Meeting NewsPerspective

Hope for renal denervation revived with new sham-controlled trials

David Kandzari
David E. Kandzari

Two sham-controlled trials demonstrating the efficacy of renal denervation presented at EuroPCR have rekindled hope for the technology as a treatment for hypertension.

The SPYRAL HTN-ON MED and RADIANCE-HTN SOLO trials tested two different devices in two different patient populations, but results from both studies linked renal denervation with significant reductions in BP on several assessments with little to no safety concerns.

“These trials thus open a new chapter in renal denervation research and in our view should not be grouped into the meta-analyses of the first wave of studies,” Sverre E. Kjeldsen, MD, PhD, from the University of Oslo and Ullelvaal University Hospital in Norway, and Murray D. Esler, MD, from the Baker Heart and Diabetes Institute in Australia, wrote in an editorial accompanying publication of the RADIANCE-HTN SOLO results in The Lancet.

“Together, [the SPYRAL HTN-ON MED and OFF MED and RADIANCE-HTN SOLO] trials suggest that a renal denervation class effect might apply, in that performing renal denervation with different intravascular techniques yields the same results. Renal denervation achieved by intravascular delivery of radiofrequency energy or ultrasound energy might produce similar blood pressure lowering and the RADIANCE-HTN SOLO and SPYRAL trials take the renal denervation field into a new era.”

Renal denervation as a treatment for resistant hypertension experienced a setback in 2014 with the failure of the SYMPLICITY-HTN 3 trial. Since then, researchers have refined how denervation should be performed and redesigned technologies.

SPYRAL HTN-ON MED

In the SPYRAL HTN-ON MED trial, researchers sought to evaluate the effect of renal denervation therapy on BP in the presence of commonly prescribed antihypertensive medications “in a context considered more representative of clinical practice — integrating both device therapies and pharmacotherapies for the treatment of uncontrolled hypertension,” David E. Kandzari, MD, from the Piedmont Heart Institute in Atlanta, said.

At EuroPCR, Kandzari presented the 6-month data from the first 80 patients enrolled in the international, randomized, single-blind, sham-controlled, proof-of-concept trial. These patients with uncontrolled hypertension, defined as systolic BP between 150 mm Hg and 180 mm Hg while taking one to three antihypertensive medications, were randomly assigned to renal denervation with the Symplicity Spyral multielectrode renal denervation catheter (Medtronic) and the Symplicity G3 renal denervation RF generator (Medtronic) or sham procedure consisting of a renal angiogram.

At 6-month follow-up, there was a 9-mm Hg decrease in 24-hour ambulatory systolic BP in the renal denervation therapy group (P < .0001) vs. a 1.6-mm Hg reduction in the sham procedure group (P = .365; difference, –7.4 mm Hg; 95% CI, –12.5 to –2.3; P = .0051). Similarly, 24-hour ambulatory diastolic BP was significantly reduced by 6 mm Hg with renal denervation (P < .0001) vs. 1.9 mm Hg (P = .172) with sham procedure (difference, –4.1 mm Hg; 95% CI, –7.8 to –0.4; P = .0292).

 

Laura Mauri

 

Moreover, office systolic BP at 6-month follow-up was reduced by 9.4 mm Hg in the renal denervation group (P < .0001) vs. 2.6 mm Hg in the sham procedure group (P = .215; difference, –6.8 mm Hg; 95% CI, –12.5 to –1.1; P = .0205). Office diastolic BP was also reduced by 5.2 mm Hg with renal denervation (P = .0001) vs. 1.7 mm Hg with sham procedure (P = .188; difference, –3.5 mm Hg; 95% CI, –7 to –0; P = .0478).

Additionally, ambulatory BP assessment over 24 hours at baseline, 3 months and 6 months showed a trajectory of progressive decline in BP for patients receiving renal denervation therapy for both systolic and diastolic BP measures, Kandzari noted. Further, with assessment over a 24-hour period, renal denervation, as compared with sham procedure, was associated with a persistent consistent reduction in BP at all time intervals.

“This may have important implications distinctive from pharmacotherapies with peak and trough levels in early morning and late evening hours or may be of special relevance to individuals with high risk for CV events, such as those with nocturnal hypertension or early morning hypertension,” he said.

There were no major adverse events at 6 months in the overall study population, but more specifically, in the renal denervation cohort, there were no major clinical events, including no new renal artery stenosis or worsening renal function and no major bleeding or vascular complications, Kandzari reported.

At baseline, the average number of medication classes prescribed per patient was 2.2 in the renal denervation therapy group and 2.3 in the sham procedure group. Slightly more than half of the study population was prescribed three antihypertensive medications, with the most commonly prescribed medication classes being ACE inhibitors/angiotensin receptor blockers, followed by calcium channel blockers and diuretic therapy.

With patient awareness, medication adherence was assessed by blood and urine testing at baseline, 3 months and 6 months. At baseline, nonadherence was approximately 38% and was similar between both study arms. Nonadherence was also observed to be highly dynamic, making adherence or nonadherence difficult to predict, according to Kandzari.

RADIANCE-HTN SOLO

The multicenter, international, single-blind, randomized, sham-controlled RADIANCE-HTN SOLO trial was conducted at 21 centers in the United States and 18 in Europe with the aim of investigating whether endovascular ultrasound-based renal denervation reduces ambulatory BP in patients mild to moderate hypertension.

Unlike SPYRAL HTN-ON MED, the researchers sought to evaluate the treatment in patients not taking antihypertensive medications, according to Laura Mauri, MD, MSc, interventional cardiologist at Brigham and Women’s Hospital, professor of medicine at Harvard Medical School and chief science advisor at Baim Institute for Clinical Research, who presented the findings.

In the study, which was powered prospectively to detect a 6-mm Hg difference in ambulatory systolic BP between treatment arms, 146 patients with ambulatory BP between 135/85 mm Hg to 170/105 mm Hg were randomly assigned to renal nerve ablation with the endovascular ultrasound renal denervation system (Paradise, ReCor; n = 74) or a sham procedure (n = 72). Eligible patients underwent a 4-week antihypertensive medication washout period.

At 2 months, there was an 8.5-mm Hg reduction compared with baseline in primary daytime ambulatory systolic BP with renal denervation vs. a 2.2-mm Hg reduction with sham procedure, resulting in a 6.3-mm Hg between-group difference (P < .0001).

Mauri and colleagues also conducted a per-protocol analysis that excluded patients who resumed treatment with antihypertensive medications during the 2-month follow-up as well as patients who did not meet entry criteria. In this analysis, there was an 8.5-mm Hg reduction in daytime ambulatory systolic BP with renal denervation vs. a 0.1-mm Hg reduction with sham procedure, yielding a significant 8.2-mm Hg between-group difference (P < .0001).

When looking at individual patient responses, the researchers found that 66% of the patients in the renal denervation group achieved a daytime ambulatory systolic BP-lowering effect of 5 mm Hg or greater, as compared with 33% in the sham procedure group (P = .0001). Additionally, 20% of patients in the renal denervation group achieved controlled daytime ambulatory BP, defined as BP lower than 135 mm Hg systolic/85 mm Hg diastolic, without antihypertensive medications vs. 3% of patients in the sham procedure group (P = .001).

No safety events occurred in either treatment arm at 1 and 2 months, Mauri noted.

‘New optimism’

The results of these new trials cast a positive light on a technology that fell out of the spotlight after SYMPLICITY HTN-3 failed to meet its primary endpoint. However, these new data should be placed in context, according to experts.

“We acknowledge that the [SPYRAL HTN-ON MED and SPYRAL HTN-OFF MED] studies mean a start of real progress in understanding the effects of renal denervation in patients with hypertension,” Peter J. Blankestijn, MD, PhD, and Michiel L. Bots, MD, PhD, both from the University Medical Center Utrecht University in the Netherlands, wrote in an editorial accompanying publication of the SPYRAL HTN-ON MED trial in The Lancet.

However, they noted that unresolved issues remain, including identifying which patients will benefit most, the long-term effects of renal denervation on BP and safety, among other issues.

In their editorial, Kjeldsen and Esler echoed these concerns, emphasizing the importance of future research, but they also highlighted the upside of these data.

“However, for now, the RADIANCE-HTN SOLO and SPYRAL studies inject new optimism into this exciting field of research,” they wrote in an editorial accompanying publication of the RADIANCE-HTN SOLO findings in The Lancet.

Kandzari noted that a larger pivotal trial in the off-medication population is ongoing and is being conducted in the United States under FDA oversight. “Perhaps more importantly, as an international global program, this trial will also further inform the safety and effectiveness of renal denervation for treatment of uncontrolled hypertension.”

Similarly, Mauri said the RADIANCE-HTN investigators plan to continue studying the technology to gather more data.

“Follow-up of the study is ongoing through 3 years to assess longer-term safety and efficacy of the procedure, and enrollment is ongoing in a parallel, blinded, sham-controlled trial of patients with resistant hypertension — the RADIANCE-HTN TRIO study,” Mauri said. – by Melissa Foster

Reference:

Böhm M, et al. Renal denervation and new drug-eluting stents. Presented at: EuroPCR; May 22-25, 2018; Paris.

Aziz M, et al. Lancet. 2018;doi:10.1016/ S0140-6736(18)31082-1.

Blankestijn PJ, et al. Lancet. 2018;doi:10.1016/ S0140-6736(18)31112-7.

Kandzari DE, et al. Lancet. 2018;doi:10.1016/ S0140-6736(18)30951-6.

Kjeldsen SE, et al. Lancet. 2018;doi:10.1016/ S0140-6736(18)31126-7.

 

Disclosure: SPYRAL HTN-ON MED was funded by Medtronic. Kandzari reports he has received institutional grant or research support from Biotronik, Boston Scientific, Medtronic CardioVascular, Medinol and OrbusNeich and he has received consulting fees from Biotronik, Boston Scientific, Medtronic CardioVascular and Cardinal Health. RADIANCE-HTN SOLO was funded by ReCor Medical. Mauri reports she has received a research grant to her institution and personal fees as principal investigator from ReCor; she has received personal fees from Medtronic; she has received grants to her institution from Abbott, Boston Scientific and St. Jude Medical; and she anticipates employment by Medtronic as of June 2018. Blanketsijn reports he has received grants to his institution from Medtronic, Recor Medical and St. Jude Medical. Bots reports no relevant financial disclosures. Kjeldsen reports he has received ad-hoc honoraria for lecturing from Bayer, Merck, Sanofi and Takeda and honoraria from Takeda. Esler reports he is a member of Medtronic’s Renal Denervation Advisory Board and he receives honoraria from Medtronic.

Editor's Note: This article was updated on May 24, 2018 to correct the period of time in which no major adverse events occurred in the SPYRAL HTN-ON MED trial.

 

David Kandzari
David E. Kandzari

Two sham-controlled trials demonstrating the efficacy of renal denervation presented at EuroPCR have rekindled hope for the technology as a treatment for hypertension.

The SPYRAL HTN-ON MED and RADIANCE-HTN SOLO trials tested two different devices in two different patient populations, but results from both studies linked renal denervation with significant reductions in BP on several assessments with little to no safety concerns.

“These trials thus open a new chapter in renal denervation research and in our view should not be grouped into the meta-analyses of the first wave of studies,” Sverre E. Kjeldsen, MD, PhD, from the University of Oslo and Ullelvaal University Hospital in Norway, and Murray D. Esler, MD, from the Baker Heart and Diabetes Institute in Australia, wrote in an editorial accompanying publication of the RADIANCE-HTN SOLO results in The Lancet.

“Together, [the SPYRAL HTN-ON MED and OFF MED and RADIANCE-HTN SOLO] trials suggest that a renal denervation class effect might apply, in that performing renal denervation with different intravascular techniques yields the same results. Renal denervation achieved by intravascular delivery of radiofrequency energy or ultrasound energy might produce similar blood pressure lowering and the RADIANCE-HTN SOLO and SPYRAL trials take the renal denervation field into a new era.”

Renal denervation as a treatment for resistant hypertension experienced a setback in 2014 with the failure of the SYMPLICITY-HTN 3 trial. Since then, researchers have refined how denervation should be performed and redesigned technologies.

SPYRAL HTN-ON MED

In the SPYRAL HTN-ON MED trial, researchers sought to evaluate the effect of renal denervation therapy on BP in the presence of commonly prescribed antihypertensive medications “in a context considered more representative of clinical practice — integrating both device therapies and pharmacotherapies for the treatment of uncontrolled hypertension,” David E. Kandzari, MD, from the Piedmont Heart Institute in Atlanta, said.

At EuroPCR, Kandzari presented the 6-month data from the first 80 patients enrolled in the international, randomized, single-blind, sham-controlled, proof-of-concept trial. These patients with uncontrolled hypertension, defined as systolic BP between 150 mm Hg and 180 mm Hg while taking one to three antihypertensive medications, were randomly assigned to renal denervation with the Symplicity Spyral multielectrode renal denervation catheter (Medtronic) and the Symplicity G3 renal denervation RF generator (Medtronic) or sham procedure consisting of a renal angiogram.

At 6-month follow-up, there was a 9-mm Hg decrease in 24-hour ambulatory systolic BP in the renal denervation therapy group (P < .0001) vs. a 1.6-mm Hg reduction in the sham procedure group (P = .365; difference, –7.4 mm Hg; 95% CI, –12.5 to –2.3; P = .0051). Similarly, 24-hour ambulatory diastolic BP was significantly reduced by 6 mm Hg with renal denervation (P < .0001) vs. 1.9 mm Hg (P = .172) with sham procedure (difference, –4.1 mm Hg; 95% CI, –7.8 to –0.4; P = .0292).

PAGE BREAK

 

Laura Mauri

 

Moreover, office systolic BP at 6-month follow-up was reduced by 9.4 mm Hg in the renal denervation group (P < .0001) vs. 2.6 mm Hg in the sham procedure group (P = .215; difference, –6.8 mm Hg; 95% CI, –12.5 to –1.1; P = .0205). Office diastolic BP was also reduced by 5.2 mm Hg with renal denervation (P = .0001) vs. 1.7 mm Hg with sham procedure (P = .188; difference, –3.5 mm Hg; 95% CI, –7 to –0; P = .0478).

Additionally, ambulatory BP assessment over 24 hours at baseline, 3 months and 6 months showed a trajectory of progressive decline in BP for patients receiving renal denervation therapy for both systolic and diastolic BP measures, Kandzari noted. Further, with assessment over a 24-hour period, renal denervation, as compared with sham procedure, was associated with a persistent consistent reduction in BP at all time intervals.

“This may have important implications distinctive from pharmacotherapies with peak and trough levels in early morning and late evening hours or may be of special relevance to individuals with high risk for CV events, such as those with nocturnal hypertension or early morning hypertension,” he said.

There were no major adverse events at 6 months in the overall study population, but more specifically, in the renal denervation cohort, there were no major clinical events, including no new renal artery stenosis or worsening renal function and no major bleeding or vascular complications, Kandzari reported.

At baseline, the average number of medication classes prescribed per patient was 2.2 in the renal denervation therapy group and 2.3 in the sham procedure group. Slightly more than half of the study population was prescribed three antihypertensive medications, with the most commonly prescribed medication classes being ACE inhibitors/angiotensin receptor blockers, followed by calcium channel blockers and diuretic therapy.

With patient awareness, medication adherence was assessed by blood and urine testing at baseline, 3 months and 6 months. At baseline, nonadherence was approximately 38% and was similar between both study arms. Nonadherence was also observed to be highly dynamic, making adherence or nonadherence difficult to predict, according to Kandzari.

RADIANCE-HTN SOLO

The multicenter, international, single-blind, randomized, sham-controlled RADIANCE-HTN SOLO trial was conducted at 21 centers in the United States and 18 in Europe with the aim of investigating whether endovascular ultrasound-based renal denervation reduces ambulatory BP in patients mild to moderate hypertension.

Unlike SPYRAL HTN-ON MED, the researchers sought to evaluate the treatment in patients not taking antihypertensive medications, according to Laura Mauri, MD, MSc, interventional cardiologist at Brigham and Women’s Hospital, professor of medicine at Harvard Medical School and chief science advisor at Baim Institute for Clinical Research, who presented the findings.

PAGE BREAK

In the study, which was powered prospectively to detect a 6-mm Hg difference in ambulatory systolic BP between treatment arms, 146 patients with ambulatory BP between 135/85 mm Hg to 170/105 mm Hg were randomly assigned to renal nerve ablation with the endovascular ultrasound renal denervation system (Paradise, ReCor; n = 74) or a sham procedure (n = 72). Eligible patients underwent a 4-week antihypertensive medication washout period.

At 2 months, there was an 8.5-mm Hg reduction compared with baseline in primary daytime ambulatory systolic BP with renal denervation vs. a 2.2-mm Hg reduction with sham procedure, resulting in a 6.3-mm Hg between-group difference (P < .0001).

Mauri and colleagues also conducted a per-protocol analysis that excluded patients who resumed treatment with antihypertensive medications during the 2-month follow-up as well as patients who did not meet entry criteria. In this analysis, there was an 8.5-mm Hg reduction in daytime ambulatory systolic BP with renal denervation vs. a 0.1-mm Hg reduction with sham procedure, yielding a significant 8.2-mm Hg between-group difference (P < .0001).

When looking at individual patient responses, the researchers found that 66% of the patients in the renal denervation group achieved a daytime ambulatory systolic BP-lowering effect of 5 mm Hg or greater, as compared with 33% in the sham procedure group (P = .0001). Additionally, 20% of patients in the renal denervation group achieved controlled daytime ambulatory BP, defined as BP lower than 135 mm Hg systolic/85 mm Hg diastolic, without antihypertensive medications vs. 3% of patients in the sham procedure group (P = .001).

No safety events occurred in either treatment arm at 1 and 2 months, Mauri noted.

‘New optimism’

The results of these new trials cast a positive light on a technology that fell out of the spotlight after SYMPLICITY HTN-3 failed to meet its primary endpoint. However, these new data should be placed in context, according to experts.

“We acknowledge that the [SPYRAL HTN-ON MED and SPYRAL HTN-OFF MED] studies mean a start of real progress in understanding the effects of renal denervation in patients with hypertension,” Peter J. Blankestijn, MD, PhD, and Michiel L. Bots, MD, PhD, both from the University Medical Center Utrecht University in the Netherlands, wrote in an editorial accompanying publication of the SPYRAL HTN-ON MED trial in The Lancet.

However, they noted that unresolved issues remain, including identifying which patients will benefit most, the long-term effects of renal denervation on BP and safety, among other issues.

PAGE BREAK

In their editorial, Kjeldsen and Esler echoed these concerns, emphasizing the importance of future research, but they also highlighted the upside of these data.

“However, for now, the RADIANCE-HTN SOLO and SPYRAL studies inject new optimism into this exciting field of research,” they wrote in an editorial accompanying publication of the RADIANCE-HTN SOLO findings in The Lancet.

Kandzari noted that a larger pivotal trial in the off-medication population is ongoing and is being conducted in the United States under FDA oversight. “Perhaps more importantly, as an international global program, this trial will also further inform the safety and effectiveness of renal denervation for treatment of uncontrolled hypertension.”

Similarly, Mauri said the RADIANCE-HTN investigators plan to continue studying the technology to gather more data.

“Follow-up of the study is ongoing through 3 years to assess longer-term safety and efficacy of the procedure, and enrollment is ongoing in a parallel, blinded, sham-controlled trial of patients with resistant hypertension — the RADIANCE-HTN TRIO study,” Mauri said. – by Melissa Foster

Reference:

Böhm M, et al. Renal denervation and new drug-eluting stents. Presented at: EuroPCR; May 22-25, 2018; Paris.

Aziz M, et al. Lancet. 2018;doi:10.1016/ S0140-6736(18)31082-1.

Blankestijn PJ, et al. Lancet. 2018;doi:10.1016/ S0140-6736(18)31112-7.

Kandzari DE, et al. Lancet. 2018;doi:10.1016/ S0140-6736(18)30951-6.

Kjeldsen SE, et al. Lancet. 2018;doi:10.1016/ S0140-6736(18)31126-7.

 

Disclosure: SPYRAL HTN-ON MED was funded by Medtronic. Kandzari reports he has received institutional grant or research support from Biotronik, Boston Scientific, Medtronic CardioVascular, Medinol and OrbusNeich and he has received consulting fees from Biotronik, Boston Scientific, Medtronic CardioVascular and Cardinal Health. RADIANCE-HTN SOLO was funded by ReCor Medical. Mauri reports she has received a research grant to her institution and personal fees as principal investigator from ReCor; she has received personal fees from Medtronic; she has received grants to her institution from Abbott, Boston Scientific and St. Jude Medical; and she anticipates employment by Medtronic as of June 2018. Blanketsijn reports he has received grants to his institution from Medtronic, Recor Medical and St. Jude Medical. Bots reports no relevant financial disclosures. Kjeldsen reports he has received ad-hoc honoraria for lecturing from Bayer, Merck, Sanofi and Takeda and honoraria from Takeda. Esler reports he is a member of Medtronic’s Renal Denervation Advisory Board and he receives honoraria from Medtronic.

Editor's Note: This article was updated on May 24, 2018 to correct the period of time in which no major adverse events occurred in the SPYRAL HTN-ON MED trial.

    Perspective
    John P. Reilly

    John P. Reilly

    It’s important to remember that a number of studies before these suggested that renal denervation would be a beneficial therapy for hypertension; SYMPLICITY HTN-3 was the outlier.

    Renal denervation will become one option to treat hypertension. We don’t yet know which patients are most likely to benefit. We need more analysis of risks and benefits, and of where it is cost-effective. The treatment effect on BP seen in these studies is similar to a patient losing 20 pounds.

    The RADIANCE HTN-SOLO trial looked at patients who were not on medications and corroborated the findings of SPYRAL HTN-OFF MED, which was published in August 2017. Both showed that renal denervation was better than being on no medications. When the TRIO trial of the ReCor device in patients with hypertension resistant to medications is published, and we get more data from SPYRAL HTN-ON MED, those will be important next steps in learning how to treat patients with truly resistant hypertension. We also need to do a cost analysis. Although renal denervation is a one-time procedure, which is very attractive, and may have a long-term benefit, hypertension drugs are relatively cheap, so the cost analysis will be important.

    These data are very exciting and deserve more attention than they are getting, given that hypertension is an underlying cause of heart disease.

    • John P. Reilly, MD, FACC
    • Vice Chairman, Clinical Affairs, Department of Cardiovascular Disease Director, Cardiovascular CT Program Director, Cardiology Fellowship Program Associate Director, Cardiac Catheterization Laboratory Ochsner Health System

    Disclosures: Reilly reports he has served as a site investigator for several renal denervation trials, including RADIANCE HTN-SOLO, without compensation.

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