Results from SPYRAL HTN-OFF MED indicate that renal denervation, compared with a sham procedure, significantly reduces blood pressure in patients with hypertension who are not receiving antihypertensive treatment. A previous study found that renal denervation did not significantly reduce blood pressure in patients with resistant hypertension.
Three years ago, renal denervation suffered a major setback when the SYMPLICITY HTN-3 trial found that the procedure did not provide a significant benefit over a sham procedure in patients with resistant hypertension. While proponents of renal denervation were disappointed by these results, many believed it still had potential as a therapy for managing hypertension. Furthermore, subanalyses of SYMPLICITY HTN-3 indicated that there were several factors—for example, variation in adherence to medication, incomplete renal denervation, and inclusion of patients with isolated systolic hypertension—that may have confounded the results. Consequently, new trials of renal denervation were initiated that were designed to ensure that these factors were not present.
SPYRAL HTN-OFF MED, for example, evaluated renal denervation in patients who were not receiving antihypertensive medication. Additionally, the study assessed a next-generation renal denervation system that used a multielectrode catheter (Symplicity Spyral, Medtronic) as opposed to the unipolar catheter (Symplicity, Medtronic) used in SYMPLICITY HTN-3 and patients with isolated systolic hypertension were excluded from the trial.
Writing in The Lancet, Raymond R Townsend (Perelman School of Medicine University of Pennsylvania, Philadelphia, USA) and others note that the “substantial differences” between the design of SPYRAL HTN-OFF MED and those of previous studies mean that the study is a “proof-of-concept” trial. They add that, as well as the differences already mentioned, patients in the study had mild-to-moderate hypertension (rather than resistant hypertension) and that the primary endpoint was change in 24-hour ambulatory blood pressure (a secondary endpoint in SYMPLICITY HTN-3).
To be included in the study, patients had to discontinue their antihypertensive medication or be drug naive. “Absence of medication usage was evaluated by use of tandem high-performance liquid chromatography and mass spectroscopy of urine and plasma by an independent laboratory,” Townsend et al comment.
Of 80 patients who met the eligibility criteria, after the screening process, 38 were randomised to undergo renal denervation and 42 were randomised to undergo a sham procedure. Throughout the three-month follow-up period, for reasons of safety, patients’ blood pressure was assessed every two weeks. The authors comment: “If a patient’s systolic blood pressure surpassed the prespecified escape criteria threshold (≥180mmHg) and this result was confirmed by repeated measurements within 72 hours, they could receive antihypertensive drug therapy at the discretion of the investigator. Otherwise, patients remained off antihypertensive medication after randomisation until follow-up at three months.” They add that, overall, compliance with requirement to be off medication was 85.6% at baseline and at three months.
At three months, both patients in the renal denervation group and those in the sham procedure group saw a drop in 24-hour systolic blood pressure compared with their respective baseline levels: -5.3mmHg (-8.6–2mmHg) for the renal denervation group and -0.7mmHg (-4–2.5mmHg) for the sham procedure. However, this reduction was only significant for the renal denervation group (p=0.0020). Noting that the study was not powered for efficacy endpoints, Townsend et al report: “The change in blood pressure was greater at three months for the renal denervation group than for the sham control group for 24-hour ambulatory systolic blood pressure [-4.6 difference; p=0.0528] and office systolic blood pressure [-7.1 difference; p=0.0212]. The same difference was documented for 24-hour diastolic blood pressure [-4.3 difference, p=0.0028, and -5.02, p=0.0076].” They add that there were no “major safety concerns” in either group despite the absence of antihypertensive therapy and “a more aggressive renal denervation procedure than that of previous trials in this setting, extending into the renal artery branch vessels”.
Presenting the data at the European Society of Cardiology (ESC) congress (26–30 August, Barcelona, Spain), Michael Böhm (Klinik für Innere Medizin III, Universität des Saarlandes, Homburg, Germany) said that the results of SPYRAL HTN-FF MED “provide biological proof of principle for the efficacy of renal denervation” and that the procedure is associated with “clinical meaningful blood pressure reductions at three months”. He added: “Results of this feasibility study will inform the design of a larger pivotal trial”.
Commenting on the results, Bryan Williams (University of College London, London, UK) said that the concept of evaluating renal denervation in patients who were not on medication was a “very innovative idea” and that the results of SPYRAL HTN-OFF MED were interesting. However, he noted that renal denervation “did not appear to control blood pressure in the patients treated” and that these patients would still need to take medication to “achieve currently recommended blood pressure targets”. According to Williams, renal denervation has two potential uses: to treat patients with resistant hypertension and to treat patients with less severe hypertension who “want to be ‘cured’ with a one-off process that removes the need for long-terms therapy”. Observing that, at present, there are no data to support the use of renal denervation for patients in the first group, he questioned whether patients in the second group would be willing to undergo renal denervation if they had to continue to take antihypertensive medication afterwards. “It is going to be difficult to state that renal denervation competes with conventional medication for mild-to-moderate hypertension,” Williams said.
Townsend told Cardiovascular News: “After SYMPLICITY HTN-3, we felt it necessary to demonstrate that renal denervation had a discernible blood pressure effect and we sought to do so in as ‘clean’ (i.e. drug-free) fashion as possible, verified by urine/blood drug surveillance. Additionally, a redesigned catheter was used to address shortcomings identified with technique in HTN-3, and based on interval discovery science the depth of kidney vessel ablation (into the first branches) was part of the current SPYRAL HTN-FF MED study. Finally, we realised that patients with low diastolic blood pressure values had less benefit so a diastolic minimum of 90 mmHg was included in the SPYRAL HTN-OFF MED study. The protocol prespecified analyses after 40, 60 and 80 patients were treated and the analyses at the 80 patient time point, who all had three-month follow-up, confirmed the presence of a blood pressure reduction signal in both office and ambulatory blood pressure and that triggered our decision to publish the proof-of-concept phase of the current renal denervation studies”.