Catheter-based renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications (SPYRAL HTN-OFF MED): a randomised, sham-controlled, proof-of-concept trial

Summary

Background

Previous randomised renal denervation studies did not show consistent efficacy in reducing blood pressure. The objective of our study was to evaluate the effect of renal denervation on blood pressure in the absence of antihypertensive medications.

Methods

SPYRAL HTN-OFF MED was a multicentre, international, single-blind, randomised, sham-controlled, proof-of-concept trial. Patients were enrolled at 21 centres in the USA, Europe, Japan, and Australia. Eligible patients were drug-naive or discontinued their antihypertensive medications. Patients with an office systolic blood pressure (SBP) of 150 mm Hg or greater and less than 180 mm Hg, office diastolic blood pressure (DBP) of 90 mm Hg or greater, and a mean 24-h ambulatory SBP of 140 mm Hg or greater and less than 170 mm Hg at second screening underwent renal angiography and were randomly assigned to renal denervation or sham control. Patients, caregivers, and those assessing blood pressure were blinded to randomisation assignments. The primary endpoint, change in 24-h blood pressure at 3 months, was compared between groups. Drug surveillance was done to ensure patient compliance with absence of antihypertensive medication. The primary analysis was done in the intention-to-treat population. Safety events were assessed at 3 months. This study is registered with ClinicalTrials.gov, number NCT02439749.

Findings

Between June 25, 2015, and Jan 30, 2017, 353 patients were screened. 80 patients were randomly assigned to renal denervation (n=38) or sham control (n=42) and followed up for 3 months. Office and 24-h ambulatory blood pressure decreased significantly from baseline to 3 months in the renal denervation group: 24-h SBP −5·5 mm Hg (95% CI −9·1 to −2·0; p=0·0031), 24-h DBP −4·8 mm Hg (−7·0 to −2·6; p<0·0001), office SBP −10·0 mm Hg (−15·1 to −4·9; p=0·0004), and office DBP −5·3 mm Hg (−7·8 to −2·7; p=0·0002). No significant changes were seen in the sham-control group: 24-h SBP −0·5 mm Hg (95% CI −3·9 to 2·9; p=0·7644), 24-h DBP −0·4 mm Hg (−2·2 to 1·4; p=0·6448), office SBP −2·3 mm Hg (−6·1 to 1·6; p=0·2381), and office DBP −0·3 mm Hg (−2·9 to 2·2; p=0·8052). The mean difference between the groups favoured renal denervation for 3-month change in both office and 24-h blood pressure from baseline: 24-h SBP −5·0 mm Hg (95% CI −9·9 to −0·2; p=0·0414), 24-h DBP −4·4 mm Hg (−7·2 to −1·6; p=0·0024), office SBP −7·7 mm Hg (−14·0 to −1·5; p=0·0155), and office DBP −4·9 mm Hg (−8·5 to −1·4; p=0·0077). Baseline-adjusted analyses showed similar findings. There were no major adverse events in either group.

Interpretation

Results from SPYRAL HTN-OFF MED provide biological proof of principle for the blood-pressure-lowering efficacy of renal denervation.

Funding

Medtronic.

Introduction

Although the ability of renal denervation to decrease renal and systemic sympathetic tone was established by Esler and colleagues¹ and early clinical trials were promising,2, 3 results of the randomised, blinded, sham-controlled SYMPLICITY HTN-3 trial⁴ did not show a statistically significant blood-pressure-lowering effect of renal denervation compared with sham treatment. Post-hoc analyses postulated that variation in adherence to medication, incomplete renal denervation, and inclusion of patients with isolated systolic hypertension might have contributed to the absence of an observable blood pressure reduction.⁵ Hence, we initiated the SPYRAL HTN-OFF MED study to test if renal denervation could indeed influence blood pressure in a blinded, sham-controlled setting. A new proof-of-concept trial was warranted because of substantial differences in trial design in previous studies. These differences included the unknown effect on blood pressure reduction because of inclusion of a different population (not treatment-resistant patients), unknown effect on blood pressure reduction with a new procedure, and unknown effect on the variability of what had previously been a secondary endpoint but was now the main focus of measurement: 24-h ambulatory blood pressure monitoring (ABPM). Since the actual blood pressure reduction relative to sham could not be predicted, a study of 120 evaluable patients randomised in a 1:1 ratio was designed to show a clinically meaningful signal focused on ABPM.

Research in context

Evidence before this study

We searched PubMed using the search terms “renal denervation” and “hypertension” for papers published in core clinical journals from Nov 1, 2012, to April 1, 2017. Ten clinical trial reports of renal denervation for treatment of hypertension were identified, as well as 27 systematic reviews, consensus statements, or meta-analyses published from Jan 1, 2015, to July 1, 2017. Early uncontrolled and unblinded trials reported large reductions in blood pressure following renal denervation in patients with uncontrolled hypertension. However, results of the randomised, sham-controlled SYMPLICITY HTN-3 trial showed no statistically significant blood-pressure-lowering benefits of this procedure compared with sham treatment, even though continued follow-ups of patients from many studies have confirmed the safety of renal denervation. Subsequent post-hoc analyses of SYMPLICITY HTN-3 suggested that ablation of the renal nerves, non-adherence to antihypertensive medications, and patient selection might have influenced these results. Continued preclinical and clinical research provided evidence for the importance of circumferential ablations in both the main renal arteries and vessel branches.

Added value of this study

The SPYRAL HTN-OFF MED trial was designed to evaluate the effect of renal denervation on blood pressure in non-medicated patients with mild to moderate hypertension. Although not powered for efficacy endpoints, patients randomly assigned to renal denervation had significant reductions in office and 24-h ambulatory blood pressure whereas those in the sham control group had much smaller, non-significant reductions. These results provide biological proof of principle for the effect of renal denervation on blood pressure when done by the described method.

Implications of all the available evidence

Results of this proof-of-concept trial will inform the design of a larger, pivotal trial that will be important for establishing the role of renal denervation in treatment of hypertension.

Because of the uncertainty of both the blood pressure reduction and standard deviation, analyses were prespecified at 40, 60, 80, or 100 patients followed up for 3 months so that if a clinically meaningful reduction was observed there could be rapid advancement to the design and initiation of a larger, powered, pivotal study. Here, we present the primary 3-month analysis of 80 patients enrolled in the SPYRAL HTN-OFF MED trial.