March 29, 2020The Lancet
Efficacy of catheter-based renal denervation in the absence of antihypertensive medications (SPYRAL HTN-OFF MED Pivotal): a multicentre, randomised, sham-controlled trial
Michael BöhmKazuomi KarioDavid E. KandzariFelix MahfoudMichael A. WeberRoland E. SchmiederKonstantinos TsioufisStuart PocockD. KonstantinidisJames W. ChoiCara EastDavid P. LeeAdrian MaSebastian EwenDebbie L. CohenRobert L. WilenskyChandan DevireddyJanice P. LeaAxel SchmidJoachim WeilTolga AgdirliogluDenise ReedusBrian JeffersonRichard D’SouzaAndrew S.P. SharpFaisal SharifMartin FahyVanessa DeBruinSidney A. CohenSandeep BrarRaymond R. TownsendErtan AkarcaSuhail AllaqabandE. AndrikouJiro AokiAhran ArnoldHerbert D. AronowMasahiko AsamiWilliam BachinskyKyle BassBryan BatsonChris BellBarry BertoletYvonne BewarderKarl BihlmaierChristian BinnerJason BloomBenjamin BlossomSomjot BrarAngela L. BrownRobert E. BurkeMartin BurkeWilliam J. CalhounNeil ChapmanCraig A. ChasenShi-Chi ChengBeth ChiaNishit ChoksiJordana B. CohenNiall ConnollyJohanna ContrerasRonan CusackGeorge DangasShukri DavidJustin E. DaviesJuliane DedererMatthew G. DenkerUdo DeschMatthaios DidangelosThomas DienemannKyriakos DimitriadisJean‐François DorvalJ. Murray EstessSarah FanKarl FenglerMarat FudimValentı́n FusterFidel GarciaSantiago GarciaAlex GartonC. GesslerMagdi GhaliBharat GummadiAmit GuptaAntonio GutiérrezPeggy HardestyPhillip HartungWalter Herbert HaughtYonghong HaunSara HaysWolfgang HelmreichIngrid HopperYu HoriuchiSatoshi HoshideJames P. HowardWanda IkedaFued JanRajiv JauharDesmond JayJames G. JohnsonSchuyler JonesSusanne JungTheodoros KalosMihar KanitkarDennis KannenkerilAlexandros KasiakogiasSamer KazzihaDaniel KeeneJayant KhithaHosei KikushimaTaisei KobayashiKota KomiyamaTakahiro KomoriJohn KotterAntonios ΚouparanisJoshua KrasnowSaarraangan KulenthiranSarwan KumarPhilippe L. L’AllierPhillip LaneyLucas LauderMarc Andre LavoieMatthias LercheElena LineskyNelson LittleCarl LomboyJelena LučićPhilipp LurzPrakash MansukhaniKatie McDuffieBrent McLaurinAshley M. MeadePerwaiz MerajDominic MillenaarNaing MoorePhillip MünchJames E. MurphyJennifer MurrayAravinda NanjundappaKai NinomiyaYusuke ObaTim O'ConnorYukiyo OgataYukako OgoyamaRachel OnsrudChristian OttBimal B. PadaliyaNeha J. PagidipatiManesh R. PatelKiritkumar PatelEmanouela PetteinidouWendy PorrAnjani RaoRabia RaziChristopher ReganMichael S. RemetzDavid G. RizikMonique RobisonKarl‐Philipp RommelLiesbeth RosseelMarcos RothsteinRandolph RoughSouhell SabaRobert S. SchwartzShaun SelcerSayan SenJacqueline SennottRamin ShadmanSamit ShahDouglas SheminHayato ShimizuMasahisa ShimpoMehdi H. ShishehborMatthew Shun‐ShinFrancisco SierraJasvindar SinghAvneet SinghYassir SirajeldinNedaa SkeikSarah A. StattonJulia StehliSusan SteigerwaltKristina StriepeJason StuckMarkus SuppanLaura P. SvetkeyGanpat TakkerKengo TanabeTetsu TanakaDaijiro TomiiSabino R. TorreJay H. TraverseCrystal C. TysonAlejandro Arias VásquezEnrique M. VelasquezSreekanth VemulapalliHirotaka WakiTony WaltonYale WangThomas WeberBryan J. WellsThomas WrightKazuyuki YahagiAlan C. YeungRay ZadeganThomas ZellerKhaled M. ZiadaAntonios ZiakasDavid Zidar
Key result
Renal denervation lowers 24-hour systolic blood pressure by ~4 mm Hg vs. sham at 3 months.
- MD -3.9 mm Hg
- 95% CI -6.2 to -1.6
- P=0.0005 (posterior probability of superiority >0.999)
- n=331
Figures
Why the study?
Following a positive pilot trial, the SPYRAL HTN-OFF MED Pivotal trial was designed to assess the efficacy of catheter-based renal denervation in the absence of antihypertensive medications.
Does catheter-based renal denervation reduce 24-h systolic blood pressure at 3 months compared with a sham procedure in hypertensive patients off antihypertensive medications?
Study Design
Type
RCT (n=331)
Blinding
Single-blind
Randomization
1:1
Multicenter
Yes
Structured PICO
Does catheter-based renal denervation reduce 24-h systolic blood pressure at 3 months compared with a sham procedure in hypertensive patients off antihypertensive medications?
P
Population
331 hypertensive patients off antihypertensive medications with office systolic blood pressure of 150 to <180 mm Hg across 44 international sites, followed for 3 months.
I
Intervention
Catheter-based radiofrequency renal denervation (Symplicity Spyral) in the absence of antihypertensive medications
C
Comparator
Sham procedure in the absence of antihypertensive medications
O
Outcome
Baseline-adjusted change in 24-h ambulatory systolic blood pressure from baseline to 3 months after the proceduresurrogate
Main Result
Mean Difference: -3.9 (95% CI -6.2–-1.6)
Absolute Event Rate: -4.7% vs -0.6%
p-value: p=0.0005 (posterior probability of superiority >0.999)
Catheter-based renal denervation safely and significantly lowers 24-hour and office systolic blood pressure at 3 months compared with a sham procedure in hypertensive patients off antihypertensive medications.
Limitations
- No renal denervation trial has been powered for hard cardiovascular outcomes, and BP reduction remains a surrogate endpoint.
- Depending on the responder definition used, 25-40% of treated patients derive no meaningful BP reduction, and no pre-procedural variable reliably identifies responders.
- Long-term durability beyond 3 months in the blinded phase is not established in this 3-month primary analysis, and renal reinnervation remains biologically plausible.
- Short primary follow-up duration of 3 months
- Assesses blood pressure (a surrogate endpoint) rather than hard cardiovascular outcomes
- 25-40% of treated patients across RDN trials derive no meaningful blood pressure reduction and no pre-procedural variable reliably predicts individual response
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
JZJeffrey ZimmetDirector, Cardiac Catheterization Laboratory, San Francisco VA
“With the modest reductions in blood pressure observed here, few patients with hypertension in the range seen in the target population would even experience a significant reduction in medication burden, let alone achieve goal blood pressures with this treatment alone.”
“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.”
“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”
Implication
Renal denervation offers a medication-free BP-lowering option; extends pilot data with definitive sham-controlled confirmation in untreated hypertension.
Abstract
BACKGROUND: Catheter-based renal denervation has significantly reduced blood pressure in previous studies. Following a positive pilot trial, the SPYRAL HTN-OFF MED (SPYRAL Pivotal) trial was designed to assess the efficacy of renal denervation in the absence of antihypertensive medications. METHODS: In this international, prospective, single-blinded, sham-controlled trial, done at 44 study sites in Australia, Austria, Canada, Germany, Greece, Ireland, Japan, the UK, and the USA, hypertensive patients with office systolic blood pressure of 150 mm Hg to less than 180 mm Hg were randomly assigned 1:1 to either a renal denervation or sham procedure. The primary efficacy endpoint was baseline-adjusted change in 24-h systolic blood pressure and the secondary efficacy endpoint was baseline-adjusted change in office systolic blood pressure from baseline to 3 months after the procedure. We used a Bayesian design with an informative prior, so the primary analysis combines evidence from the pilot and Pivotal trials. The primary efficacy and safety analyses were done in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT02439749. FINDINGS: From June 25, 2015, to Oct 15, 2019, 331 patients were randomly assigned to either renal denervation (n=166) or a sham procedure (n=165). The primary and secondary efficacy endpoints were met, with posterior probability of superiority more than 0·999 for both. The treatment difference between the two groups for 24-h systolic blood pressure was -3·9 mm Hg (Bayesian 95% credible interval -6·2 to -1·6) and for office systolic blood pressure the difference was -6·5 mm Hg (-9·6 to -3·5). No major device-related or procedural-related safety events occurred up to 3 months. INTERPRETATION: SPYRAL Pivotal showed the superiority of catheter-based renal denervation compared with a sham procedure to safely lower blood pressure in the absence of antihypertensive medications.
Discussion
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Cite This Study
Böhm et al. (2020) conducted an RCT in Hypertension off antihypertensive medications (n=331). Catheter-based renal denervation (Symplicity Spyral) vs. Sham procedure was evaluated on Baseline-adjusted change in 24-h systolic blood pressure at 3 months (MD -3.9 mm Hg, 95% CI -6.2 to -1.6, p=0.0005 (posterior probability of superiority >0.999)). Catheter-based renal denervation significantly reduced 24-h systolic blood pressure by -3.9 mm Hg (95% CrI -6.2 to -1.6; posterior probability of superiority >0.999) compared with sham at 3 months.