Positive Results for Renal Denervation Pile up at ESC

Reed Miller

August 28, 2012

August 28, 2012 (Munich, Germany) — The 18-month follow-up results of SYMPLICITY HTN 2 suggest that the blood-pressure benefits of renal sympathetic denervation are durable [1]. The release of these data headlined several well-attended sessions on the novel procedure presented at the European Society of Cardiology (ESC) 2012 Congress.

Dr Murray Esler

As reported by heartwire , earlier results of the SYMPLICITY HTN 2 trial showed ablating the renal nerves with the Symplicity radiofrequency system (Medtronic) led to average blood-pressure reductions of 32/12 mm Hg six months after the procedure in patients with drug-resistant hypertension (all of the patients were on at least three antihypertensive drugs). The six-month results also showed that 84% of patients had drops of at least 10 mm Hg in systolic blood pressure from baseline following the procedure. The patients were supposed to stay on optimal medical therapy throughout the study.

Patients in the control group were allowed to cross over to receive the renal-denervation treatment after six months. Dr Murray Esler (Baker IDI Heart and Diabetes Institute, Melbourne, Australia) presented 18-month follow-up results from this crossover analysis.

The results show that pulse pressure improved and heart rates were stable or lower following the renal-denervation treatment and that, at least in the small group of patients who had reached the 18-month follow-up, the blood-pressure benefits of the therapy endured. Also, no device-related serious adverse effects and no detrimental effects on the renal vasculature have been reported.

Baseline Preprocedure Office Blood-Pressure Measurements

Measure Patients initially randomized to renal denervation (n=52) Patients who crossed over to renal denervation at 6 mo (n=37)
Average systolic BP (mm Hg) 178.3 190
Average diastolic BP (mm Hg) 96.1 99.9

Change in Blood Pressure Six Months After Renal-Denervation Therapy

Measure Patients initially randomized to renal denervation (n=49) Patients who crossed over to renal denervation at 6 mo (n=37) p
Average change in systolic BP (mm Hg) -31.7 -23.7 <0.001
Average change in diastolic BP (mm Hg) -11.7 -8.4 <0.001

Change in Blood Pressure 12 Months After Renal-Denervation Therapy

Measure Patients initially randomized to renal denervation (n=47) Patients who crossed over to renal denervation at 6 mo (n=33) p
Average change in systolic BP (mm Hg) -28.1 -23.8 <0.001
Average change in diastolic BP (mm Hg) -9.7 -10.0 <0.001

Change in Blood Pressure 18 Months After Renal-Denervation Therapy

measure Patients initially randomized to renal denervation (n=43) Patients who crossed over to renal denervation at 6 mo (n=7) p
Average change in systolic BP (mm Hg) -32.3 -28.4 <0.001
Average change in diastolic BP (mm Hg) -12.5 -13.6 <0.001

Physicians were allowed to change the patients' medications following the six-month primary end point. The reasons for any changes are unknown, but Esler said that, if anything, these changes would bias the sustained improvements in blood pressure seen in the trial. "In my own experience, this is often driven by patients. They don't want to be on drugs after the procedure, so [reducing their medications] is a sign of progress. They want to be cured by denervation--which no one, of course, is--[but] there's a tendency for us to undermedicate over time."

Esler acknowledged that "with any device trial, there may be a greater placebo effect than in a drug trial." This "deficiency is being corrected" in the pivotal SYMPLICITY HTN 3 in which patients in the control group will have a "sham" procedure.

Nevertheless, the chair of the session during which Esler presented the results, Dr Roland Schmieder (University of Erlangen-Nürnberg, Germany), told heartwire that these 18-month results are "reassuring that the effect is lasting and sustained, because we are always discussing the [the concern of] functional renervation . . . so it's very good to see that there's no signal of that." And the lack of adverse events in the study provides reassurance of safety, "so that we can proceed to additional clinical trials to other groups, such as less severe hypertensives."

Does It Make a Difference?

Dr Denise Fischer

Psychologist Dr Denise Fischer (Universitätsklinikum des Saarlandes, Homburg, Germany) presented results from a 173-patient study of the salutary effects of renal denervation on anxiety, depression, and quality of life [2].

Patients in the study rated their physical and mental state and arousal level on a series of tests and questionnaires, and the intensity of their headaches--suffered by 60% of the patients--were measured by visual analog scale (VAS). About a third of the patients reported sleep disorders.

Three months after renal denervation, the BP of the patients in the study improved by an average of -17/-7 mm Hg (p<0.01). The patients showed significant improvement on a multitasking test designed to assess their ability to respond to stress. Average scores of quality of life, anxiety, and depression all increased significantly, and the decreases in headache intensity and sleep problems were also significant.

Given the apparent safety of the procedure, Fischer's group hopes to continue evaluating the impact of renal denervation on these so-called "soft end points" in larger and longer trials, she told heartwire .

Schmieder called the study by Fischer et al "very convincing." He pointed out that although hypertension has no "typical symptoms," survey data show that patients with hypertension consistently report high levels of anxiety, depression, and headaches. Based on neuroendocrine research, Schmieder is confident that the neurological effects of BP reduction are not just a placebo effect and will be confirmed in larger trials in the future.

"Of course, it's always nice to have hard end points, and we'll never give up asking for that, but in these patients with such a severe stage of hypertension, we are quite sure that blood pressure is a valid biomarker," he said.

Are These Results Reproducible in the Real World?

Dr Darren Mylotte (Institut Cardiovasulaire de Paris Sud, France) presented six-month results from a registry of 35 consecutive patients treated with renal denervation at his center. As in the SYMPLICITY HTN 2 study, all of the patients in this study had a BP >160 mm Hg despite treatment with at least three antihypertensive drugs [3].

Dr Darren Mylotte

The patients' average baseline BP was 181.1/100.8 mm Hg despite an average of 4.6 medications per patient, and baseline ambulatory BP was 171.6/93.5 mm Hg. Bilateral sympathetic renal denervation was successful in all but two patients; one had renal artery stenosis preventing ablation and the other had a renal artery spasm allowing for only unilateral ablation, but there were no procedural complications. The procedure required an average of 6.1 ablations per renal artery and usually lasted about 15 minutes.

At six-month follow-up, the average office BP reduction from baseline was 30.3/14.6 mm Hg (p<0.0001), and ambulatory BP was reduced 23.3/10.2 mm Hg from baseline (p<0.001). There were no adverse events during follow-up and no deterioration of renal function.

"This was a very heterogeneous population. In some patients, their blood pressure dropped within months, with others it takes six months," Mylotte said. "The important point is that we have strong follow-up. Patients come back to see us regularly, and we can reassess their blood pressure. We do have some patients who get quite upset that their blood pressure hasn't dropped significantly and that they still have to take medications, but I think we need to manage those expectations before patients have them. These are patients who don't have any other options--they're on three or four medications, but their pressure is still uncontrolled and their event rates for stroke or MI are extreme."

Esler is chief investigator of the SYMPLICITY HTN 2 trial and has received research grant, travel, and consultancy funding from Medtronic. Schmieder previously disclosed that he has served as an advisor or consultant for Servier, Boehringer Ingelheim, and Novartis Pharmaceuticals; as a speaker or a member of a speaker's bureau for Servier, Pfizer, Boehringer Ingelheim, AstraZeneca, and Sanofi; and has received grants for clinical research from Ardian.