Key Points:
- Achieving hypertension control has remained an elusive goal in the US and globally, and procedural treatments like renal denervation have gained traction as a means to successfully overcome non-adherence to traditional lifestyle and medical treatment for hypertension.
- The TARGET BP I investigated a novel percutaneous device, capable of injecting a small amount of alcohol into the renal artery perivascular space, to achieve a circumferential and confluent (yet self-limited) arc of ablation of the sympathetic nervous system.
- Between 2019 and 2023, 301 patients with hypertension despite treatment with 2-5 medications were randomized 1:1 to renal denervation or sham control. At 3 months of follow-up, there was a modest but statistically significant reduction in 24-hour ambulatory systolic blood pressure (-10.0 ± 14.2 mm Hg versus -6.8 ± 12.1 mm Hg, i.e. a delta of -3.2 mm Hg with 95%CI -6.3 to 0.0, P=0.049), but no reduction in office systolic blood pressure, nor office or ambulatory diastolic blood pressure. This was in the context of an alarmingly high rate of medication non-adherence in both arms (50-60%).
- While encouraging, these results require confirmation via longer follow-up beyond 3 months, in order to understand whether alcohol-mediated renal denervation will demonstrate persistent reduction in blood pressure and perhaps show a larger advantage of the sham control arm, which may be expected to further worsen in hypertension control over time.
Achieving hypertension control has remained an elusive goal both in the US and at the global level. As such, there has been an increasing effort to develop alternative treatment strategies that can overcome low adherence to lifestyle interventions and/or traditional medical treatment. Among those, renal denervation (i.e. denervation of the sympathetic nervous system around the renal arteries to lower blood pressure) has gained increased attention among patients with uncontrolled hypertension, and ultimately gained FDA approval in 2023, both for ultrasound- and radiofrequency-based percutaneous technologies.
To date, however, no biomarkers have been identified to confirm peri-procedural or long-term success for complete denervation, and thus the search also continues for additional denervation strategies that may achieve durable results. Among the most recent investigations, a percutaneous catheter platform has been developed, which can allow for puncture of the renal arteries (and accessory renal arteries) in order to deliver 0.6 mL of dehydrated alcohol into the adventitial perivascular space. Due to its diffusion characteristics, in turn, alcohol can allow for a circumferential and confluent (yet self-limited) arc of ablation, and perhaps achieve more durable and predictable renal denervation – potentially through a single procedure, which may also minimize patient discomfort.
The TARGET BP I trial was designed to address this important question, and the results were presented by the principal investigator, Dr. David Kandzari, (Piedmont Heart Institute Atlanta, Georgia) as a late-breaking clinical trial at the annual American College of Cardiology (ACC) scientific session, held this year on April 5-8th in Atlanta, GA.
This was a randomized, blinded, multi-center, international, sham-procedure controlled trial, comparing alcohol-mediated renal denervation in the treatment group to the sham control group (no alcohol infusion). Between May 2019 and April 2023, a total of 1,414 patients across 99 centers in 9 countries were screened for the trial, and ultimately 301 were randomized 1:1 to either renal denervation (n=148) or sham control (n=153). To qualify for the trial, patients needed to have primary hypertension with office systolic blood pressure ≥150 and ≤180 mm Hg, office diastolic blood pressure ≥90 mm Hg, or 24-hour ambulatory systolic blood pressure ≥135 and <170 mm Hg, despite the use of 2-5 anti-hypertensive agents; furthermore, their renal artery diameter had to be 3-7 mm (for procedural purposes). Exclusion criteria included type 1 or uncontrolled type 2 diabetes, chronic kidney disease with eGFR <45 mL/min/1.73 m2, and chronic atrial fibrillation. The primary endpoint was the between group difference in 24-hour ambulatory systolic blood pressure at 3 months of follow-up.
Enrolled patients had a mean age of 55 years, with ~75% male, 10% with chronic kidney disease (eGFR 45-60 mL/min/1.73 m2), and a balanced distribution of 2, 3, 4 and 5 prescribed anti-hypertensive agents at baseline (20-30% in each category). Despite medical treatment, the baseline office systolic BP was 164 mm Hg in both arms, with office diastolic BP 100 mm Hg, and mean 24-hour systolic BP of 146 mm Hg. The mean procedural time for renal denervation was 55 ± 27 minutes (versus 34 ± 24 minutes in the sham control arm), with a mean of 2.2 renal arteries treated per procedure. Furthermore, renal denervation required on average 11 ± 8 minutes of fluoroscopy and 96 ± 47 mL of contrast, versus 3 ± 3 minutes of fluoroscopy and 40 ± 23 mL of contrast in the control arm.
At 3 months of follow-up, the mean reduction in 24-hour ambulatory systolic BP was -10.0 ± 14.2 mm Hg in the renal denervation arm, compared to -6.8 ± 12.1 mm Hg in the sham control arm, i.e. a delta of -3.2 mm Hg (95% CI -6.3 to 0.0) P=0.049. Perhaps due to such unexpectedly high reduction of BP in the sham control arm, there were no significant differences in the BP reduction in office systolic BP, nor in office or ambulatory diastolic BP. Using blood and urine levels, non-adherence to anti-hypertensive medications prescribed at baseline was tested in both groups, and found to be similarly high in both arms both at baseline (~60%) and at 3 months of follow-up (~50%). Reassuringly, the alcohol-mediated renal denervation procedure was found to be overall safe, with similarly low (<1%) rates of major vascular complications, and >99.5% renal vessel patency at 6 months of follow-up.
When interviewed about the study results, Dr. Kandzari commented that it is difficult to fully explain the confounding impact that these high levels of medication non-adherence may have had on the study results in both arms. Furthermore, he explained that longer follow-up is needed to understand whether alcohol-mediated renal denervation will demonstrate persistent reduction in blood pressure and perhaps show a larger advantage of the sham control arm, which may be expected to further worsen in hypertension control (as already demonstrated with other renal denervation platforms).