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SYMPLICITY HTN-3 substudy identifies predictors of BP response
PARIS — Changes to antihypertensive medication use, differences in study populations and procedural variability were among the confounding factors to renal denervation identified in a substudy of the SYMPLICITY HTN-3 trial.
With the recent presentation of SYMPLICITY HTN-3 at the American College of Cardiology Scientific Sessions confirming the safety but not the efficacy of renal denervation (Symplicity, Medtronic), David Kandzari, MD, FACC, trial investigator with Piedmont Heart Institute, Atlanta, presented a pre-specified, post-hoc analysis here at EuroPCR that examined the confounding factors impacting the efficacy results.
David Kandzari
“I know that many clinicians would walk away from [the SYMPLICITY HTN-3] data thinking it was strictly a procedural issue and it was a technical failure that led to the results. We can’t remind them enough that this is not the case,” Kandzari told Cardiology Today’s Intervention. “There is, from these data, no singular factor that led to the lack of efficacy of renal denervation in the trial. But at the same time, these data take us many steps further in identifying the factors that led to the negative result.”
In the substudy, Kandzari and colleagues identified the following multivariate predictors of systolic BP change at 6 month among patients receiving renal denervation: baseline office systolic BP ≥180 (–14.31 mm Hg; P<.0001); total number of attempts (–.935 mm Hg; P=.04); aldosterone antagonist use (–9.77 mm Hg; P=.002); and vasodilator use (7.55 mm Hg; P=.005).
For patients in the control group, baseline office systolic BP ≥180 (–8 mm Hg; P=.064), black race (–11.97 mm Hg; P=.003) and alpha-1 blocker use (–12 mm Hg; P=.044) were predictors of 6-month systolic BP changes.
A univariate P <.2 was required to enter the model, according to Kandzari.
Additionally, about 80% of patients in both groups were on stable medication regimens for at least 6 weeks prior to inclusion, and roughly 40% of patients had medication changes between baseline and primary efficacy endpoint assessment, 69% of which were considered medically necessary.
The researchers also found that change in office systolic BP at 6 months for black patients was –15.5 mm Hg for renal denervation vs. –17.8 mm Hg in the sham procedure (P=.641), whereas the reductions in non-black patients were –15.2 mm Hg in the renal denervation arm vs. –8.6 mm Hg in the sham arm (P=.012).
Kandzari and colleagues also observed increasing reductions in systolic BP that were associated with increasing numbers of ablations, a finding consistent for office and ambulatory BP, as well as heart rate, according to Kandzari. Specifically, the delivery of ablations in four quadrants of the renal artery was consistently associated with reductions in office, home and ambulatory BP.
Although cautious about looking at these data as a blueprint for the next renal denervation trial, Kandzari said these data do raise several factors that need to considered before moving on to the next trial.
“These data, along with all the other exiting renal denervation data, remind us that the field is not over with by any means,” he said. “However, what we don’t need is another negative trial because of poor design, planning or conduct. So these subgroup analyses are insightful in informing us how we need to be attentive to trial conduct, particularly around mitigating medication changes that are going to confound the results, and how we can mitigate against the placebo effect of being in trials, perhaps by having a longer duration of stability of being on medications in ensuring compliance before the patient is randomized.”
Kandzari added that there are specific considerations regarding how to design future trials in relationship to ethnic groups, “but probably more importantly around medications, and then of course the procedure itself and the technique,” he said. “The procedure and the technique are going to be unique for each technology and the sponsors of these trials and manufacturers of these technologies are really going to need to ensure that their technology is providing effective renal denervation. That is still an open-ended statement at this time, because we haven’t standardized the preclinical assessment for these technologies, nor have we determined the measure of procedural efficacy.” – by Brian Ellis
For more information:
Kandzari D. Hot line on resistant hypertension: Trial updates and registries. Presented at: EuroPCR; May 20-23, 2014; Paris.
Disclosure: Kandzari reports serving as a consultant for Zoll Medical.
Perspective
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It becomes clear from these data that we underestimated the role of the procedure, and that it is important to concentrate on the creation of an effective lesion in terms of the number of ablations and circumferential denervation. We are still in the phase where we are figuring out where the sweet spots are in terms of where to target the sympathetic nervous system in the renal arteries. But it's also clear that the data from SYMPLICITY HTN-3 are very different from what we are doing in clinical practice. In the Global SYMPLICITY Registry, there are very few patients who have been treated with four ablations per site, almost zero. I would say we are more actively denervating in terms of number of ablations and we are going more distal in the renal artery and even into the branches if they are large enough.
It is interesting to understand that there is a clear signal in these data, and that carries important information for us in routine practice, indicating that the concept of renal denervation is working, which is reassuring.