SYMPLICITY HTN-3 at One Year: Still No BP Benefit vs Sham Control Arm

September 05, 2014

BARCELONA, SPAIN ( corrected ) — The unblinded one-year results of the SYMPLICITY HTN-3 study, a trial testing the safety and efficacy of renal denervation in patients with resistant hypertension, found there was no difference in office and ambulatory blood pressure among who those underwent renal denervation and patients in the sham control arm.

The results also included six-month data from patients in the sham control arm who crossed over to renal denervation. For those who crossed over, there was a 17.7-mm-Hg and 9.2-mm-Hg reduction in the mean office and 24-hour ambulatory blood pressure six months after receiving treatment. These reductions were similar, if not slightly larger, than the six-month reductions observed among those originally treated with renal denervation in the blinded trial.

The one-year results suggest that renal denervation is safe, however, with investigators reporting no increase in the risk of major adverse cardiac events between those treated with renal denervation and those in the sham control arm.

The follow-up data were presented this week at the European Society of Cardiology (ESC) 2014 Congress by Dr George Bakris (University of Chicago, IL). As reported previously by heartwire , the SYMPLICITY HTN-3 study was stopped in January 2013 when Medtronic, the study's sponsor, announced the study missed its primary end point. The six-month results were presented at the American College of Cardiology (ACC) 2014 Scientific Sessions.

"SYMPLICITY wasn't so simple," said Bakris during a media briefing announcing the results. "What we learned since the original results were presented at the ACC is that the anatomy of the renal nerves is much more complex than we thought." For example, researchers are learning they can't simply denervate the renal artery and that side branches must also be denervated. "There's a lot of procedural things being learned and anatomic things being learned, so I would say this is a work in progress."

The SYMPLICITY Study

Dr George Bakris

Briefly, SYMPLICITY HTN-3 was the first randomized, blinded, sham-controlled renal-denervation study, one that tested the novel procedure in 535 patients with severe resistant hypertension. After six months, the mean change in systolic blood pressure was a reduction of 14.1 mm Hg in the renal-denervation arm and 11.7 mm Hg in the sham control arm, a difference of 2.4 mm Hg that was not statistically significant. The results also showed no benefit when ambulatory blood pressure was assessed.

The longer-term data include 364 patients who underwent renal denervation and were followed for 12 months, 70 subjects in the sham control arm who did not cross over after the study's completion and were followed for 12 months (noncrossover arm), and 101 subjects who crossed over to renal denervation and were followed for six months. There were no statistically significant baseline differences among the three groups.

Patients in the original treatment arm, patients who crossed over after six months, and those who did not cross over had similar reductions in office and 24-hour ambulatory blood pressure when measured 12 months after randomization, said Bakris.

At 12 months, there was a 18.9-mm-Hg reduction in systolic blood pressure in the renal-denervation arm, a reduction that was slightly larger than the reduction seen at six months. In those who crossed over to renal denervation, systolic blood pressure was reduced 17.7 mm Hg after six months. Among patients who did not cross over, the sham control arm followed for one year, there was an increase in systolic blood pressure from six months to 12 months. At six months, the reduction in systolic blood pressure was 32.9 mm Hg, but by 12 months the reduction from baseline was 21.4 mm Hg.

"When you look at the people who did not make it into the crossover—these are people who were pharmacologically managed and continued with pharmacologic therapy—you can see that there was a fall in the blood-pressure delta compared with the six-month period," said Bakris. "That certainly was a difference that was noted."

Speaking during the press conference, Bakris was asked about the clawback in blood-pressure reduction from six to 12 months that occurred among the noncrossover patients. Whereas there was a durability of effect among those treated with renal denervation, there was no sustained reduction in systolic or diastolic blood pressure among sham control patients.

"I see this as similar to the obesity type of studies," said Bakris. "I think it relates to adherence to medication. For six months, I think you can pretty much hold any type of medication, especially when you're in a trial. But now, when the trial is finished and you didn't get denervated but you're being followed, the number of medications you might want to take, if you're taking seven or eight pills a day, might [be only] four or five. So you get some kind of fall-off effect."

12-Month Registry Data Also Presented

In a statement, Medtronic said the SYMPLICITY HTN-3 is no longer randomized, blinded, or controlled, so it is difficult to make conclusions about efficacy from the 12-month data. The company said the new report adds to the growing body of data with renal denervation and it is continuing to study unresolved questions, such as "trial design and execution, including procedural variability, patient population, and medication changes."

Elsewhere at the ESC meeting, Dr Felix Mahfoud (Saarland University Hospital, Homburg, Germany) reported interim 12-month results from 969 patients enrolled in the Global SYMPLICITY Registry . At 12 months, the reduction in office systolic blood pressure was 13.0 mm Hg. At three and six months, the reduction in systolic blood pressure was 9.9 and 11.6 mm Hg, respectively. The largest reductions in blood pressure were observed in those with the highest baseline systolic blood pressure (>180 mm Hg). Similar trends were observed for the approximately 40% of patients who underwent ambulatory blood pressure monitoring.

For the registry patients treated with renal denervation, 18% had an increase in the number of antihypertensive medications used, 25% had a decrease in the number of drugs used, and 56% had no change.

Bakris has received fees from Takeda, AbbVie, Novartis, Janssen, Medtronic, Relypsa, and Bristol-Myers Squibb. Mahfoud reports consulting fees/lecture fees/travel support from Medtronic, St Jude, Boston Scientific, Cordis, Berlin Chemie, and Boehringer Ingelheim. He has received grant/research support from Medtronic, St Jude, Recor, and Boston Scientific.

Editor's note: An earlier version of this story stated there was no significant difference in blood pressure between the 12-month renal-denervation results, the six-month crossover renal-denervation results, and the 12-month sham control arm. SYMPLICITY HTN-3 was unblinded at six months, and such a comparison was not assessed.

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