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Intuitively, it made sense: a renal denervation system that could safely reduce blood pressure in treatment-resistant hypertension patients. There was a boom of positive observational data -- but then came the bust of failed randomized trials. Several years later, however, some are not ready to give up on the treatment just yet.

"There was a quick and enthusiastic start suggesting that renal denervation worked before widespread application in Europe," in the words of , of Saarland University Medical Center in Germany. So what went wrong?

Early skeptics predicted that major blinded randomized studies would not favor renal denervation. A group led by , of Imperial College London, pointed out a trend in blood pressure reductions: the dramatic results obtained from office readings were never matched by ambulatory monitoring.

The observations came just months after positive data from SYMPLICITY HTN-2 were released. A large registry study also suggested that Medtronic's Symplicity device was tied with a 28/18 mm Hg reduction in blood pressure among patients with the highest baseline systolic blood pressure.

In 2014, Howard's prediction came true. The Symplicity procedure was shown to be no better than a sham in reducing office-based blood pressure at 6 months, according to the presentation of the pivotal SYMPLICITY HTN-3 trial at the 2014 annual conference of the American College of Cardiology. Medtronic deemed the failure important enough to announce months in advance -- along with its plans to halt SYMPLICITY HTN-4.

Believers in renal denervation came up with various ways in which SYMPLICITY HTN-3 could have been a bad trial. Many pointed to the confounders that could have felled SYMPLICITY, chief among them adherence to therapy, procedural variability, and the populations studied.

"I think overall we shouldn't throw the baby out with the bathwater. We have to learn what went wrong in HTN 3," Mahfoud told 番茄社区app.

After the flop, "there remained compelling evidence to continue with investigation of renal denervation for hypertension, although the procedure could not be recommended at this point for use in routine clinical practice," said , of Piedmont Heart Institute in Atlanta.

For instance, "we had to learn the key patient population that should be considered for renal denervation," Mahfoud said. "What we have also learned is to finally pay attention to how the procedure is done. Renal denervation was once considered a procedure that everyone can do."

Ongoing studies are taking "a very different approach" from their predecessors, agreed Kandzari, who told 番茄社区app in an email that they now include patients with "office systolic blood pressure 150-180 compared with average 180 in HTN3."

In addition, there is "greater oversight to patient adherence and physician prescriber behavior to reduce confounding effects, and a focus on less variable and more independent endpoints (e.g., ambulatory blood pressure monitoring instead of office blood pressure).

"Trial designs also permit potential demonstration of biologic efficacy both in the context of an on- and off-medication population -- the latter analogous to pharmaceutical hypertension trials. And finally, renal denervation is being evaluated with different techniques and technology to potentially achieve greater procedural efficacy."

Two such trials attempting to right old wrongs are and , the results of which Mahfoud predicted would be presented next year. One key development in these new studies is the use of the new Symplicity Spyral multi-electrode catheter. Together, the randomized, blinded trials will provide more data on patients with or without antihypertensive medication.

"There is a lot of enthusiasm back in the field. We are conducting good and scientifically sound trials at the moment," Mahfoud said.

St. Jude Medical and Boston Scientific are no strangers to the ups and downs of zapping renal nerves either. Both companies have ongoing efforts to show a benefit with their EnligHTN and Vessix devices, respectively.

But adding some more competition -- and intrigue -- are the new players entering the gauntlet. They bring with them novel techniques beyond -- namely intravascular drug delivery, /, and catheter-based , according to Kandzari.

Mahfoud expressed particular interest in the idea of . One device features three needles that infuse alcohol into the perivascular space of the renal artery. "If it works, you can specifically target alcohol to destroy only the nerves in the renal artery. That is an interesting approach," he said.

"Ultimately we have to pay attention when we go into the artery such that we have clear protocol for each specific device," Mahfoud warned. "One size doesn't fit all."

Kandzari commented that although certain technologies may provide different advantages, each must be considered independently for safety and efficacy. "A class effect cannot be assumed," he emphasized.

"However, what is common to all renal denervation therapies to date is that there is no measure or biomarker of procedural efficacy, nor a procedural predictor of treatment effect, and this is an area of active investigation."

In light of these obstacles, "what keeps us optimistic is that we have sound physiology and we have randomized controlled trials," said Mahfoud.

"There are reasons why we think renal denervation could work. If you ask me personally, I see many patients that benefit and I hope we can show with the rigor of a scientific trial that renal denervation is superior to a sham procedure."

And if, more than a hundred trials later (according to clinicaltrials.gov), renal denervation ends up never working?

There are other indications for curbing high sympathetic activity, Mahfoud answered, citing ventricular tachycardia as one example. Pulmonary vein isolation "is certainly a new area where denervation could be useful."

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