SYMPLICITY HTN-3: Predictors of Response Still Relevant After Trial’s Negative Findings

PARIS, France—Even though 6-month findings of the long-awaited SYMPLICITY HTN-3 randomized trial demonstrated little effect of renal denervation on blood pressure (BP), the study’s data can still provide lessons about potential predictors of response to the novel procedure, according to an analysis presented May 22, 2014, at EuroPCR.

Overall results of SYMPLICITY HTN-3 were presented in March at the 2014 American College of Cardiology/i2 Scientific Session. The sham-controlled randomized trial of 535 patients with severe resistant hypertension was the first to show no systolic BP benefit at 6 months from renal denervation with the Symplicity Catheter System (Medtronic, Mountain View, CA).

At EuroPCR, David E. Kandzari, MD, of the Piedmont Heart Institute (Atlanta, GA), shared results of a substudy focusing on predictors of systolic BP decrease.

Different Predictors for Treatment, Control Arms

Baseline office systolic BP, total number of ablation attempts, and aldosterone adherence were positive predictors of response in the renal denervation arm, whereas in the control arm predictors were baseline office systolic BP, African-American race, and alpha-1 blocker use. Vasodilator use, associated with an increase in BP, was the only negative predictor in the study group (table 1).

Table 1. Multivariate Predictors of Systolic BP Change


Estimate (mm Hg/attempt)

P Value

Renal Denervation
Baseline Office Systolic BP ≥ 180 mm Hg
Total Number of Attempts
Aldosterone Antagonist


< .0001

Baseline Office Systolic BP ≥ 180 mm Hg
African-American Race
Alpha-1 Blocker Use



While approximately 80% of patients were on stable regimens of antihypertensive drugs (at least 3 drugs at their maximally tolerated dose for at least 6 weeks prior to study inclusion), about 40% required medication changes between baseline and assessment of the primary efficacy endpoint, Dr. Kandzari reported. More than two-thirds of these patients required medically necessary changes and 69% of all changes occurred in patients taking drugs at their maximally tolerated dose.

Among patients taking a vasodilator at baseline, there were no significant differences by study arm in the 6-month endpoint of office systolic BP. However, for patients not on a vasodilator, the reduction in BP with renal denervation compared with the sham control was statistically significant (-17.7 mm Hg vs -11.0 mm Hg; P = .024).

Additionally, no differences at 6-month BP levels were determined for patients not taking an aldosterone antagonist at baseline. In contrast, in patients who received an aldosterone antagonist, there was a trend toward a greater reduction in BP with renal denervation (-21.9 mm Hg vs -13.8 mm Hg; P = .098).

In the denervation arm, there was a consistent and progressive reduction in office systolic BP at 6 months according to the number of ablations performed (P for trend = .01), and this pattern was not observed in the control group.

A consistent progression toward a greater reduction in office, ambulatory, and home BP was seen among patients in whom a circumferential, or 4-quadrand, ablation was achieved in at least 1 renal artery. This pattern was even stronger in patients with circumferential ablations achieved in 2 or more renal arteries.

Dr. Kandzari restated the modestly greater benefit derived from renal denervation in non-African-American patients vs African-American patients in the original study (P = .09). More specifically, the current study found that, among non-African-American patients, renal denervation imparted a statistically significant reduction in systolic blood pressure at 6 months compared with control (-15.2 mm Hg vs -8.6 mm Hg; P = .012). In contrast, African-American patients derived an almost identical magnitude of BP reduction regardless of whether they received renal denervation or the sham procedure.

Vasodilator therapy was most common among African-American patients, especially among those assigned to the sham control group, though this was not statistically significant.

“Importantly, these are exploratory analyses,” Dr. Kandzari cautioned. “They are of a trial that failed to meet its primary endpoint and they should therefore serve as…hypothesis-generating.”

Altogether, he concluded, “these findings inform the design and conduct of future investigations of renal denervation for treatment-resistant hypertension.”

Link Between Number of Ablations, Response Informative

Panelist Thomas F. Lüscher, MD, of University Hospital (Zurich, Switzerland), agreed that the analysis is “exploratory, but I think it will help us…to sort out the problems of this procedure.

“What I found particularly interesting and important for what we are going to do in the future is the relation between number of ablations and response,” he continued. “We’ve presented a number of papers that said there is no relationship, but now you have really strong data saying we need to do at least 8, maybe more, ablations particularly in large vessels to achieve a nerve block, which is conceptually the aim of the procedure.”

Dr. Kandzari emphasized the importance of procedural technique because “still there’s no singular factor from this trial that resulted or is responsible exclusively for the outcome observed in HTN-3…. However, when we perform so many additional analyses, chance has a chance.”

Optimally, Dr. Lüscher said, there would be a test for identifying the achievement of nerve block. “This is only a surrogate endpoint for guessing that we did the job properly,” he added.

“We’re humbled still today by the reality that this is a therapy that has no procedural biomarker of efficacy, that’s practical at least,” Dr. Kandzari replied.

Bridging the Gap Between the Real World and Clinical Trials

Stating the elephant in the room, panelist Chaim Lotan, MD, of Hadassah University Hospital (Jerusalem, Israel), asked Dr. Kandzari how he would redesign SYMPLICITY HTN-3 if he could.

The current design “raises issue [about] procedural technique and technology, it also raises the issue of how we mitigate changes in the control group [and] how do we mitigate the placebo effect,” he replied, adding that increasing follow-up duration and requiring that patients are on a stable regimen and adhering to medical therapy prior to randomization would make a difference. Dr. Kandzari also questioned the major differences in treatment between the real world and a trial setting given that patients enrolled in HTN-3 went through 8 points of contact with detailed examinations, which “certainly does not reflect real world practice.”


Kandzari DE. SYMPLICITY HTN-3: insights from the subgroup analysis. Presented at: EuroPCR; May 22, 2014; Paris, France.



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  • SYMPLICITY HTN-3 was sponsored by Medtronic.
  • Dr. Kandzari reports serving as a consultant to Zoll.