COMMENTARY

Renal Denervation: More Data, More Questions

Seth Bilazarian, MD; Steffen Desch, MD

Disclosures

September 19, 2014

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Seth Bilazarian, MD: Hi. This is Seth Bilazarian from theheart.org on Medscape, at the Transcatheter Cardiovascular Therapeutics (TCT) 2014 meeting in Washington, DC. I have the pleasure of being with Dr Steffen Desch from Lübeck, Germany, who is the principal investigator for the SYMPLICITY-FLEX trial.[1] This is a trial of using the Symplicity™ denervation catheter made by Medtronic (Mountain View, California).

This catheter has been used in the SYMPLICITY HTN-3 trial,[2] which I was involved with. I think those data are well known. That was a sham-controlled trial that failed to show a benefit of renal denervation.

I'm going to ask Dr Desch to review his trial, which was conducted in patients with less severe hypertension. I'm going to ask him to not only tell us the results, but to also highlight the differences between his trial and SYMPLICTY HTN-3, which enrolled patients with systolic blood pressures over 160 mm Hg on three or more maximally dosed medications (including a diuretic), As I said already, it failed to show a benefit compared with sham.

Tell us about your trial, and what was different and what you found.

Differences From HTN-3, and Key Findings

Steffen Desch, MD: The trial is different in that it included only patients with mildly elevated yet resistant blood pressure. We have the usual definitions of "resistant" (ie, three or more meds, including a diuretic, at optimal doses). The patients had mild elevations in blood pressure, defined as 135-149 mm Hg on ambulatory blood pressure monitoring (ABPM) 24-hour recordings, or 90-94 mm Hg diastolic.

At baseline, the daytime systolic blood pressure was 143 mm Hg in the renal denervation group and 144 mm Hg in the sham group. If you compare these values with the SYMPLICITY HTN-3 trial, this was 20 mm Hg less, so this is a much less hypertensive population. Otherwise, the design was pretty similar.

We had a sham procedure, similar to the one performed in HTN-3: We did a femoral access puncture and renal angiography, and we had an alarm clock that went off at two minutes. We tried to keep the procedure length and the room set-up similar to that for the actual renal denervation procedures.

Dr Bilazarian: What were the findings of your study of patients with minimally resistant hypertension -- because it's just over the goal of 140 mm Hg, compared with what we saw in HTN-3?

Dr Desch: Our primary endpoint was the change in 24-hour systolic blood pressure on ABPM. This is different from HTN-3, where an office-based blood pressure measurement was selected as the primary endpoint. We had an ABPM endpoint. In the intention-to-treat cohort, we had a reduction of 7 mm Hg in the renal denervation group and 3.5 mm Hg in the sham group; this was not a significant difference, with a P value of .15.

However we also looked at the per protocol population -- patients who actually underwent the therapies as written in the protocol. One patient randomized to sham control never received the sham procedure, and another patient had severe renal artery stenosis that was only detected after six months but had already been present at baseline, so this patient should have never been enrolled in the trial. A few patients were lost to follow-up, and two more patients had incomplete technical procedures with only one or two ablation runs owing to technical reasons. If you exclude all these patients and form the per protocol population, this difference between the treatment arms becomes significant, at a P value of .04.

Dr Bilazarian: Just to summarize: In this randomized trial, SYMPLICITY-FLEX, there was about a 4-mm Hg pressure difference in the intention-to-treat arm. Were there any other differences? Data[3] have been presented by one of the investigators of HTN-3, Dr David Kandzari, indicating that attempting more ablations seems to have a greater effect. Were there differences in the average number of ablation treatments in your trial compared with the HTN-3 trial?

Dr Desch: There were no significant differences. We only recorded complete ablations, and these were a little less than six per side: 5.7 and 5.5. We did not record the incomplete, interrupted ablations that seemed to have some kind of effect too in HTN-3. It seems that the number of total ablations, whether they are a complete two minutes or interrupted, plays a role, but unfortunately we didn't record the incomplete procedures.

Dr Bilazarian: You've presented six-month data today. Are you planning to show us 12-month data?

Dr Desch: Yes; we have 12-month follow-up coming up. Some patients are still missing at 12 months of clinical follow-up, so we'll see what we find at 12 months.

EU on Pause, and Future Trials

Dr Bilazarian: We practice on different continents. Your practice is in a continent that has very early adoption of technology, and I practice in a country that has very late adoption of technology. I obviously do not have access to this technology, and you do. How does your trial and SYMPLICITY HTN-3 inform your decision-making, and who are you currently using renal denervation in?

Dr Desch: We stopped using renal denervation as soon as the results of SYMPLICITY HTN-3 came out. In fact, we stopped it in January when the press release about the trial came out. I believe it's too early to resume. We need to make some major changes in the way we deliver this therapy, both from the technological side and from our patient selection. I think our new data are reassuring and give some hope for the future, but we need to change things.

Dr Bilazarian: Would you say that there's no renal denervation being done at many institutions in your country, or would you say it's still being reserved for the very extreme, resistant hypertension patients?

Dr Desch: I know some of my colleagues still use renal denervation occasionally in the really hard-to-treat refractory patients in the hope that it works, because it's a very safe procedure. But at my institution, we don't do it anymore. Recently, we've also had problems with reimbursement. Just continuing to do this procedure is certainly not the way forward. We need more scientific data.

Dr Bilazarian: In that vein, what would you recommend as a potential investigator for future trials? What should we fix in a next-generation trial?

Dr Desch: Let's focus on two aspects. One is the technical side of the procedure. We already have the new generation of catheters. Personally, I don't believe that the Symplicity Flex catheter is able to create circumferential lesions in all patients. This is simply not our clinical experience. It's really hard to tell whether the lesion was really circumferential or not, so the new-generation basket-like devices or spiral-like devices will probably be much better in that respect.

Dr Bilazarian: If I may just inform our audience: What you're describing is the Symplicity Flex catheter used in your trial and in the SYMPLICITY HTN-3 trial. It is just an end-hole catheter pressed against the wall of the renal artery at multiple sites.

Dr Desch: Yes.

Dr Bilazarian: And you were saying it was very difficult to evaluate circumferential ablation.

Dr Desch: Yes; this is very difficult. What seems to be clear now is that the number of ablation runs is important to the procedural success. This has always been plausible and intuitive, but the data we had never showed this in clear detail. Now it seems that we need more lesions. Because this procedure is safe, I would go for a lot more lesions. If I were to be treated, for example, I would probably go for 12-16 lesions per side; that's what I would do personally. This has to be proven in a trial, but I don't foresee any problems with doing a lot more lesions.

That is the technical side; the other one is patient selection. What we did so far was basically an all-comers approach. We included all kinds of patients, some of whom were probably presenting with sympathetic overactivity, but some were not.

Some patients adhere to medications, and some do not. We didn't have a good way of checking adherence in our trial. We need to include urinalysis, for example, in future randomized trials. In a patient who is medication-nonadherent, it is not very likely that that the primary mechanism for their hypertension is sympathetic overactivity. We need to exclude these patients to prove biological effectiveness, and then we might move onto further steps. But first we need to prove that this is a biologically effective therapy.

Dr Bilazarian: Other than adherence, you suggested that there could be clinical indicators of patients who are more likely to benefit. What do you mean by that?

Dr Desch: So far, we don't know. Some people have used clonidine in the past to identify patients. This has never been really proven to be a good strategy. This is something we have to work on.

Dr Bilazarian: Thank you very much, Dr Desch, for reviewing with us your study, the SYMPLICITY-FLEX trial, which was presented here at TCT, and helping to clarify the way forward in renal denervation. For now, you are really on pause in Europe, where these devices are currently available, while we try to sort these data out.

My hope is that industry won't give up on this. The number of patients with resistant hypertension may only be 5%, but it's 5% of an enormous hypertension population. If we had a device that could give us 10-15 mm Hg of blood pressure lowering, that could be a huge benefit. If it could give what was hoped for in the earlier HTN trials, a 30 mm Hg drop, we would be even more excited about reducing the pill burden for patients.

Thank you again for discussing this with me today. I look forward to future data on renal denervation. Until next time, goodbye from TCT in Washington.

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