Renal denervation proceeds as U.S. trial’s flaws emerge

PARIS – At least three different factors undermined the SYMPLICITY HTN-3 trial that earlier this year did not show a significant difference in blood pressure lowering between renal denervation and a sham-control procedure, most notably the failure of the vast majority of operators in the study to follow ablation instructions and produce thorough and reliable interruptions of sympathetic innervation of the kidneys, according to new data released by the trial’s investigators.

As the full range of problems with the U.S.-based SYMPLICITY HTN-3 trial, which had its main results reported in April (N. Engl. J. Med. 2014;370:1393-1401), became apparent in a report at the annual congress of the European Association of Percutaneous Cardiovascular Interventions, many top European practitioners and supporters of renal denervation voiced their belief that the treatment is an effective and safe option for many patients with true drug-resistant, severe hypertension.

During the meeting, Dr. Felix Mahfoud, an interventional cardiologist at the University Hospital of Saarland in Homburg/Saar, Germany, joined with hypertension specialist Dr. Konstantinos Tsioufis of the University of Athens and Dr. William Wijns, codirector of EuroPCR, in an official statement from the meeting that despite the SYMPLICITY HTN-3 results they continued to support renal denervation as a treatment option for selected patients with drug-resistant, severe hypertension.

Their sentiment echoed another endorsement made a few weeks earlier for continued use and study of renal denervation from the European Society of Hypertension (ESH) in reaction to the SYMPLICITY HTN-3 results.

^{Mitchel L. Zoler/Frontline Medical News}

Dr. William Wijns

The ESH "sticks to its statement" from 2013 on using renal denervation in appropriate patients with treatment-resistant, severe hypertension (Eurointervention 2013;9:R58-R66), said Dr. Roland E. Schmieder, first author for the 2013 ESH position paper and a leader in European use of renal denervation.

"We need more studies to prove that renal denervation works, and in particular to get more precise information on which patients get the greatest benefit," Dr. Schmieder said in a separate talk at the meeting. For the time being, he said he was comfortable with routine use of renal denervation in patients with an office systolic BP of at least 160 mm Hg that remains at this level despite maximally tolerated treatment with at least three antihypertensive drugs, including a diuretic, the use endorsed by current European guidelines. It remains appropriate to investigate the impact of renal denervation on other disorders, such as heart failure, arrhythmia, metabolic syndrome, and depressed renal function, said Dr. Schmieder, professor and head of hypertension and vascular medicine research at University Hospital in Erlangen, Germany.

The problems with SYMPLICITY HTN-3

While much speculation swirled around what had gone wrong in the SYMPLICITY HTN-3 trial after researchers on the study gave their first report on the results early in the spring, the full extent of the study’s problems didn’t flesh out until a follow-up report during EuroPCR by coinvestigator Dr. David E. Kandzari. In his analysis, Dr. Kandzari highlighted three distinct problems with the trial that he and his associates identified in a series of post hoc analyses:

• The failure of a large minority of enrolled patients in both arms of the study to remain on a stable medical regimen during the 6 months of follow-up before the primary efficacy outcomes were measured.

• The inexplicably large reduction in BP among the sham-control patients, especially among African American patients, who made up a quarter of the trial’s population.

• The vastly incomplete nerve-ablation treatment that most patients received, treatments that usually failed to meet the standards specified in the trial’s protocol.

The background medical regimens that patients received proved unstable during SYMPLICITY HTN-3 even though the study design mandated that patients be on a stable regimen for at least 2 weeks before entering the study. Roughly 80% of enrolled patients in both the denervation and sham-control arms of the study had been on a stable regimen for at least 6 weeks before they entered. Despite that, during the 6 months of follow-up, 211 (39%) of patients in the study underwent a change in their medication regimen. The changes occurred at virtually identical rates in both study arms, and in more than two-thirds of cases were driven by medical necessity.

^{Mitchel L. Zoler/Frontline Medical News}

Dr. Felix Mahfoud

"The pattern of drug changes challenges the notion of maximally tolerated therapy," Dr. Kandzari said during his report. "Can this [maximally tolerated therapy] be sustained in a randomized, controlled trial?" It also raised the issues of how trial design can better limit drug changes.