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PARIS -- The concept of time in target range (TTR) provided a stronger case for renal denervation as an adjunctive treatment to reduce blood pressure (BP) in people not responding to antihypertensives, according to studies presented here at the EuroPCR meeting.

Research had previously shown that the catheter-based procedure lowers BP, albeit to a modest degree that had critics questioning whether denervation would ultimately make a meaningful difference in clinical outcomes.

Now, it appears that cardiovascular event rates were especially low among people who responded to renal denervation and enjoyed more time in target BP range after the procedure, according to 3-year results from the Global SYMPLICITY Registry, which has to date enrolled 3,077 real-world patients with uncontrolled hypertension who were treated with the Symplicity Flex or Spyral radiofrequency systems.

Furthermore, compared with sham control, renal denervation with the Symplicity Spyral in particular was associated with significantly higher TTR over 3 years among participants of the small SPYRAL HTN-ON MED trial.

The presenter of this latter analysis, David Kandzari, MD, of Piedmont Heart Institute in Atlanta, asked during a EuroPCR press conference whether these data might together be enough to satisfy skeptics asking for clinical outcomes data on renal denervation.

BP is a surrogate endpoint that has historically supported pharmacological therapies, so it should also be accepted for renal denervation, argued Felix Mahfoud, MD, of Saarland University Hospital in Germany. He added that an outcomes study "will never happen" as it would require 20,000 participants.

A more pressing issue appears to be how to select people most likely to benefit from renal denervation.

TTR Up, Events Down

Although the majority of patients may not respond, those who did, and spent a greater amount of TTR right after the procedure, nevertheless had significantly fewer cardiovascular events years later, according to registry data.

For example, people who had TTRs exceeding 50% from baseline to 6 months post-procedure (n=512) were better off in terms of combined cardiovascular death, myocardial infarction, and stroke out to 36 months compared with peers who showed zero TTR (n=766) during that initial period (10.3% vs 2.9%), Mahfoud reported.

There was a progressive decline in office BP after renal denervation -- office BP sinking from -13.2 at 6 months to -16.7 mmHg at 3 years -- despite patients staying on nearly five medications per person.

Several mechanisms have been proposed for this phenomenon, including changes in vascular remodeling, a resetting of central BP, and differences in the renin-angiotensin system. "Maybe it's that over time, there is a synergistic effect of drugs with renal denervation," Mahfoud suggested.

People in the Global SYMPLICITY Registry averaged 60 years old, and 42.2% were women. Office systolic BP was 166 mmHg on average at baseline. Investigators had 3-year data available for 1,896 patients.

They had derived TTR from linear interpolation of BP data from follow-up visits, estimating the amount of time each person spent meeting the criteria of office systolic BP ≤140 mmHg and/or ambulatory systolic BP ≤130 mmHg.

TTR appeared to rise from 28.2% at 3 months to 34.9% at 3 years in the study, perhaps reassuring data for those worried about waning BP control after the procedure.

Safety events after renal denervation included end-stage renal disease (1.9%) and creatinine elevation >50% (1.3%).

Renal Denervation vs Sham for TTR

According to the SPYRAL HTN-ON MED analysis, people randomized to radiofrequency renal denervation spent more time in TTR without taking more antihypertensives than sham controls.

This was evident whether TTR was defined as time in office systolic BP ≤140 mmHg (28.0% vs 13.0%, P=0.015) or ambulatory systolic BP ≤140 mmHg over 36 months (47.8% vs 32.0%, P=0.036), Kandzari told the audience at EuroPCR.

"The greater stability of BP control after renal denervation is supported by an 'always on' effect, differentiating renal denervation from the variabilities of drug pharmacokinetics, dosing regimens, and patient adherence," he said.

Kandzari acknowledged that the question of denervation's effect on cardiovascular events requires further work with larger samples than the one in SPYRAL HTN-ON MED.

Recently, his group reported that the study's denervation cohort maintained a through 36 months of follow-up -- the benefit perhaps even growing with time.

The trial had 80 people taking BP meds randomized to renal denervation using the multi-electrode Symplicity Spyral catheter or sham. Study participants were at baseline 54 years old on average, and over 80% were men. Office systolic BP averaged 164 mmHg in both groups.

At the 6-month mark, medication changes were allowed. Denervation and control groups stayed taking a similar number of antihypertensive drugs through follow-up.

Like in the registry study, TTR here was calculated by linear interpolation between follow-up BP measurements. Imputations were also made for sham controls who crossed over to renal denervation, according to Kandzari.