New Data Add to Resurgent Renal Denervation Field

Additional analyses from the Global SYMPLICITY Registry and the RADIANCE-HTN SOLO trial, presented at the PCR e-Course 2020, help fill out the story of renal denervation as it continues to make a comeback as a treatment for uncontrolled hypertension.

Three-year results from the registry, presented by Felix Mahfoud, MD (Saarland University Hospital, Homburg/Saar, Germany), showed significant and durable reductions in blood pressure following denervation regardless of how many antihypertensive medications patients were taking.

And a look at patients from the sham-control arm of RADIANCE-HTN SOLO who ultimately qualified to undergo denervation, reported by Ajay Kirtane, MD (NewYork-Presbyterian/Columbia University Irving Medical Center, New York, NY), demonstrated significant drops in blood pressure as well.

There remains an unmet need when it comes to hypertension control, Kirtane said, noting that “even in 2020, we find that up to almost 40% of patients have [an] inability to actually control their blood pressure” despite the availability of safe and effective medications.

“One of the advantages of a device-based therapy to control blood pressure, like renal denervation, is that it can act independent of adherence and, in a sense, forms an always-on therapy for blood pressure control and as a result could be an important adjunct to the armamentarium that we have to control blood pressure today,” he said.

Global SYMPLICITY Registry

Mahfoud presented an analysis focusing on the impact of antihypertensive medication burden on the blood pressure reductions seen in the Global SYMPLICITY Registry, which has enrolled more than 2,860 patients who have undergone renal denervation with the Symplicity Flex or Spyral radiofrequency catheter (Medtronic) for uncontrolled hypertension or another condition associated with increased sympathetic activity. At baseline, office systolic BP was 166 mm Hg and 24-hour systolic BP was 155 mm Hg; patients were taking, on average, 4.6 different classes of antihypertensive medication.

By 3 years, there was an average drop of 16.7 mm Hg in office systolic BP and 9.2 mm Hg in 24-hour systolic BP, findings that were consistent in a sensitivity analysis confined to patients with baseline, 6-month, and 3-year measurements.

Reductions in office systolic BP were seen at 3 years regardless of the number of antihypertensive medication classes used by patients:

• One to two classes: 21.7 mm Hg
• Three classes: 17.1 mm Hg
• Four classes: 18.4 mm Hg
• Five or more classes: 15.2 mm Hg

This analysis, Mahfoud noted, was limited by the lack of adherence measurements in the registry. “It is quite difficult to assess rigorously the medication that patients really take because of nonadherence to medication, in particular in hypertension.”

Those reductions in blood pressure were observed even though medication burden overall changed only slightly—from an average of 4.56 medication classes at baseline to 4.39 at 3 years, which is probably not clinically meaningful, Mahfoud said.

Rates of adverse outcomes, including death (5.5%), CV death (2.9%), stroke (4.5%), and hospitalization for new-onset heart failure (4.0%), were in line with what would be expected in high-risk hypertensive patients, he reported, adding that a rate of new renal artery stenosis > 70% of just 0.3% indicates “excellent safety.”

“This study confirms the significant and clinically meaningful reductions in blood pressure that were sustained up to 3 years post-procedure,” Mahfoud said.

RADIANCE-HTN SOLO Crossovers

The RADIANCE-HTN SOLO trial randomized patients with elevated BP, after a medication washout period, to renal denervation using the Paradise ultrasound system (ReCor Medical) or a sham procedure and demonstrated a significantly greater drop in ambulatory daytime systolic BP at 2 months (primary endpoint). After that, medications were added back in to establish hypertension control. At 6 months, patients in the renal denervation group required fewer medications than those in the sham group (average 0.9 vs 1.3), and after adjusting for that difference, BP was still lower in the denervation arm. There were no major adverse events observed in either arm through 6 months.

After the 12-month follow-up, patients in the sham-control arm were offered renal denervation if they had a daytime systolic BP of at least 135 mm Hg or a daytime diastolic BP of at least 85 mm Hg on ambulatory monitoring. Kirtane presented results from the 31 patients who crossed over; they were taking an average of 1.2 antihypertensives at the time of crossover.

At 2 months after crossover, daytime systolic BP had dropped by an average of 11.2 mm Hg and daytime diastolic BP had fallen by 7.1 mm Hg. At 6 months, those figures were 12.2 and 8.6 mm Hg, respectively (P < 0.001 for all comparisons).

Most patients—71% at 2 months and 68% at 6 months—had a fall in daytime systolic BP of at least 5 mm Hg. In these responders, average reductions in ambulatory systolic BP were 17.7 mm Hg at 2 months and 20.6 mm Hg at 6 months.

Kirtane acknowledged that this analysis is limited by the fact that patients and physicians were unblinded after crossover, which could have influenced the results.

Nevertheless, he said, “the results are consistent with the primary SOLO results, and there was no drug titration in this protocol itself, so in a sense this provides some further reassurance regarding the durability of the procedure at least out to 6 months at the crossover point.”

Commenting after Kirtane’s presentation, Faisal Sharif, MBBS, PhD (University Hospital Galway and National University of Ireland Galway), said “this is another positive study that will add to . . . overall good news for renal denervation.”

Resurgence of Renal Denervation

The field of renal denervation has come a long way since the results of SYMPLICITY HTN-3, released in March 2014, showed that denervation with a first-generation Symplicity catheter did not result in greater BP reduction compared with a sham procedure. Researchers took the lessons learned from that trial and eventually started getting positive results from sham-controlled studies, first in a series of pilot studies like RADIANCE-HTN SOLO and then most recently in the pivotal SPYRAL HTN-OFF MED trial.

That turnaround was the subject of a talk at the PCR e-Course led by Mahfoud. He asked Konstantinos Tsioufis, MD, PhD (University of Athens, Greece), and Michel Azizi, MD, PhD (Paris Descartes University, France), what publication of the SPYRAL HTN-OFF Med trial means for clinical practice.

We can check the box it lowers blood pressure. We can likely check the box that it is safe. And we’re investigating new indications. Felix Mahfoud

Tsioufis said it means there is now a third pillar of antihypertensive treatment, in addition to lifestyle modification and drug therapy. “The modern clinician has the novel tool of renal denervation to be assisted in the better management of hypertension,” he said, noting that both the pivotal trial and the sham-controlled trials have shown that the treatment works in patients not on any medications but also as an adjunct in patients with severe hypertension and other comorbidities on several medications.

Azizi added that renal denervation is also lessening medication burden among patients, “so we hope that this will also help for the compliance or adherence to medication.”

Safety is a critical issue, Azizi continued, especially when considering use of an invasive procedure in patients with low CV risk. “You should not undergo a procedure which gives you an immediate risk which would be higher than your spontaneous risk,” he said. Though in the early days of renal denervation there were some complications related to catheterization of the renal artery, like dissections, the procedure is much safer in current practice. “Today, if we looked at different trials, [we see] zero complications in the short term and midterm.”

Moving forward, Azizi said, there remains a need to better identify which patients will have a response to denervation, because there is much variability between patients in its effects on blood pressure. He said targeting younger, more obese patients with increased sympathetic activation and combined systolic/diastolic hypertension “is probably one of the best things to do for our patients.”

Tsioufis agreed, but said there is a need for more long-term data on safety and efficacy and development of a procedural marker that operators can use to know that they have achieved complete denervation. Nonetheless, he said, “We are happy having one more tool in order to improve the blood pressure control, which should be the first priority.”

Mahfoud said, “We can check the box it lowers blood pressure. We can likely check the box that it is safe. And we’re investigating new indications,” including use in arrhythmias like atrial fibrillation. “So more to come. I think that was an important year, important steps that we made with respect to the investigation of renal denervation. We should all stay tuned.”

Note: Kirtane is a faculty member of the Cardiovascular Research Foundation, the publisher of TCTMD.