BOSTON – There’s an intriguing plot twist in the story of SYMPLICITY HTN-3, the sham-controlled clinical trial that nearly put the kibosh on renal denervation (RDN) therapy as a promising approach to treatment-resistant hypertension (HTN).
The trial famously showed no benefit for systolic blood pressure (BP) from the invasive procedure at 6 months and 12 months, dampening enthusiasm for RDN in HTN for both physicians and industry. But it turns out that disappointment in the study may have been premature.
Dr. Deepak L. Bhatt
The procedure led to significant improvements in systolic BP, whether in-office or ambulatory, compared with a sham control procedure, in a new analysis that followed the trial’s patients out to 3 years. Those who underwent RDN also required less intense antihypertensive drug therapy.
“These findings support that durable blood pressure reductions with radiofrequency renal artery denervation, in the presence of lifestyle modification and maximal medical therapy, are safely achievable,” Deepak L. Bhatt, MD, said in a Sept. 18 presentation at the Transcatheter Cardiovascular Therapeutics annual meeting, which was sponsored by the Cardiovascular Research Foundation.
Dr. Bhatt, of Boston’s Brigham and Women’s Hospital and Harvard Medical School, is lead author on the report published in The Lancet simultaneously with his presentation.
Strides in RDN technology and trial design since the neutral primary SYMPLICITY HTN-3 results were reported in 2014 have long since restored faith in the procedure, which is currently in advanced stages of clinical trials and expected to eventually make a mark on practice.
But Roxana Mehran, MD, not connected to SYMPLICITY HTN-3, expressed caution in interpreting the current analysis based on secondary endpoints and extended follow-up time.
And elsewhere at the TCT sessions, observers of the trial as well as Dr. Bhatt urged similar cautions interpreting “positive” secondary results from trials that were “negative” in their primary analyses.
Still, “I believe there is no question that we have now enough evidence to say that renal denervation on top of medications is probably something that we’re going to be seeing in the future,” Dr. Mehran, of the Icahn School of Medicine at Mount Sinai, New York, told this news organization.
Importantly, and a bit controversially, the RDN group in the 36-month SYMPLICITY HTN-3 analysis includes patients originally assigned to the sham control group who crossed over to receive RDN after the trial was unblinded. Their “control” BP responses were thereafter imputed by accepted statistical methodology that Dr. Bhatt characterized as “last observation carried forward.”
That’s another reason to be circumspect about the current results, observed Naomi Fisher, MD, also of Brigham and Women’s and Harvard Medical School, as a panelist following Dr. Bhatt’s formal presentation.
“With all the missing data and imputational calculations,” she said, “I think we have to apply caution in the interpretation.”
She also pointed out that blinding in the trial was lifted at 6 months, allowing patients to learn their treatment assignment, and potentially influencing subsequent changes to medications.
They were prescribed, on average, about five antihypertensive meds, Dr. Fisher noted, and “that’s already a red flag. Patients taking that many medications generally aren’t universally taking them. There’s very high likelihood that there could have been variable adherence.”
Patients who learned they were in the sham control group, for example, could have “fallen off” taking their medications, potentially worsening outcomes and amplifying the apparent benefit of RDN. Such an effect, Dr. Fisher said, “could have contributed” to the study’s long-term results.
As previously reported, the single-blind SYMPLICITY HTN-3 had randomly assigned 535 patients to either RDN or a sham control procedure, 364 and 171 patients respectively, at 88 U.S. centers. The trial used the Symplicity Flex RDN radiofrequency ablation catheter (Medtronic).
For study entry, patients were required to have office systolic BP of at least 160 mm Hg and 24-hour ambulatory systolic BP of at least 135 mm Hg despite stable, maximally tolerated dosages of a diuretic plus at least two other antihypertensive agents.
Blinding was lifted at 6 months, per protocol, after which patients in the sham control group who still met the trial’s BP entry criteria were allowed to cross over and undergo RDN. The 101 controls who crossed over were combined with the original active-therapy cohort for the current analysis.
From baseline to 36 months, mean number of medication classes per patient maintained between 4.5 and 5, with no significant difference between groups at any point.
However, medication burden expressed as number of doses daily held steady between 9.7 to 10.2 for controls while the RDN group showed a steady decline from 10.2 to 8.4. Differences between RDN patients and controls were significant at both 24 months (P = .01) and 36 months (P = .005), Dr. Bhatt reported.
All relative decreases favor the RDN group, P < .0001
The RDN group spent a longer percentage of time with systolic BP at goal compared to those in the sham control group in an analysis that did not involve imputation of data, Dr. Bhatt reported. The proportions of time in therapeutic range were 18% for RDN patients and 9% for controls (P < .0001).
As in the 6- and 12-month analyses, there was no adverse safety signal associated with RDN in follow-up out to both 36 and 48 months. As Dr. Bhatt reported, the rates of the composite safety endpoint in RDN patients, crossovers, and noncrossover controls were 15%, 14%, and 14%, respectively.
The safety endpoint included death, new end-stage renal disease, significant embolic events causing end-organ damage, vascular complications, renal-artery reintervention, and “hypertensive emergency unrelated to nonadherence to medications,” Dr. Bhatt reported.
There are many patients with “out of control” HTN “who cannot remain compliant on their medications,” Dr. Mehran observed for this news organization. “I believe having an adjunct to medical management of these patients,” that is RDN, “is going to be tremendously important.”
SYMPLICITY HTN-3 was funded by Medtronic. Dr. Bhatt has disclosed ties with many companies, as well as WebMD, Medscape Cardiology, and other publications or organizations. Dr. Mehran disclosed ties to Abbott Vascular, AstraZeneca, Bayer, Bristol-Myers Squibb, CSL Behring, Daiichi-Sankyo/Eli Lilly, Medtronic, Novartis, OrbusNeich, Abiomed; Boston Scientific, Alleviant, Amgen, AM-Pharma, Applied Therapeutics, Arena, BAIM, Biosensors, Biotronik, CardiaWave, CellAegis, Concept Medical, CeloNova, CERC, Chiesi, Cytosorbents, Duke University, Element Science, Faraday, Humacyte, Idorsia, Insel Gruppe, Philips, RenalPro, Vivasure, and Zoll; as well as Medscape/WebMD, and Cine-Med Research; and holding equity, stock, or stock options with Control Rad, Applied Therapeutics, and Elixir Medical. Dr. Fisher disclosed ties to Medtronic, Recor Medical, and Aktiia; and receiving grants or hold research contracts with Recor Medical and Aktiia.
A version of this article first appeared on Medscape.com.