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As has been known since January, renal denervation with Medtronic's Symplicity catheter was safe, but it was no better than a sham procedure for reducing office blood pressure in the SYMPLICITY HTN-3 trial, full results showed.

Through 6 months, office systolic blood pressure dropped by 14.13 mm Hg in the denervation group and by 11.74 mm Hg in the sham-control group, which received renal angiography alone (P<0.001 for both from baseline), yielding a between-group difference of only 2.39 mm Hg (P=0.26 with a superiority margin of 5 mm Hg), according to , of Brigham and Women's Hospital in Boston.

The findings were published online in the and simultaneously presented as a late-breaking clinical trial at the American College of Cardiology meeting here.

There were no differences between the groups in the occurrence of major adverse events.

Likewise, the reduction in average 24-hour ambulatory blood pressure in the denervation versus the sham-control group yielded a nonsignificant difference of only 1.96 mm Hg (6.75 versus 4.79 mm Hg, P=0.98 with a superiority margin of 2 mm Hg).

The failure of the trial -- which was initially reported with little data in January -- was not surprising to some, as Bhatt and colleagues acknowledged in their paper by pointing to a meta-analysis published last year that predicted that carefully conducted, randomized studies of renal denervation would fail to show the dramatic reductions in blood pressure observed in unblinded and uncontrolled studies. Those studies have led to widespread use of the technology around the world, although it has not been approved in the U.S.

"These results underscore the importance of blinding and sham controls in evaluations of new devices and have ramifications that go beyond interventional cardiology," Bhatt said. "Further study in rigorously designed clinical trials will be necessary -- and, indeed, such studies are warranted -- to confirm previously reported benefits of renal denervation in patients with resistant hypertension or to validate alternate methods of renal artery denervation."

SYMPLICITY HTN-3 differed from prior studies of renal denervation in that it had a sham-control group. The trial randomized 535 patients with resistant hypertension -- all had a systolic blood pressure of 160 mm Hg or higher in the office despite taking maximally tolerated doses of at least three antihypertensives, including a diuretic -- in a 2:1 fashion to denervation with the Symplicity catheter (which applies radiofrequency energy) or renal angiography only (the sham-control). Patients were taking an average of five antihypertensives.

Although renal denervation did not have an advantage for blood pressure reduction over the sham procedure, it was shown to be safe. The primary safety endpoint -- a composite of all-cause death, end-stage renal disease, embolic events resulting in end-organ damage, renovascular complications, or hypertensive crisis at 1 month or new renal-artery stenosis of more than 70% at 6 months -- occurred at similar rates in the denervation and control groups (1.4% versus 0.6%, P=0.67). There were no differences in kidney function at any point in the study.

The trial did address some of the limitations of prior studies, but it had some of its own shortcomings, according to Bhatt, including the fact that drug adherence was not confirmed through blood testing, the relatively short follow-up, the possible influence of operators who were inexperienced with renal denervation, and the lack of a direct measurement of whether the renal arteries were actually denervated.

Cardiologists who commented on the study had various explanations -- some related to those shortcomings, particularly the inability to assess the quality of the denervation -- for why the study failed to show a benefit of the intervention.

"It may not be that the procedure doesn't work, but that the technique was not adequate," according to , medical director of research at Carolinas HealthCare System's Sanger Heart & Vascular Institute. "This could suggest that we need better devices, which are more complete in their denervation and in a more targeted way."

Other potential explanations for the failure to show a difference between the two groups included the placebo effect, the Hawthorne effect (where behavior -- adherence to treatment, in this case -- improves when someone is paying close attention), patient selection, the lack of experience for many of the operators, or some problem with the Symplicity device itself.

"But we don't really know these things for sure, and I don't think we're ever going to come up with one smoking gun per se," said , an interventional cardiologist at Columbia University Medical Center in New York City. "I think it's likely multifactorial, but I don't think the field is dead."

Nobody else was ready to kick the technology into the grave either.

"A single trial showing negative results shouldn't end our efforts, and we need to try harder to figure out which patients respond positively and which patients do not," Rinaldi said.

Despite having a front row seat for the trial's failure, Bhatt said he still remains "cautiously optimistic" about renal denervation's chances.

"I don't think the field should end," he said. "Future investigations should occur, but in a careful way. And the first step has got to be to make sure we are actually denervating on a biological level."

But of the Mayo Clinic in Rochester, Minnesota said he believed the results should dampen enthusiasm for renal denervation and should, he said, severely limit its use in the U.S.

From the American Heart Association:

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