April 14th, 2014
The Uncertain Future of Renal Denervation
Following the spectacular crash and burn of the SYMPLICITY HTN-3 trial at the American College of Cardiology (ACC) meeting two weeks ago, the future of renal denervation (RDN) — the once highly promising catheter technology that many thought would cure resistant hypertension — appears in doubt.
Although the device has not been approved in the U.S. — and will not be approved without further clinical trials — in Europe and other places it remains on the market. So the questions about the technology’s future revolve around the future direction of research in the field and how the existing renal denervation market will be affected by the trial results.
The uncertainty and confusion is driven by the very wide disparity between the findings of the SYMPLICITY HTN-3 randomized controlled trial, which found a vanishingly small blood pressure lowering effect for RDN when compared to controls who underwent a sham procedure, and the SYMPLICITY global registry, which found a very large effect similar to that seen in all the other previous uncontrolled or poorly controlled trials.
Medtronic, which manufactures the Symplicity RDN system and sponsored the SYMPLICITY HTN-3 trial, said that it “remains committed to advancing renal denervation.” The trial “confirmed the profound safety of the Symplicity system,” the company said. “We do not believe… that this trial proves renal denervation does not work; further clinical research is needed to confirm this hypothesis.” The company said that “a panel of independent experts made up of global physicians and researchers… affirmed that Medtronic should continue to provide access to the Symplicity system as long as the company continues to study it, which we intend to do. Medtronic believes physicians should make clinical decisions based on the totality of evidence, including their own independent experience.”
Boston Scientific said its own RDN technology is “highly differentiated” from Medtronic’s and is “supported by compelling clinical evidence and a strong clinical program.” The company has yet to determine its next steps.
Michael Böhm, who presented the registry findings at the ACC meeting last month, supports the continued clinical use of the device, especially in carefully chosen patients with uncontrolled hypertension who have exhausted other options and when performed by experienced operators. The operators in the registry, he said, had far more experience with the procedure than the operators in SYMPLICITY HTN-3. Along with others, he noted that there are currently no objective ways to measure the technical success of the procedure. It is possible, he said, that the greater experience of the registry operators produced better results.
Many commenters at the ACC meeting struggled to strike a delicate balance. There was wide agreement that research in renal denervation should continue, but many thought use of RDN outside of a clinical trial was hard to justify. But since the device remains on the market in many countries, and since there is little precedent for removing a product from the market once it has gained approval in the absence of a safety issue, some believe that the decision to employ RDN should be left to the individual physician.
Not Steve Nissen. “I think sales should be suspended,” Nissen told Reuters. “You (now) have a trial with no evidence it works.” PK Shah told Reuters that physicians in Europe “would be better off doing the right clinical trials and perhaps putting a short-term moratorium” on RDN except in the context of a clinical trial.
The new president of the ACC, Patrick O’Gara, said he thought that some patients may have benefited from RDN. “We need to convene a group of experts to weigh the positives and negatives of a moratorium,” O’Gara told Reuters.
Speaking on behalf of the European Society of Cardiology, François Schiele told me that RDN “should not be used except in clinical trials,” but he was clearly unhappy with the current situation. As a former strong believer in RDN, he said “it is difficult for me to understand that it doesn’t work.”
At a Late Breaker Deep Dive session, Robert Califf said that physicians should “hold off on clinical use until someone can produce rigorous supportive data using God’s gift of randomization.” He also said it “would be good to have a functional assay” to measure the effect of the catheter procedure.
Milton Packer defended the use of sham procedures because “there’s so much bias in the wonderment of having done something to somebody.” “Procedures,” he said, “are fundamentally a religious experience.”
Darrel Francis, who predicted early on that SYMPLICITY HTN-3 would not meet its primary endpoint, said that the registry does send “a resoundingly clear message” that Symplicity “is safe, which is of paramount importance for patients.” But the results of SYMPLICITY HTN-3 “teach crucial lessons in human behaviour, underlining for us why we must do blinded randomized controlled trials on these questions if we want the real answer.”
We need to look carefully through the SYMPLICITY 3 data to help design future trials that will have a better chance of detecting effects that are smaller than we hoped, and may be more variable than we guessed. I hope we are witnessing the origin of a new interest in meticulous methodology.”