No Benefit Found in First Real Test of Renal Denervation

SYMPLICITY HTN-3, the eagerly awaited first rigorous test of renal denervation, shows that the real effect of the novel blood-pressure-lowering technology is dramatically lower than earlier expectations, which had been fueled by data from previous uncontrolled trials. Results of SYMPLICITY HTN-3 were presented at the American College of Cardiology conference in Washington, DC, and published simultaneously in the New England Journal of Medicine.

The Medtronic-sponsored trial tested the effect of renal denervation in patients with resistant hypertension, defined as a sustained office systolic BP of at least 160 mm Hg confirmed by home BP and 24-hour ambulatory BP documentation of a systolic BP of at least 135 mm Hg. In all, 535 patients were randomized in a 2:1 ratio to either renal denervation or a sham procedure.

At 6 months, only a very small 2.39-mm-Hg difference was evident between the two groups in the change in office systolic BP since baseline. This difference — a drop of 14.13 mm Hg in the denervation group versus 11.74 mm Hg in the control group — did not reach statistical significance.

A similar pattern emerged with the secondary endpoint of ambulatory BP at 6 months, with only a 1.96-mm-Hg difference between the groups (a drop of 6.75 mm Hg in the denervation group vs. 4.79 mm Hg in the control group). No difference was found in the home BP measurements. The same results were observed when diastolic BP was examined.

There were 5 adverse events in the renal denervation group and 1 in the sham-procedure group.

The authors write, “These findings contradict the published clinical data regarding renal denervation, which showed larger reductions in blood pressure 6 months after denervation and, in the unblinded SYMPLICITY HTN-2 trial, no reduction of systolic blood pressure in control patients.”

The investigators also noted that despite the widespread hype, enough information was available to predict that the trial would not produce the large, dramatic reductions in BP that many experts had predicted: “A meta-analysis of antihypertensive- drug trials predicted that the change in office systolic blood pressure would be smaller than reported in two early renal-denervation trials… when a more rigorous study design was used to reduce bias. The current trial underscores the importance of conducting blinded trials with sham controls in the evaluation of new medical devices before their clinical adoption.”

The authors proposed a number of possible explanations for the discrepancy in the findings between their study and previous studies. They noted that some prior studies had not had a control arm and had compared the treatment effect to baseline observations, “leading to a false impression of treatment efficacy,” perhaps due at least in part to a regression to the mean. Without proper blinding and controls “both patients and assessors may be subject to bias in favor of a new treatment that is expected to have increased efficacy.” Given the results in the sham-treatment arm, it also seems likely that a placebo effect was interpreted as a treatment effect.

The study findings, the investigators wrote, have “important therapeutic implications for the design of trials of antihypertensive (and other) medications, devices, and strategies.”

In an accompanying editorial, Franz Messerli and Sripal Bangalore discuss the discrepancy between the earlier SYMPLICITY trials, which found systolic BP reductions as high as 32 mm Hg, and SYMPLICITY HTN-3. The earlier results were “unprecedented” and “continued to fan the flames of renal denervation.” Symplicity HTN-3, they write, “brings the renal-denervation train to a grinding halt.”

Click here to read an interview on CardioExchange with Deepak L. Bhatt, co-principal investigator of SYMPLICITY HTN-3.

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