Long-term efficacy and safety of renal denervation in the presence of antihypertensive drugs (SPYRAL HTN-ON MED): a randomised, sham-controlled trial

Summary

Background

Renal denervation has been shown to lower blood pressure in the presence of antihypertensive medications; however, long-term safety and efficacy data from randomised trials of renal denervation are lacking. In this pre-specified analysis of the SPYRAL HTN-ON MED study, we compared changes in blood pressure, antihypertensive drug use, and safety up to 36 months in renal denervation versus a sham control group.

Methods

This randomised, single-blind, sham-controlled trial enrolled patients from 25 clinical centres in the USA, Germany, Japan, the UK, Australia, Austria, and Greece, with uncontrolled hypertension and office systolic blood pressure between 150 mm Hg and 180 mm Hg and diastolic blood pressure of 90 mm Hg or higher. Eligible patients had to have 24-h ambulatory systolic blood pressure between 140 mm Hg and less than 170 mm Hg, while taking one to three antihypertensive drugs with stable doses for at least 6 weeks. Patients underwent renal angiography and were randomly assigned (1:1) to radiofrequency renal denervation or a sham control procedure. Patients and physicians were unmasked after 12-month follow-up and sham control patients could cross over after 12-month follow-up completion. The primary endpoint was the treatment difference in mean 24-h systolic blood pressure at 6 months between the renal denervation group and the sham control group. Statistical analyses were done on the intention-to-treat population. Long-term efficacy was assessed using ambulatory and office blood pressure measurements up to 36 months. Drug surveillance was used to assess medication use. Safety events were assessed up to 36 months. This trial is registered with ClinicalTrials.gov, NCT02439775; prospectively, an additional 260 patients are currently being randomly assigned as part of the SPYRAL HTN-ON MED Expansion trial.

Findings

Between July 22, 2015, and June 14, 2017, among 467 enrolled patients, 80 patients fulfilled the qualifying criteria and were randomly assigned to undergo renal denervation (n=38) or a sham control procedure (n=42). Mean ambulatory systolic and diastolic blood pressure were significantly reduced from baseline in the renal denervation group, and were significantly lower than the sham control group at 24 and 36 months, despite a similar treatment intensity of antihypertensive drugs. The medication burden at 36 months was 2·13 medications (SD 1·15) in the renal denervation group and 2·55 medications (2·19) in the sham control group (p=0·26). 24 (77%) of 31 patients in the renal denervation group and 25 (93%) of 27 patients in the sham control group adhered to medication at 36 months. At 36 months, the ambulatory systolic blood pressure reduction was −18·7 mm Hg (SD 12·4) for the renal denervation group (n=30) and −8·6 mm Hg (14·6) for the sham control group (n=32; adjusted treatment difference −10·0 mm Hg, 95% CI −16·6 to −3·3; p=0·0039). Treatment differences between the renal denervation group and sham control group at 36 months were −5·9 mm Hg (95% CI −10·1 to −1·8; p=0·0055) for mean ambulatory diastolic blood pressure, −11·0 mm Hg (−19·8 to −2·1; p=0·016) for morning systolic blood pressure, and −11·8 mm Hg (−19·0 to −4·7; p=0·0017) for night-time systolic blood pressure. There were no short-term or long-term safety issues associated with renal denervation.

Interpretation

Radiofrequency renal denervation compared with sham control produced a clinically meaningful and lasting blood pressure reduction up to 36 months of follow-up, independent of concomitant antihypertensive medications and without major safety events. Renal denervation could provide an adjunctive treatment modality in the management of patients with hypertension.

Funding

Medtronic.

Introduction

Hypertension is the leading cause of death worldwide,¹ and a reduction in blood pressure has been shown to lower the risk of cardiovascular events and mortality.2, 3, 4, 5 Poor adherence to pharmacological treatments is frequently observed in hypertension management and highlights the need for additional treatment options.⁶ Randomised sham-controlled trials have shown the safety and efficacy of catheter-based renal denervation to lower blood pressure in the presence7, 8 and absence9, 10, 11 of antihypertensive medications. Since randomised trial primary endpoints are limited to short follow-up, whether reductions in blood pressure following renal denervation are durable or further decreased over long-term follow-up is unclear. Non-randomised catheter-based renal denervation studies have shown sustained reductions in blood pressure for up to 3 years;12, 13, 14, 15 however, data from randomised sham-controlled trials on long-term safety and efficacy are lacking and challenging to obtain because of variance in medications, influence of unblinding status among patients and health-care providers, and control group crossover to renal denervation.¹⁶ The SPYRAL HTN-ON MED trial was initially designed as a proof-of-concept study with non-powered endpoints to minimise exposure of patients to an interventional procedure. We previously reported a favourable safety and efficacy profile in these patients at 6 months⁷ and this report represents long-term safety and efficacy results. In this pre-specified analysis of the SPYRAL HTN-ON MED study,¹⁷ we compared changes in blood pressure, antihypertensive drug use, and safety up to 36 months in renal denervation versus a sham control group.

Research in context

Evidence before this study

We searched PubMed using the terms “renal denervation”, “hypertension”, and “clinical trial” for papers published in English between Jan 1, 2018, and Jan 31, 2022. The search returned 39 clinical trial reports of renal denervation for treatment of hypertension, as well as 24 review papers, 11 meta-analyses, five design papers, and two position papers or consensus. Adding the search term “medication adherence” resulted in identification of four clinical trials and three review articles.

Added value of this study

This trial investigated the long-term safety and efficacy of catheter-based renal denervation in patients with uncontrolled hypertension who were taking one to three antihypertensive drugs. The procedure was safe and associated with significant and consistent clinically meaningful long-term reductions in ambulatory blood pressure compared with a sham control procedure, with no differences in the number of antihypertensive medications. The reduction in ambulatory blood pressure following renal denervation was progressive throughout follow-up.

Implications of all the available evidence

Significant reductions in night-time and early morning ambulatory blood pressure at 24 months and 36 months could translate into reductions in cardiovascular events, including stroke and heart failure. The sustained nature of 24-h blood pressure reduction with renal denervation might be superior to treatments with antihypertensive drugs, which are often associated with non-adherence. The data support the favourable long-term safety profile of catheter-based renal denervation. Renal denervation provides an adjunctive treatment modality besides lifestyle modifications and antihypertensive medications in the management of patients with uncontrolled hypertension.