Updated March 25, 2012 (Chicago, Illinois) — An intriguing finding is emerging from longer-term follow-up of clinical studies of renal denervation for severe resistant hypertension: some initial nonresponders are, in fact, showing drops in blood pressure months after the intervention, prompting doctors to deem these patients slow responders rather than nonresponders.

In one of a series of presentations here today at the American College of Cardiology 2012 Scientific Sessions, Dr Paul A Sobotka (Ohio State University, Columbus) reported that among 45 patients initially deemed nonresponders immediately after renal denervation in the Symplicity HTN-1 trial, 58% responded (defined as a systolic BP reduction of 10 mm Hg or more) three months after the procedure, 64% by one year, 82% by two years, and 100% by three years.

Dr George Bakris

Program cochair Dr George Bakris (University of Chicago, IL) told heartwire :"The sexiest message is the fact that the nonresponders are responding over time. Nobody understands why, but it's definitely a huge novel finding in terms of better understanding what this whole thing is doing. We are learning as we go."

Sobotka reported additional results with the Symplicity catheter (Medtronic) from Symplicity HTN-1 out to three years: the treatment effect of renal denervation appears to be significant, sustained, and consistent across subgroups, he noted, including the elderly--in whom he said it may be a particularly beneficial therapy--and those with diabetes and those with renal impairment. And there do not appear to be any major safety issues with the intervention, he said.

Meanwhile, Dr Murray Esler (Baker IDI Heart and Diabetes Institute, Melbourne, Australia) reported one-year data from the Symplicity HTN-2 study; six-month results were first released at the AHA 2010.

Dr Paul A Sobotka

One sticking point, however, may be the seemingly lesser effect of renal denervation on ambulatory (24-hour) blood-pressure measurement (ABPM). ABPM was not measured consistently in the Symplicity HTN-1 and -2 trials, but a few single-center experiences in Europe reported ABPMs at the session today with mixed results. ABPM is set to play a central role going forward in terms of gauging the success of this technique and could turn out to be the "fly in the ointment," cochair Dr Suzanne Oparil (University of Birmingham, AL) told heartwire .

ABP and Blinding Key in Symplicity HTN-3

Dr Axel Bauer (Eberhard Karls Universitat, Tuebingen, Germany) reported on ABPM outcomes after renal denervation in a small series of patients from his institution, saying that although the effects of office BP and ABPM were well correlated, the effects of renal denervation appear be "much less pronounced" when the latter was used as the outcome; in fact, he and his colleagues found only borderline significance of the intervention using APBM reduction.

Oparil commended Bauer: "Congratulations on a heroic effect to get all the ABPMs, which is very difficult to do. [ABPM] is clearly one of the questions that remain with this technique."

Dr Michiel Voskuil (University Medical Center, Utrecht, the Netherlands), who reported on 28 patients treated with the procedure at his institution, also did not find a significant effect of renal denervation when ABPM was used as the outcome. And in another report on their initial experience with this technique, Dr Darren Mylotte (Institut Cardiovasculaire Paris Sud, France) and colleagues found that the effect of renal denervation on ABPM is "less dramatic" than its effect on office BP, Mylotte said.

Dr Darren Mylotte

But Sobotka stressed to heartwire that the independent studies performed by these investigators showed office BP reductions that were identical to the reductions seen in the Symplicity trials and that the ABPM reductions--although lower than the office BPs, as would be expected-- were commendable. "The ABPM lowering in Mylotte's study was, at an average of 21 mm Hg, a huge reduction, the largest reported to date," he noted.

[ABPM] is clearly one of the questions that remain with this technique.

Oparil underscored that "more still needs to be known about the out-of-office BP," which is recognized as a more robust, objective end point, she reiterated.

Bakris agreed that ABPM is "critical" and pointed out that in the pivotal US trial of renal denervation, SYMPLICITY HTN-3, which is ongoing, "everybody is going to have an ABPM."

And he noted that another often-quoted limitation of the existing Symplicity trials--the fact that there was no sham procedure--is being addressed in SYMPLICITY HTN-3. Esler agreed this was a "potential weakness. If you do these high-tech things, the placebo response potentially can be great, but this is being corrected in the pivotal US study, where there is actual blinding."

One-Year Symplicity HTN-2 Data and Real-World Results

The one-year data reported by Esler are the results from the crossover patients who originally acted as controls in Symplicity HTN-2; there were 35 of these patients.

A comparison of six-month BP outcomes in the early and late denervation groups showed that although those who did not have denervation until six months into the study (the 35 crossover patients) had good falls in office BP (average drop of 24/8 mm Hg), "the outcome was not quite as good, which partly represented a slipping during six months of medication only," Esler noted.

There were also a handful of safety issues, he said. One case of renal dissection during the procedure was successfully treated with renal stenting. One patient suffered severe hypotension that required hospitalization, but the long-term outcome was good and the patient ended up being a good responder, he noted. And there was another patient in the original control group (late denervation) who had several severe hypertensive episodes and needed hospitalization, "fortunately without any catastrophes," he noted. But this illustrates a potential cost of delaying denervation treatment, he noted.

"We now have one-year follow-up to complement the three-year follow-up that you heard [from Sobotka], which indicates that the procedure seems to be both sustained and safe," Esler concluded.

What's the Story With the Delay in Response?

Both Voskuil and Mylotte said that they set out to see whether the encouraging results from the Symplicity trials so far would extend out into the community. Voskuil observed, "A lot of us are thinking: What will be the result if we start to do this in real clinical practice?" Mylotte agreed: "The question is, are these results applicable to the real world?"

Voskuil found that more patients (five out of 28) were nonresponders to renal denervation compared with the Symplicity data, even when office BP was used as an outcome. "Our main finding is that we might see a higher number of nonresponders in the real world," he said, although he acknowledged that, given the findings reported by Sobotka, only time would tell whether these people were slow responders as opposed to true nonresponders. Mylotte, too, had three nonresponders in his series--9% of patients. "We will hopefully see if they turn out to be responders," he commented.

There was much speculation during the sessions as to what is happening with these patients who do not seem to immediately respond to renal denervation but have a later drop in BP.

Sobotka said: "The assumption had been that the nonresponders represented either inadequate treatment related to the device or the operator. That would not appear to be the case at this point. We can identify no patient or drug characteristic that predicts early nonresponse and late response. It's a wonderful area to begin to look into."

Esler commented: "We haven't done the fancy measures of renal sympathetic function on enough patients to apply that. It could well be that the magnitude of response is dictated by the importance of neural mechanisms in patients' hypertension, but we can't prove that, and I doubt that we ever will."

Sobotka is an advisor to Medtronic. Esler is chief investigator of the Symplicity HTN-2 trial and is a recipient of research grant, travel, and consultancy funding from Medtronic.

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