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Multiple Factors Examined for Contributing to SYMPLICITY HTN-3 Failure


Presented by George L. Bakris, USA

Multiple limitations of the Renal Denervation in Patients With Uncontrolled Hypertension trial [SYMPLICITY HTN-3; NCT01418261] may have contributed to its failure to meet the primary endpoint of change in office blood pressure at 6 months, according to George L. Bakris, MD, University of Chicago Medicine, Chicago, Illinois, USA, presented data from a subanalysis of this trial.

The sham arm of the SYMPLICITY HTN-3 trial demonstrated greater than expected reduction in systolic blood pressure (SBP) [Bhatt DL et al. N Engl J Med 2014]. This may explain the negative results in terms of the primary endpoint of the trial. The purpose of this subanalysis was to determine the significant of several potential confounders that may have driven the response observed in the sham arm, including procedural changes, change in antihypertensive therapy, variability in adherence, and differences in patient populations according to different geographic regions.

In the prospective, sham-controlled, SYMPLICITY HTN-3 trial, 535 patients with severe resistant hypertension were randomly assigned in a 2:1 fashion to undergo renal denervation of a sham procedure. Resistant hypertension was defined as patients taking ≥3 antihypertensive medications at maximally tolerated doses. There was no significant difference in change in SBP between the 2 arms at 6 months, as the sham arm demonstrated a significant change in SBP from baseline (p<0.001).

In the subanalysis, procedural variability was analyzed such that the mean number of ablations in patients who underwent renal denervation was matched 1:1 using propensity scores. Patients were categorized according to by 4 quadrant ablations in both, one, or neither renal artery. As the number of ablations increased, there was a progressive decrease in office SBP in the patients who underwent denervation. There was a similar, but less consistent, trend in the patients who underwent the sham procedure. Similarly, ambulatory BP decreased as the number of ablations increased.

In terms of medication changes, about 40% of the patients in the sham arm required a change in medication between baseline and 6 months, and 69% of the first medication change was medically necessary. However, there was no significant difference in medication changes between the active treatment and sham arms, as 38% of patients who underwent renal denervation also required a change in medication. Medication changes due to adverse events from aldosterone antagonists were 14% in the sham arm compared with 4% in the renal denervation arm.

Predictors of response in patients in the sham arm included alpha-blockers, higher baseline office BP, aldosterone antagonists, and total number of attempts. However, vasodilator use was inversely associated with response in both the sham and renal denervation arms.

A secondary analysis of potential racial differences demonstrated that patients who were black were less likely to respond to the sham treatment compared with patients who were not black.

Geographic location did result in some differences to note. Patients who lived in the North East United States (Boston-New York region) demonstrated a change in office BP, albeit to a lesser extent in ambulatory BP. However, patients living in the South West, South, and West United States had results that reflected that of the trial at large. It is unclear as to why there was a difference based on geographic region.

Dr. Bakris concluded by stating that there were some limitations in the SYMPLICITY HTN-3 trial that may have led to the negative results of the primary endpoint. He further suggested that the limitations discussed in his presentation were exploratory and were meant to be hypothesis-generating.



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