Renal Denervation: Blood Pressure Benefit in New Meta-analysis

April 03, 2019

A new meta-analysis of six sham-controlled studies of renal sympathetic denervation (RSD) has shown a significant reduction in blood pressure with the technique.

"After the SYMPLICITY HTN-3 trial, which failed to show a benefit of denervation, there was a loss of hope in this approach, but our results suggest there is something there, and denervation may well be effective if used in the right patients, delivered in the right way and with blood pressure being measured appropriately," senior author Herbert Aronow, MD, Warren Alpert Medical School of Brown University in Providence, Rhode Island, told Medscape Medical News.

The meta-analysis is published in the April 9 issue of the Journal of the American College of Cardiology.

Aronow explained that a number of early studies suggested that renal sympathetic denervation was associated with reduced blood pressure, and the results with surgical denervation were very positive. Unfortunately, in the largest and most rigorous trial to be done — SYMPLICITY HTN-3 — there was no difference between medical therapy and denervation.

"This led to a loss of interest in the approach, but many of us held out hope that denervation could still be effective," he said.

Aronow suggested several hypotheses why SYMPLICTY HTN-3 failed to show a benefit. "Perhaps the trial did not involve the most ideal patient population or the procedure used was itself not optimal, or the primary outcome of office-measured blood pressure was not the best way of assessing blood pressure."

He noted that the latest round of studies have included patients with combined hypertension, where both systolic and diastolic pressures are raised; combined hypertension seems to respond better to denervation than isolated systolic hypertension.

The procedure used is also evolving. Later studies have included more extensive denervation than earlier studies and also have used ambulatory blood pressure monitoring to assess pressures over the full 24-hour period, which are much more reliable, he said.

"This meta-analysis as a whole has shown a significant benefit of denervation over sham control, but when we looked at the more recent trials we saw a larger reduction in blood pressure with denervation than was seen in the earlier trials. So perhaps we are making some headway," Aronow commented.

"These later studies are all very small, so this can only be considered proof of concept. We now have to a conduct larger trial to see if we can confirm these results," he added.

For the current meta-analysis, Aronow and colleagues included six studies comparing catheter-based renal sympathetic denervation with a sham control in a total of 977 patients. The studies included were the SYMPLICITY HTN-3 trial, the SPYRAL HTN-OFF MED and SPYRAL HTN-ON MED studies, and the RADIANCE-HTN SOLO study, as well as two smaller studies.   

Results showed that the reduction in 24-hour ambulatory systolic blood pressure (ASBP) was significantly greater for patients treated with RSD than sham procedure (-3.65 mm Hg; 95% confidence interval [CI], -5.33 to -1.98 mm Hg; P < .001).

Compared with sham, denervation was also associated with a significant decrease in daytime ambulatory systolic blood pressure, office systolic blood pressure, 24-hour ambulatory diastolic blood pressure, daytime ambulatory diastolic blood pressure, and office diastolic blood pressure.

Compared with three first-generation trials, a significantly greater reduction in daytime ambulatory systolic blood pressure was observed with denervation in the three second-generation trials (6.12 mm Hg vs. 2.14 mm Hg; P interaction = .04); however, this interaction was not significant for 24-hour ambulatory systolic blood pressure (4.85 mm Hg vs. 2.23 mm Hg; P interaction = .13).

The researchers suggest the better results with denervation in the second-generation studies might be explained by differences in patients enrolled, procedural technique employed, antihypertensive drug regimens prescribed, and endpoint ascertainment.

"Altogether, the present study affirms the safety and efficacy of renal denervation for blood pressure reduction and highlights the importance of incorporating the previously described modifications in trial design," the authors write.

They add: "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.

"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," they conclude.

The Evidence Is There

In an accompanying editorial, Sverre E. Kjeldsen, MD, PhD, Oslo University Hospital, Norway; Fadl Elmula, MD, PhD, University of Oslo, Norway; and Alexandre Persu, MD, PhD, Université Catholique de Louvain, Brussels, Belgium, say that "the evidence is now there to conclude that renal sympathetic denervation does lower blood pressure in hypertensive patients," a conclusion they say is consistent with the known contribution of sympathetic overactivity in the pathogenesis of essential hypertension.

They point out that the overall 6-mm Hg BP-lowering effect of denervation observed in the second-generation trials is relatively modest, roughly corresponding to the effect of one antihypertensive drug, and the associated clinical benefit remains to be demonstrated.

However, they note that there is a large variability in response to denervation, with 20% to 30% of patients experiencing a "dramatic" blood pressure decrease within 3 months after the procedure, which they suggest may reflect the variable contribution of the sympathetic system to blood pressure elevation in the individual patient.

"Accordingly, we feel that identification of characteristics allowing us to spot these 'extreme-responders' should be a priority for the near future."

The editorialists also cite a study showing that ultrasound-based denervation may elicit a larger blood pressure decrease than a radiofrequency-based approach.

"Hence, optimized patient selection and technical improvements may allow breaking the 'glass ceiling' of 6 mm Hg," they conclude. "Research on renal sympathetic denervation still has good days to come, and patients may eventually benefit from this research effort."

Aronow, Elmula and Persu have disclosed no relevant financial relationships. Kjeldsen has received lecture and/or consultancy honoraria from Merck KGaA, Merck Sharp and Dohme, Sanofi, and Takeda; and has served on a study committee for Takeda.

J Am Coll Cardiol. April 9, 2019 issue. Abstract, Editorial

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