There is an intriguing plot twist to the story of HTN-3 SIMPLICITYthe sham-controlled clinical trial that nearly ruled out renal denervation therapy (RDN) as a promising approach for treatment-resistant patients. hypertension (HTN).
It is well known that the trial did not show any benefit for systolic blood pressure (BP) from the invasive procedure at 6 and 12 months, which dampened the enthusiasm for RDN in HTN for both clinicians and the industry. But it turns out the disappointment in the studio may have been premature.
The procedure led to significant improvements in systolic BP, either in the office or outpatient, compared with a sham-control procedure, in a new analysis that followed trial patients for 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, can be safely achieved,” said Deepak L. Bhatt, MD. , in a presentation on September 18 at Transcatheter Cardiovascular Therapeutics (TCT) 2022, held in Boston, Massachusetts.
Bhatt, of Brigham and Women’s Hospital in Boston and Harvard Medical School, is also the lead author of the report. published the same day in the lancet.
Advances in RDN technology and trial design since the neutral primary results of SYMPLICITY HTN-3 were reported in 2014 have long since restored faith in the procedure, which is now in advanced stages of clinical trials and he hopes that over time it will leave a mark in practice.
But Roxana Mehran, MD, who is not associated with SYMPLICITY HTN-3, expressed caution in interpreting the current analysis based on secondary endpoints and long follow-up time.
And in other parts of the TCT sessions, trial observers, as well as Bhatt, called for similar caution in interpreting “positive” secondary results from trials that were “negative” in their primary analysis.
Still, “I think there’s no question that we now have enough evidence to say that renal denervation in addition to drugs is probably something we’ll see in the future,” Mehran, of the Icahn School of Medicine at Mount Sinai, New York City. york said elcorazon.org | Medscape Cardiology.
Importantly, and somewhat controversially, the RDN group in the 36-month analysis of SYMPLICITY HTN-3 includes patients originally assigned to the sham control group who crossed over to receive RDN after the trial was unblinded. Thereafter, their “control” PA responses were imputed using accepted statistical methodology that Bhatt characterized as “last observation carried forward.”
That’s another reason to be cautious with the current results, noted Naomi Fisher, MD, also of Brigham and Women’s and Harvard Medical School, as a panelist after Bhatt’s formal presentation.
“With all the missing data and imputation calculations,” he said, “I think we need to be cautious in interpretation.”
He also noted that blinding in the trial was lifted at 6 months, allowing patients to learn their treatment assignment and potentially influence subsequent changes in medications.
They were prescribed, on average, about five antihypertensive medications, Fisher noted, and “that’s already a red flag. Patients who take that many medications usually don’t take them universally. There’s a very high chance that there could be a variable adhesion.
Patients who found out they were in the sham control group, for example, might have “stopped” taking their medications, potentially worsening outcomes and amplifying the apparent benefit of RDN. Such an effect, Fisher said, “might have contributed” to the long-term results of the study.
As previously reported, the single-blind SYMPLICITY HTN-3 randomized 535 patients to RDN or a sham-control procedure, 364 and 171 patients, respectively, at 88 US centers. The trial used the SimplicityFlex RDN radiofrequency ablation catheter (Medtronic).
To enter the study, patients were required to have an office systolic BP of at least 160 mm Hg and a 24-hour ambulatory systolic BP of at least 135 mm Hg despite stable maximally tolerated doses of a diuretic plus at least one other. two 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 crossover controls were combined with the original active therapy cohort for the current analysis.
From baseline to 36 months, the mean number of drug classes per patient remained between 4.5 and 5, with no significant difference between groups at any time point.
However, medication load expressed as number of daily doses remained constant between 9.7 and 10.2 for controls, while the RDN group showed a constant decrease from 10.2 to 8.4. Differences between RDN patients and controls were significant at 24 months (P = .01) and 36 months (P = .005), reported Bhatt.
Table. Difference in mean BP change from baseline, RDN relative to sham control at 24 and 36 months
|tracking time||Systolic BP in office
|office diastolic BP
|24 hour external consultation
|24 hour external consultation
diastolic BP (mmHg)
All relative decreases favor the RDN group, P < 0.0001
The RDN group spent a greater percentage of time with systolic BP on target compared with those in the sham control group in an analysis that did not involve data imputation, 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 were no adverse safety signals associated with RDN at the 36- and 48-month follow-up. As reported by Bhatt, the composite safety endpoint rates in RDN patients, crossovers, and noncrossover controls were 15%, 14%, and 14%, respectively.
Safety endpoints included death, new end-stage renal disease, significant embolic events causing end-organ damage, vascular complications, renal artery reoperation, and “hypertensive emergency unrelated to medication nonadherence.” “Bhatt reported.
There are many patients with “out of control” hypertension “who are unable to adhere to their medications,” Mehran noted. elcorazon.org | Medscape Cardiology. “I think having a plug-in for the medical management of these patients,” that is, RDN, “is going to 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 have other relationships with Medscape Cardiology and other publications or organizations.
METER ehran discloses receiving 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; receiving fees or honoraria as a consultant or being part of a speakers bureau for Novartis, Abbott Vascular, Janssen, Medtronic, Medscape/WebMD, and Cine-Med Research; and holdings of stock, shares or stock options with Control Rad, Applied Therapeutics and Elixir Medical.
Fisher discloses having received honoraria or consultant fees or having worked in a speakers bureau for Medtronic, Record Medical and Aktiia; and receive grants or maintain research contracts with Record Medical and Aktiia.
Transcatheter Cardiovascular Therapeutics 2022. Breaking Clinical Science in Vascular Diseases and Hypertension: Session III, in collaboration with the Journal of the American Medical Association. Presented on September 18, 2022.
the lancet Published online on September 18, 2022. Text complete