A post-study analysis of data from Medtronic‘s (NYSE:MDT) failed Symplicity-3 trial of renal denervation in treating hypertension reveals several "confounding factors" that may have contributed to the trial missing its efficacy endpoint.
Early this year the results of the Symplicity-3 trial, widely expected to be a home fun for RDN in hypertension, shocked the medical device world when Medtronic reported no significant difference between treatment with its Symplicity device and a sham procedure.
The results prompted Medtronic to suspend enrollment in 3 other RDN trials around the world and led to other companies in the space either suspending their programs or abandoning them altogether.
But a Medtronic-sponsored examination of the data from Symplicity-3, published last month in the European Heart Journal, suggest that medication adherence, changes in drug regimens and variations in the RDN procedure may have led to the surprising results of the trial.
Researchers found that "although nearly all patients were prescribed maximal medical therapy at least 6 weeks prior to randomization, many patients (39%) underwent medication changes between the randomization and the 6-month endpoint assessment."
"These changes typically represented both alterations in dose and class of prescribed medications, a finding that challenges the premise that patients were actually receiving maximally tolerated doses at enrollment," they wrote.
Performance of the denervation procedure also varied within the trial, they found. The number of ablations varied from 1 to 26, with most patients receiving at least 8, according to the study.
"The majority of patients received at least the minimum recommended number of ablations (4 to 6 per artery) but there were 4 patients who received fewer than 8 ablations including 2 who received only 1. Just 19 patients received 4-quadrant ablations in both renal arteries," the researchers wrote. "In our analysis, the lack of ablations in all 4 quadrants and the number of ablation attempts were highly correlated with blood pressure reductions. These 2 variables may be correlated, and more ablation attempts may well increase the probability of ablating within all 4 quadrants."
In a sub-group analysis, African-American patients showed a higher response to the sham procedure than non-African-American subjects, according to the study. Unlike earlier trials, Symplicity-3 enrolled a large number of African-Americans, who comprised 26.2% of the 535 patients in Symplicity-3.
"The African-American sham patients demonstrated an unusually large decrease in [systolic blood pressure] compared with non-African-American controls. Although a genetic basis has been postulated for differential response to hypertension and heart failure therapies among African Americans, the marked reduction in blood pressure in the sham group could be related to a change in medical adherence and/or type of therapy; notably, a higher proportion of African Americans were prescribed vasodilator therapy," according to the post-hoc analysis. "The exact reasons for blood pressure differences observed between African-American and non-African-American control patients are unclear and highlight the importance of consistent and standardized [blood pressure] care in subsequent denervation trials."
In an editorial accompanying the post-hoc study, Drs. Felix Mahfoud of Germany’s Saarland University and Thomas Felix Luscher of the University of Zurich wrote that future renal denervation trials should be designed to address the variables revealed by the analysis.
"It might have indeed been oversimplistic to assume that 1 single interventional therapy could uniformly treat a heterogeneous disease, such as hypertension. The post-hoc analyses derived from the overall negative Symplicity HTN-3 trial helped to generate interesting hypotheses related to confounding variables and to provide important insights for the design of future renal denervation studies, which will be launched soon," they wrote. "Specifically, recruiting centers should have experienced hypertension specialists and interventionalists available, and stabilization of medication and blood pressure before randomization appears particularly important. 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."