Will the SPYRAL-OFF MED pivotal trial switch our interest in renal denervation back on?

Arterial hypertension represents a major cause of death and disability, and it affects nearly one-third of the adult population worldwide.1 Our current treatment strategies are based on life-style modification and anti-hypertensive drugs. However, one-third of treated patients have poorly controlled hypertension and nearly 50% of treated patients do not comply with their medical therapy.2 Consequently, both improved blood pressure control and better compliance with therapy are significant unmet clinical needs in the management of arterial hypertension. Surgical lumbar sympathectomy was one of the initial treatment approaches,3 and it was effective in controlling blood pressure but because of postural hypotension, it was ultimately dismissed as ‘easier’ pharmacological alternatives became available. Notably however, surgical lumbar sympathectomy did demonstrate the role of the sympathetic nervous system in blood pressure regulation and it demonstrated the potential to control hypertension by modulating the activity of the afferent and efferent renal nerves. On this premise, percutaneous catheter-based renal denervation (RDN) has been extensively investigated over the past decade. Different approaches, ranging from radiofrequency, to ultrasound, to alcohol-ablation have all been investigated with the aim of interrupting both the afferent and efferent renal nerves, with the ultimate goal to modulate the hyper-sympathetic drive of the body and thus lowering blood pressure. A large body of evidence coming from basic science and animal model studies has identified various pathways through which RDN could impact on blood pressure control. By affecting the activity of the noradrenergic efferent renal nerves, RDN can impact on the renin–angiotensin–aldosterone axis by reducing the release of renin, with a consequent increase in sodium and water excretion and reduction of renal vascular resistance.2 Because of the known role of angiotensin in the inflammatory cascade, an anti-inflammatory effect of RDN has also been proposed.2 By affecting the activity of the afferent renal nerve, RDN could promote a neuronal remodelling of the brain stem and stellate ganglion, providing another explanation to the reported antihypertensive and anti-arrhythmic potential of RDN.2 The SYMPLICITY HTN-1 and 2 studies were the first to prove the feasibility and safety of radiofrequency-based RDN, reporting a striking 20–30 mmHg reduction in-office systolic blood pressure.4,5 This treatment effect was well above the ‘clinically meaningful’ threshold of 10 mmHg reduction in-office blood pressure, which had been related, in previous literature, to a 15% reduction in death rate, and a 25% reduction both in stroke and cardiovascular events.6 The results of these two studies generated a massive enthusiasm, which was then stalled by the outcome of the SYMPLICITY HTN-3 trial. This study was the first double-blinded sham-controlled trial ever conducted using RDN, and despite still showing a reduction in blood pressure with RDN, it did not demonstrate a significant difference when compared to the sham-control group.7 Consequently, almost overnight, the results of SYMPLICTY HTN-3 transformed RDN from being a highly promising novel therapy to it being almost completely dismissed. For this reason, the results of the SPYRAL-OFF-MED pivotal trial presented at the American College of Cardiology 2020 and published in the Lancet, were widely anticipated.8 The SPYRAL-OFF-MED pivotal trial is the result of a massive investigators’ effort in conducting a rigorous, sham-controlled double-blind study, designed to address the main limitations of the SYMPLICITY HTN-3 and powered to provide definitive proof-of-concept data about the blood-pressure-lowering effect of RDN (Figure 1). In this regard, in the SPYRAL-OFF-MED trial particular attention was focused on: restricting enrolment to patients with moderate hypertension (both systolic and diastolic) diagnosed by both office and 24-h ambulatory pressure-monitoring restricting enrolment to patients naïve to anti-hypertensive medications or in wash-out from any antihypertensive medications, as confirmed by toxicological measurement of drugs level in urine and blood mandating circumferential RDN, of both main renal artery and distal branches, to be performed by experienced and high-volume operators. In the SPYRAL-OFF-MED pivotal study, RDN was confirmed to be safe with no intra- or peri-procedural adverse events and resulted to be superior in reducing both 24-h ambulatory systolic (Δ = −4.7 mmHg) and diastolic (Δ = −3.7 mmHg) pressure (primary efficacy outcome) as office systolic (Δ =−9.2 mmHg) and diastolic (Δ =−5.1 mmHg) pressure (secondary efficacy outcome). Of note, the magnitude of RDN effect could have been even underestimated because of the short study follow-up (3 months) and because of the higher rate of patients excluded at follow-up in the control arm (16.9% vs. 9.6%) due to poor blood pressure control requiring premature re-introduction of medical therapy. Moreover, the effect of RDN on blood pressure appeared well-maintained throughout the 24-h, hinting at a therapeutic potential in nocturnal and early-morning hypertension, which is the hypertension-phenotype typically associated with the risk of future cardiovascular events. Despite these promising results, it is probably too early to consider RDN ready for prime time. The outcome of the SPYRAL-ON-MED pivotal study is awaited, and it will inform us whether the efficacy of RDN is maintained when it is combined with standard medical therapy. Moreover, further research is needed to address open questions on RDN. It remains matter of debate what are the parameters that configure the phenotype of the ideal ‘responder’ to RDN. Similarly, there is still a need to define markers or techniques to monitor, intra- or peri-procedurally, when renal nerve ablation has been optimal and whether it is complete.2 While the role of RDN in treating arterial hypertension is now under the spotlight again, thanks to the SYPRAL-OFF-MED results, the application of RDN in other clinical conditions may also be considered. Because of its effect on the afferent renal nerve, it is anticipated that RDN will lead to a reduction of the sympathetic drive and in general to a remodelling of the whole autonomic sympathetic nervous system.2 This could explain how RDN seems to be effective in reducing the occurrence of atrial fibrillation or in increasing the efficacy of atrial fibrillation ablation,9 as initially pointed by animal models, showing a lower degree of atrial fibrosis and remodelling associated with RDN.10 Similar observation was reported in models of ventricular fibrosis providing mechanistic insights about the potential of RDN in modulating left ventricular remodelling or in reducing the risk of ventricular arrhythmias or in improving the efficacy of ventricular arrhythmias ablation.11,12 By causing a reduction in the level of neuropeptide Y (marker of sympathetic nervous system activity) RDN has recently been associated with a higher degree of platelets inhibition,13 potentially opening the way about investigating the role of RDN, both in primary and secondary prevention, in selected patients with ischaemic heart disease. In conclusion, it is likely that thanks to the results of the SPYRAL-OFF-MED pivotal trial, the interest in RDN will be revitalized in the upcoming years. Hopefully, this will also open the way to a new season of well-coordinated translational and clinical research about the applicability and effectiveness of RDN, in a wide spectrum of clinical conditions which feature sympathetic overdrive. Conflict of interest: none declared. Biography: Dr Giovanni Luigi De Maria is an Interventional Cardiology Consultant working at the Oxford Heart Centre, Oxford University Hospitals NHS Foundation Trust, Oxford. He had his Medical Education and General Cardiology Training at the Catholic University of the Sacred Heart of Rome in Italy. He then completed his Clinical Fellowship in Interventional Cardiology in Oxford (UK), being also an Oxford—BRC Research Fellow from 2014 to 2018. He got awarded a PhD In ‘Clinical, Molecular and Cellular Research’ at the Catholic University of the Sacred Heart of Rome in 2019. His research activity is particularly focused in exploring the pathophysiology of acute coronary syndrome with a specific focus in investigating new cath-lab-based diagnostic and prognostic tools to guide the implementation of novel therapies. He has a significant experience in invasive coronary physiology assessment and in techniques of coronary intravascular imaging, and he is the Intracoronary Imaging Lead of the Oxford Academic Cardiovascular CT (OXACCT) corelab.