Shelley Wood

May 26, 2014

PARIS, FRANCE – No one could accuse EuroPCR 2014 of giving up on renal denervation following the negative results of the only large, randomized, sham-controlled trial of this cutting-edge technology.

In its plumpest program to date, this year's EuroPCR meeting once again had a dedicated track focused on catheter-based interventions for hypertension (and heart failure), featuring more than 60 renal-denervation sessions. These included live cases, new data, how-to sessions, plus additional poster and oral abstract sessions. The two frontrunner companies in this space, Medtronic and St Jude Medical, even had conference rooms named for them, hosting training and information sessions for the duration of the meeting, funded by unrestricted grants.

And the sessions were packed. Without question, the sexiest technology of last year's conference remained the hottest topic of 2014, with everyone seeking answers to the question: Why was SYMPLICITY HTN-3 negative when so many preclinical studies, phase 1 and 2 studies, and mushrooming registry data point to beneficial effects of sympathetic modulation via denervation of the renal artery?

Dr David Kandzari (Piedmont Heart Institute, Atlanta, GA), one of the steering committee members for SYMPLICITY HTN-3, acknowledged the unabated enthusiasm in Paris.

"At first glance I was surprised to see there was so much [renal denervation] in the 2014 program," he admitted. But only by examining the randomized control trial data and other studies addressing procedural techniques and patient appropriateness will researchers learn more about why the SYMPLICITY HTN-3 results were so strikingly at odds with smaller, nonrandomized studies, he said. "So I think the organizers intentionally directed the program toward focusing more on the science of renal denervation and what the next steps are."

More Insights From SYMPLICITY HTN-3

Kandzari presented a new analysis from SYMPLICITY HTN-3 focused on three variables that may have influenced efficacy in the trial: drug changes/drug adherence, patient population, and procedure-related factors.

For the first, he noted, patients in the study were required to be "stable" on their antihypertensive drug regimen for at least six weeks prior to trial enrollment. Yet during the trial, roughly two out of five participants required medication changes during the study, including 69% that were deemed "medically necessary."

"This challenges the notion that patients were on their maximum tolerated drugs and that they can be maintained on stable drug regimens," Kandzari said. Not only that, "it also highlights how different these trials are from clinical practice." For example, in SYMPLICITY HTN-3, patients in both the intervention and sham arms had, on average, eight points of contact where blood pressure and medication were being closely scrutinized, he said—a factor that would have helped boost BP control in both arms.

Another important factor to emerge in these exploratory analyses was race, he said. Just under one-third of patients enrolled in SYMPLICTY HTN-3, by design, were African American (this was, after all, the pivotal trial designed in consultation with the FDA required for regulatory approval in the US). And, when non–African Americans were analyzed separately, renal-denervation–treated patients experienced drops in office systolic BP that were significantly greater than the sham-control group, something not seen in African American patients.

This finding was part of a larger discussion at EuroPCR circling around the fact that the pivotal phase 3 trial, which enrolled 535 patients in the US, was designed according to findings from SYMPLICITY 1 and 2 . Those earlier trials were conducted in non-US patients whose distribution of risk factors and ethnic makeup is very different.

"I've been doing renal denervation since 2009, and I have never once seen an African American patient, or a black patient for that matter," Dr Thomas Zeller (Universitäts-Herzzentrum Freiburg, Bad Krozingen, Germany) said in a Friday session.

Technical Success in the Limelight

Not only were the patients different, so too was the experience of the operators performing the ablations. A hint of that appears in other factors Kandzari zeroed in on: technical success and procedure variability.

In Kandzari's analysis, the number of ablations per patient was significantly associated with the degree of procedure success, with patients who had the most ablations (>15 or >16 per patient) seeing average ambulatory systolic BP drops of –14.3 and –21.1 mm Hg, respectively, compared with drops in the range of 6 mm Hg for the sham comparator and denervation-treated patients who received just >8 or >9 ablations. The number of ablation "quadrants" also appeared to matter, with patients who had all four quadrants of both renal arteries ablated showing significantly greater systolic BP reductions.

"This highlights a technical issue," Kandzari said, although he cautioned that no single factor emerged that is exclusively responsible for the negative efficacy outcome of SYMPLICITY HTN-3. "You need to take all these data together to design how to do the next trials," he said.

Insights from the Global SYMPLICITY Registry

Dr Felix Mahfoud (Universitätskliniken des Saarlandes, Saar, Germany), one of the most prominent researchers and proponents in this space, also presented a new analysis from the single-arm GLOBAL SYMPLICITY Registry . Data from this large European series set chins wagging at the 2014 American College of Cardiology meeting because outcomes in the multicenter registry were so wildly at odds with the randomized controlled trial results.

At EuroPCR, Mahfoud presented predictors of success with renal denervation identified to date in the registry patients, treated in non-US countries where the devices have been approved. As previously reported by heartwire , the registry now includes approximately 5000 "real-world" patients enrolled at one of 231 sites in 37 countries. As with Kandzari's analysis, the number of ablations attempted per patient was significantly associated with better outcomes in the registry. A higher number of comorbidities, higher baseline office systolic BP, and male gender were also associated with bigger BP reductions. By contrast, nonresponders were typically taking a higher number of hypertension drugs.

Dr Felix Mahfoud [Source: EuroPCR]

Asked whether he thought the sheer volume of sessions in the EuroPCR program and forward momentum they implied was incongruous in light of the negative randomized controlled data, Mahfoud disagreed, pointing out that resistant and uncontrolled hypertension are "a great unmet need." "In clinical practice, we are facing rates of uncontrolled hypertension of 30% to 50%," he observed. Moreover, animal data and early clinical studies as well as postapproval registries in Europe all point to a benefit of renal denervation.

"We're learning that this is much more complicated than we originally thought," Mahfoud acknowledged, adding that he is not criticizing the quality of SYMPLICTY HTN-3. "It was a very important trial, and it made us all stop and [ask]: How we could improve the technology? What are the next future studies?"

It's entirely appropriate, he continued, that a meeting like EuroPCR tackle these questions. "What could happen is we say, 'this isn't working, so we'll stop.' But the problem I have with that is this [technology] is too young and too promising to stop now."

Moving Forward

And so it was that session after session at EuroPCR circled around the need for complete circumferential ablation, better patient selection, and better ways of confirming that the therapy was effectively delivered. In SYMPLICTY HTN-3, for example, 60% of patients had just one or no "ablation notches," suggesting that there was inadequate contact with the vessel wall. Moreover, as several presentations last week noted, many of the US operators in the randomized clinical trial had had no prior experience with the denervation catheter before treating their first trial patient.

Dr Steven Worthley [Source: EuroPCR]

Elsewhere, investigators studying other up-and-coming devices presented new longer-term data or outcomes with new and improved devices. Another long-time leader in this field, Dr Steven Worthley (University of Adelaide, Australia), presented six-month data in 39 patients from EnligHTN III , using the latest iteration of St Jude Medical's multielectrode device. In this study, which had no sham control, office systolic BP remained 25 mg Hg lower than baseline at six months, with four out of five patients experiencing SBP drops of 10 mm Hg or more.

This next generation device is the one the company plans to move forward with in its FDA-sanctioned trial, Worthley noted. EnligHTN IV was canceled late last year because of slow enrollment, but "expect an announcement soon," Worthley predicted.

More Answers, More Questions

In the meantime, debate persists as to whether any renal-denervation procedures should be performed outside of clinical studies. Five different catheter designs already hold CE Mark approval in Europe and are being used with varying degrees of enthusiasm in different healthcare environments. Everyone who spoke with heartwire agreed it was a good idea to limit their use to a research environment, although the definitions of "research" were mixed.

"I would advocate that all patients receiving renal denervation should be [included] in some form of early-stage randomized clinical trial, but even for a more clinically relevant perspective, in one of the large registries, such as [Dr Mahfoud] is doing in Germany," Worthley told heartwire . "We are still learning about this technology, so we need to glean all the information we can from patients receiving this therapy."

Kandzari, likewise, said, "In selected cases, it would be appropriate to perform renal denervation as part of clinical practice, but with the caveat that these patients are followed in some type of program, whether it's a registry or some other type of study program to monitor any BP changes, device safety, and medical compliance."

Data coming out now about responders and nonresponders "remind us that this procedure, which was initially positioned as such a simple procedure, is actually more technical than we might have initially appreciated," Kandzari added.

Patient Consent and Eligibility

Are would-be patients in Europe informed of the negative efficacy results from the sole randomized controlled trial before consenting to the procedure? Absolutely, said Mahfoud, who points out that in Germany the procedure is not reimbursed unless the patient is participating in a study. He said he starts by explaining to patients that the procedure has proved itself safe out to three years in registry studies and in the lone randomized trial and that the registry data point to significant reductions in BP, although these reductions were not seen in the sham-controlled study.

Finally, there's the question of how to ascertain whether patients are truly resistant-hypertension patients. Mahfoud, for his part, repeatedly used the phrase "resistant or uncontrolled hypertension" and said all he can do in the clinic is ask patients whether they are taking their drugs and encourage them to use prescription diaries.

"But taking the drugs or not taking the drugs, if they have a systolic BP of 200 mm Hg they are at high risk of stroke, and potentially that is an interesting patient population to investigate scientifically with renal denervation. You can say, 'okay, take your drugs,' but everybody makes their own decision whether to take them or not." Many, he points out, refuse on the basis of side effects, most commonly erectile dysfunction or gynecomastia. "What if you have a patient sitting in front of you who says, 'I will not take them'?" he said. "We need to take those patients into consideration."

No doubt different patients, who take or drop different medications, will be featured in renal-denervation studies at meetings to come. Some signals are already emerging. In the SYMPLICITY HTN-3 analysis that Kandzari presented, patients taking aldosterone antagonists were more likely to respond to renal denervation, whereas those taking vasodilators were more likely to be nonresponders—a finding, he says, that warrants further study.

Dr Jean Fajadet [Source: EuroPCR]

In the meantime, researchers and sponsors who've invested many years and dollars in this technology are clearly forging full-steam ahead. In the middle of a Thursday morning live-case session, EuroPCR course codirector Dr Jean Fajadet invited Mahfoud and European Society of Hypertension (ESH) secretary Dr Konstantinos Tsioufis on stage in the main auditorium to deliver a formal statement on the state of renal denervation, also published on the ESH website. This proved to be a somewhat staged affair, serving only to assure a no doubt already-persuaded audience that research efforts would and should continue.

Indeed, in a Friday morning session entitled "SYMPLICITY HTN-3: What should be the impact on clinical practice?" only two or three hands went up when the audience was asked whether the trial results would have any effect on their practice. A much bigger proportion said the trial would not have an impact, while the largest group abstained from voting.

Defending the Science

Asked about the heavy focus on renal denervation in this year's line-up, EuroPCR course codirector, Dr William Wijns (Cardiovascular Center, Aalst, Belgium), stood by the program he and his colleagues had put together.

"If you look at what's being discussed, all of it has the right critical spirit," he told heartwire. "I think the program has continued to explore and investigate what the role of sympathetic modulation can be or will be and the treatment of a number of disease states, including resistant hypertension. Of course we need to reflect on and take in the key learnings from SYMPLICITY HTN-3, but why should one trial all of a sudden erase all of the other data? The unmet need is still there."

Plus, he continued, there is mounting data from registry studies that continue to demonstrate dramatic, lasting BP drops with the procedure. "We have a constant dialogue here at EuroPCR, which is the cross talk between scientific evidence, trial data, publications, and clinical experience," Wijns said. "Our objective is trying to find the right blend between those in the interest of patients without compromising safety."

Mahfoud took a similar line, telling heartwire: "It would be great if the message were not that we are here at EuroPCR, running around unscientifically and saying that renal denervation is the greatest thing," he said. "You have to understand [SYMPLICITY HTN-3] is one trial, and when you look closely at the data, there are at least some issues that might lead you to question the overall effectiveness of the procedures in that trial."

Kandzari disclosed receiving grant/research support from Abbott Vascular, Boston Scientific, and Medtronic and consulting fees/honoraria from Abbott Vascular,Boston Scientific, Medtronic, Micell Technologies, and Terumo Medical. Mahfoud disclosed receiving research grants from Deutsche Hochdruckliga, Deutsche Gesellschaft für Kardiologie, and Saarlandisches Ministerium für Wissenschaft und Forschung; consultant/lecture fee/travel support from Medtronic, St Jude, Boston Scientific, Cordis, Berlin-Chemie, Boehringer Ingelheim (each <$25 000); and institutional support from Medtronic, St Jude Medical, ReCor Medical, and Boston Scientific. Worthley disclosed receiving honoraria from Medtronic (<$25 000) and St Jude ($25 000–$50 000). Wijns disclosed receiving institutional grant support from Abbott Vascular, Biosensors International, Biotronik, Boston Scientific, Cordis, Medtronic, and St Jude Medical. Zeller disclosed being a consultant for Abbott Vascular, Boston Scientific, Cook, Medtronic, and ReCor Medical (each <$25 000), and receiving institutional grant support from Bard-Angiomed, Biotronik, Boston Scientific, Cook, Covidien, Gore, Medtronic, ReCor Medical, St Jude Medical, and Volcano.


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