In the Journals

BP down with renal sympathetic denervation in sham-controlled trials

In a recent meta-analysis of randomized, sham-controlled trials, renal sympathetic denervation significantly decreased various measures of BP.

Results showed a greater reduction in 24-hour ambulatory systolic BP in patients who received renal sympathetic denervation, as compared with sham procedure (weighted mean differences, –3.65 mm Hg; 95% CI, –5.33 to –1.98). Similarly, renal sympathetic denervation, as compared with sham procedure, decreased the following:

  • 24-hour ambulatory diastolic BP (weighted mean difference, –1.71 mm Hg; 95% CI, –3.06 to –0.35);
  • daytime ambulatory systolic BP (weighted mean difference, –4.07 mm Hg; 95% CI, –6.46 to –1.68); and
  • daytime ambulatory diastolic BP (weighted mean difference, –1.57 mm Hg; 95% CI, –2.73 to –0.42).

Ambulatory systolic BP and nighttime ambulatory diastolic BP, however, did not differ significantly between those treated with renal sympathetic denervation vs. sham control.

Greater reductions were also seen with renal sympathetic denervation vs. sham procedure in office systolic BP (weighted mean difference, –5.53 mm Hg; 95% CI, –8.18 to –2.87) and office diastolic BP (weighted mean difference, –3.37 mm Hg; 95% CI, –4.86 to –1.88).

The differences from baseline in estimated glomerular filtration rate were not significant between treatment groups.

The meta-analysis included six trials with 977 patients — of whom 582 were randomly assigned to renal sympathetic denervation and 395 to sham procedure. Four trials allowed continued use of stable optimal medical therapy in both treatment groups, and two trials included patients who had stopped antihypertensive medications for at least 3 to 4 weeks before randomization. Radiofrequency energy was used in five trials, and ultrasound was used for renal denervation in one trial.

First-generation vs. second-generation trials

The researchers included three first-generation trials, including a study of radiofrequency ablation with the Symplicity Flex catheter (Medtronic), RADIANCE-HTN SOLO and ReSET. They also analyzed three second-generation trials — SPYRAL HTN-ON MED, SPYRAL HTN-OFF MED and RADIANCE-HTN SOLO — that were designed and performed renal sympathetic denervation with more focus on patient selection and procedural technique.

In second-generation trials, as compared with first-generation trials, the reduction in daytime ambulatory systolic BP was greater with renal sympathetic denervation than with sham control (6.12 mm Hg vs. 2.14 mm Hg; P for interaction = .04). In first-generation trials, however, the researchers found no significant reduction in ambulatory systolic BP, and renal sympathetic denervation only had a statistically significant effect on ambulatory diastolic BP in second-generation trials.

Fixed-effects analysis of ambulatory systolic BP showed consistent results. Lowering of ambulatory systolic BP with renal sympathetic denervation vs. sham procedure remained consistent with removal of each study one at a time. Meta-regression with multiple covariates identified no confounding factors or effect modifiers for changes in ambulatory systolic BP.

There were no reports of major periprocedural adverse events in either treatment group in five of the trials. In SYMPLICITY HTN-3, however, 1.4% of the renal sympathetic denervation group and 0.6% of the sham procedure group reported major adverse events.

This meta-analysis, according to the researchers, should inform future studies.

“A large pivotal trial should be designed in a manner consistent with the second-generation trials included in this analysis. These include minimization of participants with isolated systolic hypertension, performance of procedures by highly experienced operators, employment of more complete techniques of radiofrequency ablation, and use of other novel approaches such as endovascular ultrasound renal denervation,” they wrote. “Also, based on our analysis, future large trials should include longer follow-up, be powered for efficacy endpoints including clinical outcomes, and incorporate objective measurement of medical adherence.”

Future research

In an accompanying editorial, Sverre E. Kjeldsen, MD, PhD, Fadl E.M. Fadl Elmula, MD, PhD, both from Oslo University Hospital, Ullevaal and the University of Oslo, and Alexandre Persu, MD, PhD, from Pole of Cardiovascular Research, Institut de Recherche Experimentale et Clinique, Universite Catholique de Louvain, and division of cardiology, Cliniques Universitaires Saint-Luc, Universite Catholique de Louvain in Brussels, questioned several aspects of the meta-analysis.

For instance, they noted that restricting the meta-analysis to sham-controlled studies only and combining the first- and second-generation trials may not have been appropriate. They also highlighted problems with controlling drug intake in earlier trials that may have led to bias.

The editorialists also pointed out that the overall 6-mm Hg decrease in BP with renal sympathetic denervation observed in the second-generation trials was relatively modest. However, there may still be benefit to renal sympathetic denervation, they noted. For instance, researchers have observed large variability in response to renal sympathetic denervation seen in previous trials, noting that future trials should try to identify those who respond best to the treatment. Additionally, data from RADIOSOUND-HTN suggest that ultrasound-based renal sympathetic denervation may lead to a greater reduction in BP than radiofrequency-based renal sympathetic denervation.

“Hence, optimized patient selection and technical improvements may allow breaking the ‘glass ceiling’ of 6 mm Hg,” they wrote. “Research on [renal sympathetic denervation] still has good days to come, and patients may eventually benefit from this research effort.” – by Melissa Foster

Disclosures: Sardar reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures. Kjeldsen reports he has received lecture and/or consultancy honoraria from Merck KGaA, Merck Sharp & Dohme, Sanofi and Takeda, and he has served on a study committee for Takeda. Fadl Elmula and Persu report no relevant financial disclosures.

In a recent meta-analysis of randomized, sham-controlled trials, renal sympathetic denervation significantly decreased various measures of BP.

Results showed a greater reduction in 24-hour ambulatory systolic BP in patients who received renal sympathetic denervation, as compared with sham procedure (weighted mean differences, –3.65 mm Hg; 95% CI, –5.33 to –1.98). Similarly, renal sympathetic denervation, as compared with sham procedure, decreased the following:

  • 24-hour ambulatory diastolic BP (weighted mean difference, –1.71 mm Hg; 95% CI, –3.06 to –0.35);
  • daytime ambulatory systolic BP (weighted mean difference, –4.07 mm Hg; 95% CI, –6.46 to –1.68); and
  • daytime ambulatory diastolic BP (weighted mean difference, –1.57 mm Hg; 95% CI, –2.73 to –0.42).

Ambulatory systolic BP and nighttime ambulatory diastolic BP, however, did not differ significantly between those treated with renal sympathetic denervation vs. sham control.

Greater reductions were also seen with renal sympathetic denervation vs. sham procedure in office systolic BP (weighted mean difference, –5.53 mm Hg; 95% CI, –8.18 to –2.87) and office diastolic BP (weighted mean difference, –3.37 mm Hg; 95% CI, –4.86 to –1.88).

The differences from baseline in estimated glomerular filtration rate were not significant between treatment groups.

The meta-analysis included six trials with 977 patients — of whom 582 were randomly assigned to renal sympathetic denervation and 395 to sham procedure. Four trials allowed continued use of stable optimal medical therapy in both treatment groups, and two trials included patients who had stopped antihypertensive medications for at least 3 to 4 weeks before randomization. Radiofrequency energy was used in five trials, and ultrasound was used for renal denervation in one trial.

First-generation vs. second-generation trials

The researchers included three first-generation trials, including a study of radiofrequency ablation with the Symplicity Flex catheter (Medtronic), RADIANCE-HTN SOLO and ReSET. They also analyzed three second-generation trials — SPYRAL HTN-ON MED, SPYRAL HTN-OFF MED and RADIANCE-HTN SOLO — that were designed and performed renal sympathetic denervation with more focus on patient selection and procedural technique.

In second-generation trials, as compared with first-generation trials, the reduction in daytime ambulatory systolic BP was greater with renal sympathetic denervation than with sham control (6.12 mm Hg vs. 2.14 mm Hg; P for interaction = .04). In first-generation trials, however, the researchers found no significant reduction in ambulatory systolic BP, and renal sympathetic denervation only had a statistically significant effect on ambulatory diastolic BP in second-generation trials.

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Fixed-effects analysis of ambulatory systolic BP showed consistent results. Lowering of ambulatory systolic BP with renal sympathetic denervation vs. sham procedure remained consistent with removal of each study one at a time. Meta-regression with multiple covariates identified no confounding factors or effect modifiers for changes in ambulatory systolic BP.

There were no reports of major periprocedural adverse events in either treatment group in five of the trials. In SYMPLICITY HTN-3, however, 1.4% of the renal sympathetic denervation group and 0.6% of the sham procedure group reported major adverse events.

This meta-analysis, according to the researchers, should inform future studies.

“A large pivotal trial should be designed in a manner consistent with the second-generation trials included in this analysis. These include minimization of participants with isolated systolic hypertension, performance of procedures by highly experienced operators, employment of more complete techniques of radiofrequency ablation, and use of other novel approaches such as endovascular ultrasound renal denervation,” they wrote. “Also, based on our analysis, future large trials should include longer follow-up, be powered for efficacy endpoints including clinical outcomes, and incorporate objective measurement of medical adherence.”

Future research

In an accompanying editorial, Sverre E. Kjeldsen, MD, PhD, Fadl E.M. Fadl Elmula, MD, PhD, both from Oslo University Hospital, Ullevaal and the University of Oslo, and Alexandre Persu, MD, PhD, from Pole of Cardiovascular Research, Institut de Recherche Experimentale et Clinique, Universite Catholique de Louvain, and division of cardiology, Cliniques Universitaires Saint-Luc, Universite Catholique de Louvain in Brussels, questioned several aspects of the meta-analysis.

For instance, they noted that restricting the meta-analysis to sham-controlled studies only and combining the first- and second-generation trials may not have been appropriate. They also highlighted problems with controlling drug intake in earlier trials that may have led to bias.

The editorialists also pointed out that the overall 6-mm Hg decrease in BP with renal sympathetic denervation observed in the second-generation trials was relatively modest. However, there may still be benefit to renal sympathetic denervation, they noted. For instance, researchers have observed large variability in response to renal sympathetic denervation seen in previous trials, noting that future trials should try to identify those who respond best to the treatment. Additionally, data from RADIOSOUND-HTN suggest that ultrasound-based renal sympathetic denervation may lead to a greater reduction in BP than radiofrequency-based renal sympathetic denervation.

“Hence, optimized patient selection and technical improvements may allow breaking the ‘glass ceiling’ of 6 mm Hg,” they wrote. “Research on [renal sympathetic denervation] still has good days to come, and patients may eventually benefit from this research effort.” – by Melissa Foster

Disclosures: Sardar reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures. Kjeldsen reports he has received lecture and/or consultancy honoraria from Merck KGaA, Merck Sharp & Dohme, Sanofi and Takeda, and he has served on a study committee for Takeda. Fadl Elmula and Persu report no relevant financial disclosures.