Alcohol-mediated renal denervation (RDN) significantly reduces 24-hour ambulatory systolic blood pressure (SBP) in patients with uncontrolled hypertension, results of a new phase 3 trial showed.
But the results, overall, are not as promising as researchers had hoped.
“We saw a modest but statistically significant difference in the primary endpoint, but there were no significant differences in other measures of blood pressure, including office systolic or diastolic blood pressure,” said lead author David E. Kandzari, MD, chief of the Piedmont Heart Institute and cardiovascular service line, director of interventional cardiology at Piedmont Heart Institute, and chief scientific officer for Piedmont Health Care, Atlanta.
The findings were presented at the American College of Cardiology (ACC) Scientific Session 2024 and published online on April 8, 2024, in Circulation.
The international, sham-controlled phase 3 trial called TARGET BP I included 301 mostly male patients, mean age 56 years, with uncontrolled hypertension despite antihypertension therapy. Most patients were prescribed three or more antihypertensive medications at baseline.
Patients were randomized to either alcohol-mediated RDN or sham control, consisting of diagnostic renal angiography only. In the intervention group, the infusion catheter (Peregrine Systems; Ablative Solutions, Inc.) delivered very small doses of dehydrated alcohol into the perivascular space of the renal artery to achieve circumferential ablation of the afferent and efferent sympathetic nerves.
Patients were blinded to treatment status by sensory deprivation and sedation during the procedure. Patients, the sponsor, and outcome assessors were also blinded, while the interventionalist performing the procedure was unblinded but not involved in patient follow-up.
Baseline mean 24-hour SBP/diastolic BP (DBP) was 146.3/87.2 mmHg for the RDN group and 146.2/87.6 mmHg for the sham control group, with a corresponding mean office BP of 164.3/98.4 mmHg and 163.9/100.0 mmHg for the RDN and sham control groups, respectively.
Each treatment involved administration of 0.6 mL dehydrated alcohol per renal artery with a maximum dose of 2.4 mL per patient.
Patients were assessed monthly through 6 months and then at 1, 2, and 3 years post procedure. Assessments included BP measurements, adverse events, and vessel patency, defined as an absence of renal artery stenosis > 60% diameter by imaging.
The primary efficacy endpoint was change in mean 24-hour ambulatory SBP from baseline to 3 months post procedure.
Here, the change was greater in the RDN group than in the sham control (−10.0 vs −6.8 mmHg) with a significant between group difference favoring RDN (−3.2 mmHg; 95% CI, −6.3 to 0.0; P = .0487).
Subgroup analyses according to age, gender, and ethnicity found no significant interaction, although there was a greater treatment effect of RDN than sham control in US vs non-US sites.
Mean changes in ambulatory daytime and nighttime and 24-hour BP were proportionally consistent with the 24-hour ambulatory SBP findings. There was no significant difference in 24-hour ambulatory DBP between RDN and sham control.
Unexpected Finding
There was also no significant difference in office BP between groups at 3 months, with a large BP reduction seen in the sham control group (−12.7 mmHg for the RDN cohort vs −9.7 mmHg in the sham group; difference, −3.0; 95% CI, −7.0 to 1.0; P = .173).
The unexpectedly large reduction in BP observed in the sham control group merits further study, said Kandzari.
Adherence evaluated through blood and urine testing showed 43% and 41% of patients in the RDN and sham control groups, respectively, were fully adherent to their prescribed medications at baseline (P = .712). At 3 months, these adherence rates increased to 51% and 49%, respectively (P = .765).
Rates of partial nonadherence were also similar between groups at all timepoints and did not vary statistically.
The authors noted adherence rates were considerably lower than reported in previous on-medication trials enrolling patients with lesser medication burden, and that the rate and degree of adherence varied at different timepoints.
The inconsistency of medication adherence could confound results and is a limitation of the study, although the proportion of patients demonstrating nonadherence was similar between groups at all time intervals, said the authors.
There were very few adverse events related to the device or the procedure.
The safety endpoint was occurrence of major adverse events (MAEs) including all-cause death, end-stage renal disease, significant embolic event resulting in end-organ damage or requiring intervention, major vascular complications, major bleeding events, post-procedural renal artery stenosis, and hypotension requiring intervention or antihypertensive medication change.
At 30 days, the proportion of patients with MAEs was 4.7% for the RDN group and none for the sham control group (P = .007). Most adverse events (4.0%) were related to hypotension requiring intervention or medication change.
By 6 months, cumulative occurrence of MAEs was similar between treatment groups (5.3% RDN vs 4.0% sham control; P = .224).
Renal function remained unchanged from baseline through 3 and 6 months in both the RDN and sham groups.
Important Work
During a press briefing, Jennifer A. Rymer, MD, an interventional cardiologist and assistant professor, Medicine, Duke University, said the study “is important work that really adds to the increasing body of evidence” on the role of RDN in patients with uncontrolled BP.
“This population very much mirrors the population we take care of in a routine clinical practice.”
She noted about 20% of study participants were prescribed five or more antihypertensive medications. “If you’re thinking about methods to offer patients to reduce their blood pressure when they’re already maxed out on blood pressure medicines, this potentially offers them another treatment option,” she said.
However, compliance was an issue even among patients who should be more be compliant as they’re getting more follow-up, said Rymer. “You can certainly imagine if there are these types of compliance issues within a clinical trial setting what it would be like in real world practice.”
Commenting for theheart.org | Medscape Cardiology, Samin K. Sharma, MD, director of the Mount Sinai Cardiovascular Clinical Institute, New York City, said injecting alcohol into the perivascular space of the renal artery is “very innovative” and could offer a “much cheaper” alternative to currently approved RDN procedures using radiofrequency or ultrasound energy.
He noted doctors use alcohol in other areas of cardiology, including for hypertrophic cardiomyopathy.
But he’s concerned about the possibility of alcohol getting outside the renal artery wall, as this could cause pain, fibrosis, and other complications. Although this doesn’t appear to have occurred in this study, Sharma noted the procedure was carried out by “very expert people.”
And the results are reported to only 6 months. “I want to see what happens at one or two years; if this alcohol is going to cause more fibrosis, we don’t know that yet.”
The TARGET BP I trial was funded by Ablative Solutions, Inc. Kandzari received institutional research/grant support and support for attending meetings from Medtronic and Ablative Solutions, Inc. and personal consulting honoraria from Medtronic and HyperQure and has equity in BioStar (none related to Ablative Solutions, Inc.). Sharma had no relevant conflicts of interest.
