Legacy of Neutral SYMPLICITY HTN-3 Recast by Long-term Outcomes


There is an intriguing plot in the story of SYMPLICITY HTN-3, the sham-controlled clinical trial that nearly threw the kibosh on renal denervation therapy (RDN) as a promising approach for treatment-resistant hypertension (HTN).

The study reportedly showed no benefit for systolic blood pressure (BP) from the invasive procedure at 6 months and 12 months, dampening enthusiasm for RDN in HTN among both physicians and industry. But it turns out the disappointment in the study may have been premature.

In a new analysis that followed study patients for up to 3 years, the procedure resulted in significant improvements in systolic blood pressure, whether in-office or outpatient, compared to a sham control procedure. Those who underwent RDN also required less intensive antihypertensive drug therapy.


“These results support that durable blood pressure reductions are safely achievable with radiofrequency renal artery denervation coupled with lifestyle modifications and maximal medical therapy,” said Deepak L. Bhatt, MD, in a Sept. 18 presentation at Transcatheter Cardiovascular Therapeutics (TCT). 2022, held in Boston, Massachusetts.

Bhatt, of Boston’s Brigham and Women’s Hospital and Harvard Medical School, is also lead author of the report, published in The Lancet on the same day.

Advances in RDN technology and study design since the publication of the neutral primary SYMPLICITY HTN-3 results in 2014 have long restored confidence in the procedure, which is currently in advanced stages of clinical trials, and is expected to will eventually shape practice.


However, Roxana Mehran, MD, not associated with SYMPLICITY HTN-3, expressed caution in interpreting the current analysis based on secondary endpoints and extended follow-up.

And elsewhere at the TCT sessions, observers of the study as well as Bhatt called for similar caution in interpreting “positive” secondary results from studies that were “negative” in their primary analysis.

Still, “I think there’s no question that we now have enough evidence to say that adding renal denervation to medication is likely something we’ll see in the future,” says Mehran of the Icahn School of Medicine in Mount Sinai, New York City, said | Medscape Cardiology.


Importantly, and somewhat controversially, the RDN group in the 36-month SYMPLICITY HTN-3 analysis includes patients originally assigned to the sham control group who switched to RDN treatment after the study was unblinded. Their “control” BP responses were then imputed by accepted statistical methods, which Bhatt referred to as “the last observation presented”.

That’s another reason to view the current results with caution, noted Naomi Fisher, MD, also of Brigham and Women’s and Harvard Medical School, as a panelist following Bhatt’s formal presentation.

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“With all the missing data and imputed calculations,” she said, “we have to be careful about interpretation.”


She also noted that the study was unblinded at 6 months, allowing patients to know their treatment assignment and possibly influencing subsequent medication changes.

They were prescribed about five blood pressure medications on average, Fisher noted, and “that’s already a red flag.” Patients who take this many medications generally don’t take them everywhere.

For example, patients who learned they were in the sham control group may have “lapsed” from taking their medication, potentially worsening outcomes and amplifying the apparent benefits of RDN. Such an effect, according to Fisher, “may have contributed to the long-term results of the study.”


As previously reported, the single-blind SYMPLICITY HTN-3 study randomized 535 patients at 88 US centers to either RDN or sham control, 364 and 171 patients, respectively. The Symplicity Flex RDN (Medtronic) radiofrequency ablation catheter was used in the study.

For inclusion in the study, patients had to have an in-office systolic blood pressure of at least 160 mm Hg and an ambulatory 24-hour systolic blood pressure of at least 135 mm Hg despite stable, maximally tolerated doses of a diuretic plus at least two other antihypertensive drugs.

Per protocol, blinding was broken at 6 months, after which patients in the sham control group who still met the study’s BP entry criteria were allowed to cross over and undergo RDN. The 101 controls that switched were combined with the original active therapy cohort for the current analysis.

From baseline to 36 months, the mean number of medication classes per patient remained between 4.5 and 5, with no significant difference between groups at any time point.

However, the drug load, expressed as the number of daily doses, remained constant between 9.7 and 10.2 in the controls, while the RDN group showed a steady decrease from 10.2 to 8.4. The differences between RDN patients and controls were significant at both 24 months (p=0.01) and 36 months (p=0.005), Bhatt reported.

Table. Difference in mean BP change from baseline, RDN relative to sham control at 24 and 36 months

run-on time Office Systolic Blood Pressure
Office diastolic BP
24h outpatient
systolic blood pressure
24h outpatient
Diastolic blood pressure (mm Hg)
24 Months -20.7 -12.0 -16.5 -11.2
36 months -22.1 -9.5 -12.6 -7.5

All relative decreases favor the RDN group, P<0.0001

The RDN group spent a longer percentage of time with systolic blood pressure compared to those in the sham control group in an analysis that did not involve imputation of data, Bhatt reported. The proportions of time in the therapeutic range were 18% for RDN patients and 9% for controls (p<0.0001).

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As in the 6 and 12 month analyses, there was no adverse safety signal associated with RDN at either 36 or 48 months of follow-up. As reported by Bhatt, the composite safety endpoint rates in RDN patients, crossover, and non-crossover 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 emergencies unrelated to medication non-compliance,” Bhatt reported.

There are many patients with “runaway” HTN who “can’t keep to their medications,” observed Mehran for | Medscape Cardiology. “I believe that an adjunct to the medical management of these patients,” i.e. RDN, “will be tremendously important.”

SYMPLICITY HTN-3 was funded by Medtronic. Bhatt has disclosed grants and/or personal fees from many companies; personal fees from WebMD and other publications or organizations; and other relationships with Medscape Cardiology and other publications or organizations.

M ehran acknowledges receipt of grants or research support from Abbott Vascular, AstraZeneca, Bayer, Bristol-Myers Squibb, CSL Behring, Daiichi-Sankyo/Eli Lilly, Medtronic, 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 Group, Philips, RenalPro, Vivasure and Customs; Received honoraria or consulting fees or speaker agency fees for Novartis, Abbott Vascular, Janssen, Medtronic, Medscape/WebMD and Cine-Med Research; and holding stocks, shares or stock options in Control Rad, Applied Therapeutics and Elixir Medical.

Fisher states that he has received consultant fees, honoraria, or worked in a speaking agency for Medtronic, Recor Medical, and Aktiia; and receipt of grants or research contracts with Recor Medical and Aktiia.

Transcatheter Cardiovascular Therapeutics 2022. Latest Clinical Science in Vascular Disease and Hypertension: Session III, in collaboration with the Journal of the American Medical Association. Presented on September 18, 2022.

The lancet. Published online September 18, 2022. Full text

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