The US Food and Drug Administration (FDA) is expected to have data next year that could lead to approval of a renal denervation device to lower blood pressure—but will the data be strong enough to sway skeptics?
Medscape interviewed three cardiologists to help answer this and other questions about this procedure, which is investigational in the United States but has the CE mark in Europe.
Renal denervation—where nerves in the wall of the renal artery are ablated by applying radiofrequency pulses or ultrasound to the renal arteries, to blunt their activity—dramatically lowered systolic blood pressure in early non–sham-controlled trials of patients with hypertension.
However, enthusiasm for the procedure was dampened in 2014, when the SYMPLICITY HTN-3 trial using the first-generation Symplicity (Medtronic; Minneapolis, Minnesota) catheter did not lead to better blood-pressure lowering than a sham procedure.
Since then, 3-month and 6-month outcomes from initial patients enrolled in three sham-controlled trials[3,4,5] of second-generation devices have hinted that the procedure confers a "modest" blood pressure-lowering benefit with no safety issues.
"I think there's once again excitement about renal artery denervation, and that it's justified," said Deepak Bhatt, MD, Brigham and Women's Hospital, Boston, Massachusetts, co-primary investigator of the SYMPLICITY HTN-3 trial, which in his words "basically caused a reset in the field."
However, "we just have to be careful to demand a high quality and quantity of data before jumping on board too soon," he told Medscape, "so that history doesn't repeat itself."
Felix Mahfoud, MD, University Hospital of Saarland, Saarland University, Homburg, Germany, was hopeful that the device would become available in the United States sometime next year, while noting that "[t]he pivotal studies are being completed [in 2020], and it depends on the FDA's review and approval."
Franz H. Messerli, MD, professor of medicine and cardiology at the University of Bern, Switzerland, told Medscape that "despite that I'm exposed to [the use of renal denervation, in Switzerland], I'm still not 100% convinced."
Better Technology, but Uncertainties Remain
Since the field hit the reset button, the devices and procedure have evolved. Current second-generation devices include the Symplicity Spyral (Medtronic) multielectrode catheter that delivers radiofrequency energy to treat the renal arteries circumferentially and can ablate the distal renal artery and branch arteries, and the Paradise (ReCor Medical; Palo Alto, California) renal denervation system that uses ultrasound.
The RADIOSOUND-HTN trial, published in January 2019, hinted at better blood pressure lowering with ultrasound versus radiofrequency ablation. However, principal investigator Philipp Lurz, MD, PhD, Heart Center Leipzig at University of Leipzig, Germany, told theheart.org | Medscape Cardiology at the time that "it is too early to prefer one technology over the other."
For Bhatt, "ultimately if this is really going to fly, it has to be something...where the majority of well-trained physicians can actually do it. That doesn't mean that training wouldn't be necessary."
A lot of strides have been made, he added, and "hopefully as the technology improves, technique will matter less," like going from balloon angioplasty to advanced-generation drug-eluting stents.
Messerli thinks the technique can be learned quickly, but that the disappointing results of SYMPLICITY HTN-3 showed that operators need experience to get good results.
He cited a number of reasons for his continued skepticism. First, studies so far suggest that there is a "glass ceiling" of a 6-mm Hg lowering of ambulatory systolic blood pressure—which is less than that obtained with current classes of antihypertensive medications.
Second, patient responses vary greatly: In some, blood pressure drops but reverts to pretreatment levels after a few weeks, whereas in others, it stays lower longer.
Finally, there are no published clinical trial data beyond 3 years, and it is not clear whether the nerves may regenerate over time.
In contrast, Messerli said that if you give a patient antihypertensive medication, "blood pressure will be down within a few days...by about 10 to 12 mm Hg over 7 to 8 mm Hg," and it will stay down for the next week, month, year, or 10 years, "provided that the patient takes the tablet every day."
And it is well documented that "this [drug-induced] blood pressure reduction will reduce the risk for stroke, heart attack, and death over the next several years compared with no therapy."
Potential Candidates for Renal Denervation
So who might be eligible for the procedure if it were to gain FDA approval? According to Bhatt, if the ongoing pivotal trials are positive, catheter-based renal denervation may be considered for patients "who have high uncontrolled blood pressure that's prompting frequent hospital admissions."
However, he "and probably 99% of other referring physicians are going to be uncomfortable just doing a procedure on someone who could just be on a generic diuretic."
For Mahfoud—who practices in Germany, where the procedure is currently used—"the ideal patient is [someone] with combined systolic and diastolic hypertension, a high heart rate, and a younger age."
Messerli noted that in Switzerland, the procedure is "not used intensely," but it is used to treat younger patients who have never been on antihypertensive therapy and who do not want to take pills (eg, a young man who is about to do his military service), or patients who still have elevated blood pressure despite being on three to five antihypertensive medications.
"I would want to see in the current series of randomized trials successfully completed, good safety data on longer-term follow-up, and durable results before premature approval," Bhatt reiterated. The ongoing two SPYRAL trials are "really the ones that will potentially lead to FDA approval," according to Bhatt (Table).
He speculates that the modest blood pressure lowering with renal denervation may underwhelm many referring physicians and third-party payors.
Mahfoud's hospital group first performed the procedure on patients 9 years ago, and he said that they plan to publish longer-term results, noting that certain patients have sustained blood pressure lowering.
|Table. Three Pivotal Sham-Controlled Trials of Renal Denervation|
|Trial||Participants (n)||Intervention||Primary BP Endpoint||Primary Completion Date|
|SPYRAL HTN-OFF MED||433 with uncontrolled HTN, no medication||Medtronic Symplicity Spyral multielectrode renal denervation system||Δ SBP by 24-hr AMBP at 3 mo||June 2020|
|SPYRAL HTN-ON MED||340 with uncontrolled HTN on medication||Medtronic Symplicity Spyral multielectrode renal denervation system||Δ SBP by 24-hr AMBP
|RADIANCE II||225 with uncontrolled HTN on medication||ReCor Medical Paradise System||Δ daytime SBP by AMBP
AMBP = ambulatory blood pressure; BP = blood pressure; HTN = hypertension; SBP = systolic blood pressure
Meta-analyses Identify Knowledge Gaps
Recent optimism was spurred by the overall positive results from a meta-analysis of six sham-controlled randomized trials by Bhatt and others published in April 2019, as reported by theheart.org | Medscape Cardiology.
In an accompanying editorial, Sverre E. Kjeldsen, MD, PhD, Oslo University Hospital, Norway, and colleagues commented that despite the modest overall 6-mm Hg blood pressure-lowering effect, there is large variability in response, with 20%-30% of patients experiencing a "dramatic" decrease within 3 months after the procedure.
The editorialists speculate that "optimized patient selection and technical improvements may allow breaking the 'glass ceiling' of 6 mm Hg."
Similarly, a more recent review by Mahfoud and others concluded that the current trials have established the safety and efficacy of the procedure, and "we must now define how [transcatheter renal denervation] will fit into a clinical practice."
The accompanying editorial for that review  agreed that final data from the pivotal trials may "convince the last skeptic, thereby paving the way to proceed with clinical use of" renal denervation.
The editorialists highlighted that "4 major questions remain...: 1) How does it work?; 2) Whom to treat?; 3) How to treat?; and 4) How long does it last?"
Dr Bhatt reports grant support/research contracts with Abbott Vascular, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo/Eli Lilly, Medtronic, Sanofi-Aventis, The Medicines Company, and Chiesi. Dr Messerli has disclosed no relevant financial relationships. Dr Mahfoud is supported by Deutsche Gesellschaft für Kardiologie, Deutsche Hochdruckliga, and Deutsche Forschungsgemeinschaft and has received grant support and personal fees from Medtronic and ReCor Medical.
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Cite this: Will Renal Denervation for Hypertension Rise Again? - Medscape - Sep 16, 2019.