Confounding factors may partially explain results of SYMPLICITY HTN-3

Post-hoc analyses derived from patient subgroups indicated several potential confounding factors that may help explain the unexpected BP results in the control and intervention groups from the SYMPLICITY HTN-3 trial, researchers reported.

SYMPLICITY HTN-3 evaluated the Symplicity renal denervation system (Medtronic) in 535 patients with treatment-resistant hypertension. Despite positive results from earlier studies, SYMPLICTY HTN-3 showed no difference in the primary endpoint of office systolic BP change at 6 months between patients assigned renal denervation and those assigned a sham procedure.

David E. Kandzari

David E. Kandzari, MD, and colleagues conducted post-hoc analyses to identify predictors of systolic BP change, examine the influence of medication changes, review results from selected subgroups and assess procedural factors.

Kandzari, director of interventional cardiology and chief scientific officer at the Piedmont Heart Institute in Atlanta, and colleagues found that 39% of patients underwent medication changes between randomization and 6 months.

Predictors of reduction in office systolic BP in both groups included a baseline office systolic BP ≥180 mm Hg, use of aldosterone antagonists and nonuse of vasodilators. In the renal denervation group, number of ablations also was identified as a predictor.

Differences by race

The treatment effect of renal denervation was more pronounced in nonblack patients compared with black patients, according to Kandzari and colleagues. Nonblack patients assigned renal denervation had a greater reduction in office systolic BP at 6 months compared with nonblack patients assigned the sham procedure (–15.2 mm Hg vs. –8.6 mm Hg; P=.012).

When the groups were propensity-score matched by baseline characteristics, differences in office systolic BP, ambulatory systolic BP and heart rate increased with a rising number of ablations in the treatment group; it was statistically significant for office systolic BP (P for trend=.01) and heart rate (P for trend<.01), as well as for ambulatory systolic BP in patients who received 12 or 13 ablations (P=.002). A similar but nonsignificant trend was observed in patients who had delivery of ablations in a four-quadrant pattern to at least one renal artery.

“The failure of [renal denervation] to significantly reduce [BP] in a well-conducted study provides an opportunity to redefine methods of study and endpoints that may more carefully reveal its potential,” Kandzari and colleagues wrote. “Findings from these analyses will considerably influence both preclinical investigation and performance of clinical trials related to further [renal denervation] study.”

Refined strategies needed

Felix Mahfoud

In a related editorial, Felix Mahfoud, MD, and Thomas F. Lüscher, MD, FRCP, wrote: “These results argue in favor of an incomplete and insufficient ablation of renal sympathetic nerves as a major cause of inadequate [BP] responses to catheter-based interventions and inevitably lead to some questions. Can catheter design and/or specific treatment strategies help to reduce the variability and increase conformity of the response renal nerve ablation? Does renal denervation exert a class effect of will different devices with distinct electrode designs and/or energy delivery show similar efficacy and safety?”

In future trials, “stabilization of medication and [BP] before randomization appears particularly important,” Mahfoud, from the departments of cardiology, angiology and intensive care medicine at University of Saarland, Homburg/Saar, Germany, and Lüscher, professor and chairman of cardiology at University Heart Center, University Hospital, Zurich, Switzerland, wrote. “Furthermore, treatment strategies should be refined and ablations should probably be performed more distally where the deployed energy is able to reach the renal nerves in the adventitia. Finally, multielectrode devices are probably more reliable in achieving effective renal nerve blockade than single electrode catheters.”

For more information:

Kandzari DE. Eur Heart J. 2014;doi:10.1093/eurheartj/ehu441.

Mahfoud F. Eur Heart J. 2014;doi:10.1093/eurheartj/ehu450.

Disclosure: The analyses were funded by Medtronic. Several researchers report various financial ties, including with Medtronic. Mahfoud reports financial ties with Boston Scientific, Cordis, Medtronic/Ardian and St. Jude Medical. Lüscher reports financial ties with Biotronik, Boston Scientific, Medtronic and St. Jude Medical.