Baroreflex amplificatie als behandeling voor hypertensie: hype of hoop? Wilko Spiering Afdeling Vasculaire Geneeskunde

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1 Baroreflex amplificatie als behandeling voor hypertensie: hype of hoop? Wilko Spiering Afdeling Vasculaire Geneeskunde Nederlands Vasculair Forum, 1 december 2017

2 Disclosure potential conflicts of interest Research contracts: Vascular Dynamics Consulting: Vascular Dynamics Employment in industry: - Stockholder of a healthcare company: Owner of a healthcare company: Other: - - Voorzitter Nederlandse Hypertensie Vereniging Member ESC-ESH 2018 Guideline on hypertension

3 Unmet need in resistant hypertension Prevalence true resistant hypertension: ~8-10% all hypertensives ~100 million worldwide Associated with increased cardiovascular risk 1 Poor adherence to pharmacotherapy major issue 2 No promising developments in pharmacotherapy 1 Daugherty, Circulation Jung, J Hypertens 2013

4 Device-based therapy of hypertension Renal denervation Iliac AV anastomosis Carotid body ablation Deep brain stimulation Baroreflex amplification

5 Baroreflex in blood pressure control From: Freeman, N Engl J Med 2008

6 Heymans, Circulation 1951

7 Sundlöf, J Physiol 1978

8 Bristow, Circulation 1969

9 From: Wilson-Pauwels, Cranial Nerves, 3 rd edition, 2010

10 Bilgutay, Am J Cardiol 1966

11 CVRx Rheos system

12 Mechanism of action

13 Rheos Pivotal Trial: design Evaluation efficacy and safety of BAT (with Rheos) in resistant hypertension Randomized, double-blind, placebo-controlled, prospective, multicenter 2:1 randomization to immediate (n=181) or delayed (n=84) BAT 5 coprimary endpoints: Acute SBP responder rate at 6 months Sustained responder rate at 12 months Procedure safety BAT safety Device safety Sponsor: CVRx, Inc. Bisognano, J Am Coll Cardiol, 2011

14 Rheos Pivotal Trial: BP responses Bisognano, J Am Coll Cardiol, 2011

15 Rheos Pivotal Trial: efficacy and safety Efficacy: Acute SBP responder rate at 6 months Sustained responder rate at 12 months Safety: Procedure safety BAT safety Device safety

16 Long-term efficacy of Rheos de Leeuw, Hypertension 2017

21 Barostim neo Trial: design Evaluation safety and efficacy of BAT (with Barostim neo) in resistant hypertension Non-randomized, multicenter, open label n=30 Primary endpoints: Safety at 6 months Office SBP at 6 months Sponsor: CVRx, Inc. Hoppe, J Am Soc Hypertens, 2012

22 Barostim neo Trial: results Hoppe, J Am Soc Hypertens, 2012

23 Efficacy vs. side effects in Barostim neo Heusser, Hypertension 2016

24 Meta-analysis efficacy BAT Wallbach, Nephrol Dial Transplant 2017

25 Effects of BAT on office SBP Wallbach, Nephrol Dial Transplant 2017

26 Effects of BAT on office SBP Wallbach, Nephrol Dial Transplant 2017

27 Barostim neo ongoing clinical trials Study n Design Primary outcome Completion date ESTIM-rHTN, NCT Randomized, open label (PROBE) 24-hr daytime SBP, incremental costeffectiveness ratio at 12 months November 2018 Nordic BAT, NCT Randomized, double blind 24-hr SBP at 16 months November 2020

28 Vergoeding

29 BAT: de nadelen Chirurgie noodzakelijk Risico op zenuwbeschadiging Mapping met electrode noodzakelijk Duur (~ voor eerste implantatie) Pacemaker (~ ) moet elke 3-5 jaar vervangen worden Geen vergoeding

30 Samenvatting BAT Niet bewezen effectief Lijkt veilig (Barostim neo) Meeste klinische data van systeem dat niet meer bestaat Duur Geen vergoeding In afwachting van 2 RCTs

31 MobiusHD device Transfemoral delivery 3 different sizes: ( mm) Implanted into carotid sinus Increases wall tension and sensitizes baroreceptor

32 MobiusHD mechanism of action Diastole Systole Untreated vessel r Strain proportional to radius MobiusHD implant r eff r ε = p 2r te Carotid stent r 0 Baroreceptor function blunted ε = p 2r te ε = wall strain p = pressure inside artery r = radius t = wall thickness E = Young s modulus

33 MobiusHD in canine model

34 Controlling And Lowering blood pressure with the MobiusHD (CALM-FIM) study Prospective, open-label, multicenter, first-in-man, safety study CALM-FIM_US (20 patients) and CALM-FIM_EUR (30 patients) Severe resistant hypertension: Office SBP 160 mmhg 3 antihypertensives, of which one is a diuretic Main exclusion: obstructive carotid disease Primary outcome: incidence of SAEs and unanticipated adverse device effects (UADE) at M6 Secondary outcomes: changes in OBP, 24-hr ABP, antihypertensive medication Follow-up: 3 years Sponsor: Vascular Dynamics Inc.

35 Procedures All interventionalists had experience with >100 carotid stent placements Duplex and CTA/MRA prescreening of ICAs with central review Start DAPT 3 days before implantation 30 implantations: Netherlands: 28 implantations in 5 centers (14, 7, 4, 2, 1) Germany: 2 implantations in 1 center 19 in right ICA and 11 in left ICA 8 size A, 20 size B and 2 size C

36 Baseline characteristics Patients undergoing implantation Total 30 Age, years 52 (12) Women 15 (50%) Ethnic origin (non-white) 3 (10%) Cardiovascular disease -coronary artery disease -cerebrovascular disease -peripheral artery disease 5 (17%) 4 (13%) 2 (7%) Prior renal denervation 8 (27%) BMI, kg/m (5.2) egfr, ml/min/1.73m 2 83 (17)

37 Blood pressure and medication Patients undergoing implantation Office blood BP, mmhg 184/110 (19/15) Office heart rate, bpm 76 (11) Ambulatory BP, mmhg 166/100 (17/14) Number of antihypertensives 4.4 (1.3) DDD 6.8 (4.8) Diuretic 30 (100%) Taking A/C/D regimen 25 (83%) Mineralocorticoid antagonist 17 (57%)

38 Serious adverse events Event Number (%) of patients Intervention Hypotension* 2 (7%) Reduction in antihypertensive dose Worsening hypertension* Intermittent claudication 2 (7%) Increase in antihypertensive dose Outcome Resolved without sequelae Resolved without sequelae 1 (3%) Thromboendarterectomy Resolved without sequelae Wound infection 1 (3%) Wound irrigation and antibiotic *Occurred subsequently in the same patient and were coded as 1 event Resolved without sequelae

39 Adverse events 2 Event Number (%) of patients Intervention Dizziness 9 (30%) Reduction in antihypertensive dose Outcome Resolved without sequelae Musculoskeletal pain 7 (23%) Pain medication Resolved without sequelae Hypotension 5 (17%) Reduction in antihypertensive dose Resolved without sequelae Groin haematoma 3 (10%) No treatment required Resolved without sequelae Fatigue 2 (7%) No treatment required Resolved without sequelae Headache 2 (7%) Pain medication Resolved without sequelae Pseudo-aneurysm 2 (7%) Thrombin injection Resolved without sequelae TIA 2 (7%) No treatment required Resolved without sequelae

Change from baseline, mmhg Office blood pressure DDD -12.4% -17.2% -22.5% -19.9% -18.4% 0-5 -10-15 -20-25 -30-35 -40 p<0.0001 p=0.0002 p=0.0003 p=0.0020 p=0.0169 p=0.

40 Change from baseline, mmhg Office blood pressure DDD -12.4% -17.2% -22.5% -19.9% -18.4% p< p= p= p= p= p= p= p= p= SBP DBP p< day 7 days 1 month 3 months 6 months Baseline SBP, mmhg Baseline DBP, mmhg

Change from baseline, mmhg 24-hr ambulatory blood pressure DDD -19.9% -18.4% 0-5 -10-15 p=0.0020 p<0.

41 Change from baseline, mmhg 24-hr ambulatory blood pressure DDD -19.9% -18.4% p= p< SBP DBP p= p< months 6 months Baseline SBP, mmhg Baseline DBP, mmhg

42 Determinants of blood pressure response Subgroup n Baseline 24-hr asbp, mmhg Change 24-hr asbp at 6 months, mmhg p value All (153 to 179) -18 (-33 to -6) p=0.008 Age 50 years (149 to 179) -20 (-40 to -6) p=0.697 Age >50 years (153 to 181) -18 (-33 to -2) Male (152 to 179) -18 (-32 to -7) p=1.000 Female (153 to 180) -18 (-43 to -5) Baseline BMI <29.0 kg/m (153 to 180) -18 (-31 to -5) p=0.951 Baseline BMI 29.0 kg/m (149 to 178) -19 (-42 to -6) Baseline 24-hr asbp <168 mmhg Baseline 24-hr asbp 168 mmhg (141 to 163) -9 (-19 to -3) p= (176 to 183) -29 (-44 to -14)

43 Determinants of blood pressure response Subgroup n Baseline 24-hr asbp, mmhg Change 24-hr asbp at 6 months, mmhg p value Baseline heart rate 75 bpm (153 to 178) -15 (-29 to -7) p=0.377 Baseline heart rate >75 bpm (152 to 183) -18 (-43 to -5) Baseline egfr (161 to 179) -16 (-33 to -6) p=0.914 ml/min/1.73m 2 Baseline egfr > (148 to 181) -19 (-42 to -5) ml/min/1.73m 2 Prior renal denervation (162 to 183) -31 (-49 to -7) p=0.219 No prior renal denervation (151 to 179) -16 (-30 to -6) Device implantation right ICA (149 to 183) -14 (-32 to -4) p=0.216 Device implantation left ICA (159 to 178) -24 (-44 to -12)

44 The Lancet, September 1, 2017

45 Samenvatting EBA Lijkt veilig Substantiele bloeddrukverlaging met minder gebruik bloeddrukverlagers In afwachting van sham-gecontroleerde, dubbelblinde RCTs

46 Hype of hoop?

CIC-P Nancy. Disclosures

CIC-P Nancy. Disclosures Pr Patrick Rossignol Inserm 1433 Clinical Investigation Center Hypertension and Heart Failure Unit Association Lorraine pour le Traitement de l Insuffisance Rénale (ALTIR) CHRU, Lorraine University Nancy,