Renal Denervation Lowers BP in Pivotal SPYRAL HTN-OFF MED Trial

In patients who are not taking medications for uncontrolled hypertension, renal denervation reduces both ambulatory and office blood pressure compared with a sham procedure, results of the pivotal SPYRAL HTN-OFF MED trial show.

At 3 months, the reduction in systolic BP on 24-hour ambulatory monitoring was 4.0 mm Hg greater in the renal denervation arm, and the drop in office systolic BP as 6.6 mm Hg greater, Michael Böhm, MD (Saarland University, Homburg, Germany), reported during the virtual American College of Cardiology (ACC) 2020 Scientific Session. Denervation also was more effective for reducing diastolic readings.

The treatment effect was “always on” throughout the day, including at night, when the relationship between BP and cardiovascular events is strongest, Böhm said.

Moreover, renal denervation was shown to be safe, with no major device- or procedure-related safety events observed through 3 months.

SPYRAL investigator David Kandzari, MD (Piedmont Heart Institute, Atlanta, GA), said these findings—published simultaneously online in the Lancet—have both regulatory and clinical implications, explaining that the trial was designed in conjunction with the US Food and Drug Administration as the pivotal study to consider for potential approval of the technology.

More broadly, “this is the largest sham-controlled, randomized experience we have with this method of renal denervation, and it confirms the biologic proof of principle or the efficacy of renal denervation to reduce blood pressure,” he told TCTMD. “If there might still be naysayers of renal denervation with regards to its potential to reduce blood pressure, I think this issue is now completely resolved.”

If there might still be naysayers of renal denervation with regards to its potential to reduce blood pressure, I think this issue is now completely resolved. David Kandzari

He pointed out that more information is forthcoming from the SPYRAL HTN-ON MED trial in patients with uncontrolled BP on up to three antihypertensive medications, which is temporarily on hold in the midst of the COVID-19 pandemic. Even so, Kandzari said, the investigators hope to complete that trial in 9 to 12 months.

Commenting for TCTMD, Dipti Itchhaporia, MD (Hoag Hospital, Newport Beach, CA), incoming ACC vice president, said the trial “validates that renal denervation can augment what we can do with regards to controlling hypertension” and shows that “it does work and it is safe.”

Although the observed reductions in BP are modest, they would be expected to lower the risks of stroke and other adverse cardiovascular outcomes if sustained over time, she said, adding, too, that the expectation based on prior denervation trials is that there will be further declines in BP beyond the 3-month mark.

Itchhaporia called for additional data before giving a definitive answer on whether renal denervation will have a future role in clinical practice, but said she thinks it will: “I’m going to say that cautiously. I say [it will have a role] not because I’m wowed by the degree of blood pressure reduction, but [because] I think that we probably need additional tools in our toolbox . . . for patients who have resistant hypertension.”

Renal Denervation in the Absence of Drug Therapy

Enthusiasm for renal denervation was high several years ago before the results of the sham-controlled SYMPLICITY HTN-3 trial—reported at ACC 2014—provided a reality check to the community. Since then, researchers have applied the lessons learned to complete multiple sham-controlled pilot studies, most of which showed that renal denervation lowers BP, albeit with smaller reductions than seen in preliminary research. That restored optimism to the field.

The pivotal SPYRAL HTN-OFF MED trial—performed at 44 worldwide sites—continues renal denervation’s comeback, using a Bayesian adaptive study design that incorporated 80 patients from the similarly named pilot study and 251 newly randomized participants. Patients were required to not be taking antihypertensive medications (or be able to stop them) and to have an office systolic BP of 150 to less than 180 mm Hg, an office diastolic BP of 90 mm Hg or higher, and a 24-hour systolic BP of 140 to less than 170 mm Hg.

Patients were randomized to denervation with the Symplicity Spyral multielectrode catheter and the Symplicity G3 radiofrequency generator (Medtronic) or sham control after a medication washout period of 3 to 4 weeks. They were followed for 3 months, at which point antihypertensive medications were restarted if the office systolic BP was 140 mm Hg or higher.

At baseline, blood pressure was roughly 163/101 mm Hg in the office and 151/98 mm Hg on 24-hour monitoring. Although some patients had antihypertensive medications detected by drug testing during the first 3 months, off-med compliance was similar in the two trial arms.

The primary outcome was the change in 24-hour systolic BP from baseline to 3 months, and the reduction was greater in the denervation arm (4.7 vs 0.6 mm Hg; P < 0.001). The secondary outcome was the change in office systolic BP, and that reduction, too, was larger with denervation (9.2 vs 2.5 mm Hg; P < 0.001). Diastolic BP also was improved to a larger degree with denervation versus sham control.

For 24-hour systolic BP, consistent effects were seen in subgroups defined by age, sex, body mass index, smoking status, type 2 diabetes, and race.

There were no major adverse safety events identified in the first month of follow-up. By 3 months, there was only one major adverse event (a hospitalization for hypertensive crisis/emergency in the denervation arm) and one new stroke (in the sham arm).

Reductions May Be Greater Long-term

Commenting at a press conference, Dhanunjaya Lakkireddy, MD (Kansas City Heart Rhythm Institute and Research Foundation, Overland Park, KS), said that the reductions in BP seen with renal denervation are “actually reasonably impressive for an antihypertensive study” but “are not enough to really make a case for it to be a stand-alone therapy.” He added that employing denervation “as an adjunct to . . . medications may be a very reasonable strategy to adapt.”

The follow-up data are very, very important to show how many patients need a drug and how much drug we might be able to save in this population. Michael Böhm

Indeed, Kandzari said, if renal denervation is eventually cleared for use in clinical practice, it would most likely find a place in the treatment of patients who cannot get their BP under control despite medical therapy.

Regarding the magnitude of the BP-lowering effects, Kandzari said they were comparable to reductions seen in with many routinely prescribed antihypertensive agents and would be expected to prevent adverse clinical outcomes. Even greater drops would be expected, he noted, in patients with higher starting pressures. Moreover, the pilot ON MED study in patients who were uncontrolled despite antihypertensive therapy demonstrated even larger reductions in BP than observed in the OFF MED setting. It remains to be seen whether that will be replicated in the more definitive ON MED study that is ongoing, Kandzari said.

Like Itchhaporia, Kandzari said the follow-up of 3 months may not fully capture the treatment effects of renal denervation, as the on-med pilot study showed continuing declines in BP beyond that time point. Even though longer-term analyses will be confounded by the fact that patients who still have uncontrolled BP at 3 months reinitiate drug therapy, they can still show differences in the burden of medication, both in terms of the number of drugs and dose, he said.

In a panel discussion after his presentation, Böhm agreed that “the follow-up data are very, very important to show how many patients need a drug and how much drug we might be able to save in this population.”