SYMPLICITY HTN-3 Results Continue to Spur Discussion
Several common theories as to why renal denervation failed to reduce systolic BP at 6 months in the SYMPLICITY HTN-3 trial can be dispelled, according to a presentation on Sunday at TCT 2015.
SYMPLICITY HTN-3 randomized 535 patients with severe resistant hypertension to renal denervation with the Symplicity Catheter System (Medtronic) or a sham procedure.
Darrel P. Francis, MA, MB, Bchir, MD, FRCP, of the National Heart and Lung Institute at Imperial College London, said one myth is that the trial results were “accidentally incorrect.” However, this is an “extremely unlikely explanation,” he emphasized. “The probability of a true 30-mm Hg effect accidentally emerging as small as 2.39 mm Hg — when the standard error is 2.3 mm Hg — is 1.7 x 10-33.”
Francis also ruled out several other theories, such as:
- That the decline in office BP was three times the size of the decline in ambulatory BP, because the white-coat effect was treated effectively by renal denervation. “This sounds good, except it would require that the white-coat effect be 20 mm Hg and completely terminated by denervation. It would be the first case of a complex biological phenomenon to be totally mediated by a single pair of nerves in the body,” he said.
- That the trial was underpowered because antihypertensive drug trials are typically much larger. This is not an adequate explanation because SYMPLICITY HTN-3 was “much larger than several other positive studies that were unblinded,” Francis said. “It also published its power calculation in advance, unlike the positive studies that were unblinded.”
- That U.S. operators of SYMPLICITY HTN-3 did not perform the procedure as well as did non-U.S. operators in previous studies. “The problem is there is no evidence that American interventionalists are particularly worse, and none of the previous unblinded studies reported the need for extensive training or an elaborate learning curve that produces that 10-fold difference in effect size,” he noted.
- That patients in the sham arm of SYMPLICITY HTN-3 may have increased their medications. Because SYMPLICITY HTN-3 was a blinded study, Francis asserted, this should have happened in both arms.
- That final measurements were taken too early rather than being repeated in long-term follow-up. “This is an inadequate explanation because, in the unblinded studies, it worked at such a time point,” he commented. “Moreover,... when SYMPLICITY HTN-3 finished its primary endpoint, it became unblinded. If a therapy works only when it is unblinded, what does that tell you?”
- That prescribing additional drugs to patients already receiving more than five antihypertensive therapies does not appear to substantially reduce BP and, therefore, renal denervation might follow a similar pattern. Unblinded studies show an approximate 30-mm Hg reduction in these patients, Francis said.
In a separate presentation, Felix Mahfoud, MD, of Saarland University Hospital, Homburg, Germany, discussed additional gray areas.There is a need to “optimize technique and technology,” he said. “We’re not talking about a drug that can be administered easily to every patient. We’re talking about a procedure, and there are physicians who are potentially carrying out these procedures in different manners.”Efforts also must be made to continue reconciling current evidence and to identify appropriate patients for device-based therapies, Mahfoud said.
“We have to ask ourselves whether all these patients who suffer from hypertension, with different phenotypes, respond to renal denervation in the same manner,” he said. “There are some very interesting studies ongoing, some of which will be released very soon, that hopefully will address some of these unresolved issues.”
- Francis received grant/research support from Medtronic and consultant/honoraria fees from CVRx, Medtronic, ReCor Medical and Vascular Dynamics.
- Mahfoud received research grants from Deutsche Hochdruckliga, Deutsche Gesellschaft für Kardiologie, Medtronic, Saarländisches Ministerium für Wissenschaft und Forschung and St. Jude Medical, and consultant/lecture fees from Medtronic and St. Jude Medical.