA approved. To date, several devices have been granted approval for renal denervation in Europe and other countries worldwide, including the Symplicity Renal Denervation System (Medtronic/Ardian; CE mark approval in 2010); EnligHTN Multi-Electrode Renal Denervation System (St. Jude Medical; CE mark approval in 2012); V2 Renal Denervation System (Vessix Vascular; CE mark approval in 2012); OneShot System (Covidien; CE mark approval in 2012); and Paradise System (Recor; CE mark approval in 2012). A number of other devices are being evaluated.
Renal denervation has been an area of interest at recent scientific meetings and conferences. Most recently, a number of sessions at the European Society of Cardiology Congress 2012 in Munich in August were devoted to research on this procedure.
George L. Bakris, MD, a Cardiology Today Editorial Board member, is involved in a pivotal trial of renal denervation.
Source: George L. Bakris, MD; reprinted with permission
“There have been a lot of consistent data showing benefits in patients who have failed to achieve BP control with medication. Renal denervation appears to provide a meaningful alternative to be able to control BP and, importantly, reduce CV risk when drugs have failed to do so,” George L. Bakris, MD, director of the American Society of Hypertension Comprehensive Hypertension Center at University of Chicago Medicine, said in an interview.
William B. White, MD, FASH, president of ASH for 2012-2014, said many experts are enthusiastic about renal denervation for patients with resistant hypertension because they are a tough-to-care-for population.
“We continue to look forward. Drug development in hypertension is currently at a near standstill. And, tolerability of available hypertension drugs is still an important issue for some patients with resistant hypertension,” said White, who is professor of medicine and chief of the division of hypertension and clinical pharmacology at Calhoun Cardiology Center, University of Connecticut School of Medicine.
In addition to effects in patients with resistant hypertension, researchers are also investigating outcomes related to HF, mental health, sleep apnea, diabetes, and other disease and conditions.
“There have been a lot of interesting developments in the field, largely coming from outside the United States, showing that renal denervation, to the extent it has been studied, looks very promising for patients with resistant hypertension,” Deepak L. Bhatt, MD, MPH, chief medical editor of Cardiology Today Intervention, said in an interview. “It is all very exciting and very provocative, but needs further confirmation in a large study.”
In the United States, a criticism of renal denervation is the lack of long-term clinical data. Most evidence comes from studies of the Symplicity Renal Denervation System, which currently has more than 5 years of clinical experience and 3 years of follow-up data, according to Medtronic.
At the American College of Cardiology’s 61st Scientific Sessions in March, Paul A. Sobotka, MD, presented 3-year results from Symplicity HTN-1, a series of pilot studies that enrolled 153 patients with resistant hypertension (systolic BP >160 mm Hg despite use of at least three antihypertensive drugs, including a diuretic, at target or maximal tolerated doses).
“A sustained, significant BP reduction has been observed through 36 months,” Sobotka, professor of medicine and cardiology at the Ohio State University, said during an oral session. “There is no evidence of reversal or regression of BP advantage bestowed early on.”
The response rate for nonresponders, defined as patients who failed to reduce BP more than 10 mm Hg, was 0% at 1 month, but the full cohort responded with reductions of 10 mm Hg by 36 months. Fifty-eight percent of late responders, defined as patients with no response at 1 month, experienced a 10-mm Hg drop in BP at 3 months, and at 36 months all late responders recorded clinical response to the initial renal denervation.
Long-term data from the Symplicity HTN-2 trial show that significant BP reductions with renal denervation were sustained through 18 months. At the ESC Congress, Murray D. Esler, MD, associate director of the Baker IDI Heart and Diabetes Institute of Melbourne, Australia, presented 18-month data from 43 patients with resistant hypertension who received renal denervation and 31 crossover patients. Compared with baseline, patients randomly assigned renal denervation recorded an average BP reduction of –32 mm Hg/–12 mm Hg (P<.01) and crossover patients recorded BP reduction of –28 mm Hg/–11 mm Hg (P<.01).
“These 18-month BP reductions are consistent with the 12-month follow-up for both groups (–28/–10 mm Hg from baseline for the initial treatment group and –24/–10 mm Hg from baseline for the crossover group),” Esler said in a press release.
Further, the procedure was deemed safe at 18 months in both treatment groups. Safety results were maintained and researchers noted no significant decline in kidney function, according to chief investigator Michael Böhm, MD, from Universität der Saarlandes, Homburg/Saar, Germany.
Commenting on these studies, Bhatt said it is important to remain cautious about the take-home message because the absolute number of patients studied out to 3 years is small.
The ESC Congress featured a press conference at the August meeting devoted entirely to renal denervation.
Results of a study by Darren Mylotte, MD, from the Institut Cardiovasculaire de Paris Sud, France, and colleagues provide evidence that renal denervation successfully treats patients with resistant hypertension in real-world patient populations. Examining “real-world patients” is important because patients in clinical trials are often highly selected and therefore may not reflect the patients encountered by physicians on a day-to-day basis, Mylotte said at the meeting.
Successful bilateral sympathetic denervation was performed in 33 of 35 consecutive patients with resistant hypertension taking an average of 4.6 medications at baseline who were treated at the Institut Cardiovasculaire de Paris Sud. At 6 months, average office BP was reduced from baseline by –30.3 mm Hg/–14.6 mm Hg (P<.0001) and ambulatory BP was reduced –23.3 mm Hg/–10.2 mm Hg (P<.001). The researchers observed no procedural complications, no adverse events and no deterioration in renal function during follow-up.
In another study presented at the press conference, renal denervation improved BP and arterial stiffness in patients with resistant hypertension. The small pilot study included 21 patients with resistant hypertension and six control patients. All were taking more than three antihypertensive medications at baseline and had peripheral BP of at least 150 mm Hg.
Renal denervation was associated with improvement in all parameters at 6 months, compared with baseline. Peripheral systolic BP improved by 7.5% (145 mm Hg vs. 156 mm Hg; P<.05) at 3 months and by 5.4% (148 mm Hg vs. 156 mm Hg; P<.05) at 6 months; central systolic BP improved by 9.5% (147 mm Hg vs. 161 mm Hg; P<.01) at 3 months and by 6.6% (151 mm Hg vs. 161 mm Hg; P<.05) at 6 months; and pulse wave velocity improved at both 3 months (9.4 m/s vs. 10.9 m/s; P<.01) and 6 months (9.7 m/s vs. 10.9 m/s; P<.01). Univariate analysis of variance (f-test) showed that the improvement in pulse wave velocity was, at least in part, BP independent, according to a press release. No significant changes in BP or pulse wave velocity were observed in control patients.
“Since central aortic pressures and arterial stiffness are much better predictors for future CV events than peripheral pressures, we focused the present study on the effects of renal denervation on central hemodynamics and arterial stiffness,” researcher Klaas Franzen, MS, from University Hospital of Schleswig-Holstein, stated in the release.
“According to age-adjusted reference values, the improvement of approximately 1 m/s pulse wave velocity observed in our study could be interpreted as a blood vessel rejuvenation of almost 10 years. This suggests that renal denervation might be a fountain of youth for blood vessels in patients with therapy-resistant hypertension,” Franzen said.
The effects of renal denervation on mental health have been the focus of other recent preliminary research. According to a study presented by Denise Fischer, PhD, a psychologist at Saarland University Hospital, Germany, at ESC Congress 2012, renal denervation led to beneficial effects on anxiety, depression, quality of life and stress in patients with resistant hypertension.
The study was conducted in 173 patients with resistant hypertension (BP 174 mm Hg/88 mm Hg and median of five antihypertensive medications). Three months after renal denervation, patients showed more correct reactions (P<.0001) and fewer errors (P<.05) in a multitasking situation (Determination Task) that evaluated stress compared with baseline. In addition, patients reported improvements in their physical state (P<.01); mental state (P<.05); quality of life (P<.05); anxiety scores (P<.0001); depression scores (P<.0001); and arousal levels (P<.0001). At baseline, 32% of patients reported sleeping disorders and 60% reported headaches. Three months after renal denervation, sleeping quality improved (P<.0001) and intensity of headaches decreased (P<.0001).
“Renal denervation may have a positive effect on psychological processes, stress perception and processing, as well as quality of life,” Fischer said at a press conference. Future research should investigate the long-term effects of renal denervation on psychological processes, quality of life, rehospitalization and mortality rates in a larger cohort of patients, she added.
Renal denervation is also being studied in a variety of patient populations other than those with resistant hypertension.
“Based on data coming out of Europe and other countries, renal denervation appears to have tremendous benefit in people who have not just resistant hypertension,” said Bakris, a member of the Vascular Medicine section of the Cardiology Today Editorial Board. “I think the subgroup of patients who qualify for this procedure are going to get much more than just BP control as a benefit.”
More data presented at the ESC Congress suggest that renal denervation may be a nonpharmacologic alternative for the treatment of patients with advanced HF and may help stabilize the disease. Results from the Olomouc I pilot study demonstrated that renal denervation led to better outcomes than optimal medical therapy 1 year after the procedure.
Miloš Táborský, MD, from University Hospital Olomouc, Czech Republic, discussed results from 26 patients with congestive HF treated with renal denervation and standard medical therapy and 25 patients who received standard medical therapy with beta-blockers, ACE inhibitors or angiotensin receptor blockers and diuretics. After 1 year, renal denervation improved left ventricular ejection fraction (P<.01), LV end-systolic volume index (P<.01), LV end-diastolic volume index (P<.01) and NT-proBNP (P<.01), compared with standard therapy.
“The improvement of the contractile function of the left side of the heart by more than 10% in patients after renal denervation was a surprise. This parameter has practically not changed in patients treated by the classic drugs. The difference in response might be explained by a continuous decrease of the renal sympathetic activity in the complex pathophysiology of HF,” Táborský said at the meeting.
Additionally, during follow-up, twice as many patients assigned standard medical therapy were admitted to the hospital for HF than patients assigned renal denervation. The researchers recorded two complications associated with the procedure: formation of a fistula by the artery and the vein at the place of puncture and the formation of thrombi, according to Táborský.
“Renal denervation in a pilot study with HF and low ejection fraction patients is a safe procedure, with no significant BP decrease. Renal denervation did not change the renal function,” Táborský concluded.
Overall, experts interviewed by Cardiology Today are cautiously optimistic about the future of renal denervation in the United States.
“While I am quite excited about this new technology, it is important to step back and realize that a lot of things seem exciting until they are subjected to proper studies. All of the data, to date, from sources outside the United States are provocative, but there are some significant, methodological limitations to those studies. What’s really needed is a rigorous, methodologically sound, randomized clinical trial,” said Bhatt, who is also senior physician at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School.
The FDA granted Medtronic approval to conduct the Symplicity HTN-3 trial in August 2011. The prospective, single blind, randomized controlled trial is designed to evaluate the safety and effectiveness of renal denervation with the Symplicity system in patients with uncontrolled hypertension despite compliance with at least three antihypertensive medications (at least one of which is a diuretic) at maximal tolerated doses. The primary efficacy endpoint is change in office-based systolic BP from baseline to 6 months. The study will include approximately 530 treatment-resistant hypertension patients at up to 90 US medical centers. Search for the trial on ClinicalTrials.gov for more information.
“Symplicity HTN-3 is the pivotal trial that will trump all other studies of renal denervation. It is, on average, 4.5 times bigger than the previous study and controls for other variables that previous studies did not control for in a meaningful systematic way,” Bakris said. He and Bhatt are co-principal investigators for the trial.
Preliminary 30-day data from the St. Jude Medical-sponsored EnligHTN I trial demonstrated that renal denervation using the EnligHTN system helped to reduce systolic BP by an average of 28 points 30 days after treatment, according to a company press release.
More data on the EnligHTN system are scheduled to be presented during a late-breaking clinical trial session at the American Heart Association’s Scientific Sessions in November.
A disadvantage of denervation, as with any invasive treatment, is the potential for subsequent complications. One adverse effect of concern is renal artery damage occurring after renal denervation.
William B. White
“It makes you wonder if there is potential for damage to structures other than the sympathetic nerves. Can renal denervation cause inflammation or fibrosis of the arteries in the renal vascular circulation or effects on renal function? These issues will need to be fully assessed over a long-term follow-up period,” White said.
“Different systems have been tested and they each appear to lower BP. That’s always an encouraging sign with a new drug or device; it’s great if it works, but if several other members of the same class work, you feel more reassured that there is some basic biological truth that has been uncovered.
“Overall, the field of renal denervation research is generating an enormous amount of excitement and it appears that, at least based on the current data, it is warranted. Being first isn’t always best [with regard to] drug or device approval. I think the cautious approach we’re taking in the United States is the right way to do things,” Bhatt said.
Disclosure: Bakris and Bhatt are co-principal investigators of the Symplicity HTN-3 trial, which is funded by Medtronic. Böhm reports receiving research grants, travel and consultancy funding from Ardian and Medtronic. Sobotka is an employee of Medtronic. Fischer, Franzen, Mylotte, Táborský and White report no relevant financial disclosures.