Les techniques interventionnelles dans le traitement de l hypertension artérielle: faut-il y croire encore?

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1 Les techniques interventionnelles dans le traitement de l hypertension artérielle: faut-il y croire encore? Prof M Burnier Service de Néphrologie et Hypertension, CHUV, Lausanne Evian 2015

2 Approches non-médicamenteuses du traitement de l hypertension La dénervation rénale: encore en vie? La barostimulation La création d une fistule AV

3 The Renal Sympathetic Nervous System Johns E et al. Compr Physiol 2011, 1:

4 Catieter-based reoam synqatietjc deoervatjpo gpr resjstaot iyqerteosjpo- a numtjceotre sagety aod qrppg-pg-qrjocjqme cpiprt study Krum H et al. Lancet 2009; 373:

5 Symplicity HTN-2: OBP reduction at 6 months Symplicity HTNI. Lancet. 2010;376(9756):

6 RDN Basemjoe vamues aod 6-npoti ciaohes jo systpmjc qressure jo 109 qatjeots 0 Oggjce 24-i Daytjne Njhittjne Uoadkusted Adkusted Fpr basemjoe BP Aod ceoter P<0.03 gpr amm Meao N druhs- 4.7 tp 4.4 (q=0.001) Persu A. et am., Jpuroam pg Hunao Hyqerteosjpo (2013), 1 7

7 RDN 24-i systpmjc bmppd qressure resqpose at 6 npotis -5.9 mmhg % Basemjoe FU Ppst-RDN Persu A. et am., Jpuroam pg Hunao Hyqerteosjpo (2013), 1 7

8 RDN/SE 24-h systolic blood pressure response at 6 months compared with Syst-Eur mmhg mmhg mmhg % % % Baseline FU -75 Baseline FU -75 Baseline FU Post-RDN Syst-Eur placebo Syst-Eur treatment Persu A. et al., Journal of Human Hypertension (2013), 1 7

9 SYMPLICITY HTN-3: Severe Drug-Resistant HTN Office SBP 160 mm Hg 2:1 randomization, blinded and controlled Sham procedure in control patients that included renal angiogram 535 subjects randomized out of 1441 enrolled (63% screen failure rate) 2-week screening process, including maximum tolerated doses of antihypertensives 2 weeks Home BP & HTN med confirmation 1 mo Sham Procedure 2 weeks 3 mo 6 mo Home BP & HTN med confirmation Screening Visit 1 Office SBP 160 mm Hg Full doses 3 meds No med changes in past 2 weeks No planned med changes for 6 mo Screening Visit 2 Office SBP 160 mm Hg 24-h ABPM SBP 135 mm Hg Documented med adherence Renal angiogram; Eligible subjects randomized Renal Denervation 1 mo 3 mo Home BP & HTN med confirmation 2 weeks Primary endpoint 6 mo mo Patients, BP assessors, and study personnel all blinded to treatment status No changes in medications for 6 M Bhatt et al. NEJM DOI: /NEJMoa

10 Prjnary Eggjcacy Eodqpjot Oggjce Systpmjc Bmppd Pressure at 6 Mpotis, 5 nnhh Suqerjprjty Marhjo N = 353 N = 171 RDN Control P value Baseline SBP mo SBP Change P < P < (-6.89, 2.12), P = (Primary analysis with 5 mm Hg superiority margin) Did not meet primary efficacy endpoint Bhatt et al. NEJM DOI: /NEJMoa

11 Secondary Efficacy Endpoint Ambulatory Systolic Blood Pressure at 6 Months, 2 mm Hg Superiority Margin N = 325 N = 159 Baseline SBP RDN Control P value mo SBP Change P < P < (-4.97, 1.06), P = (ITT analysis with 2 mm Hg superiority margin) Did not meet secondary efficacy endpoint Bhatt et al. NEJM DOI: /NEJMoa

12 Pre-Sqecjgjed Subhrpuq Aoamysjs RDN Sham Difference (95% CI) P value Interaction P value All patients (-8.63, 0.49) All patients* (-6.89, 2.12) Diabetics (-11.51, 2.46) Non-diabetics (-9.55, 2.62) Male (-7.63, 3.03) Female (-14.94, 1.65) African American (-7.27, 11.78) c Non-African American (-11.81, -1.44) BMI < (-11.47, 5.93) BMI (-9.76, 1.03) On AA at BL (-17.63, 1.52) Not on AA at BL (-8.42, 1.93) egfr < (-8.29, 9.37) c c egfr (-10.51, 0.06) Age < (-11.06, -0.40) Age (-8.80, 8.99) Any med change (-13.49, 2.67) No med change (-8.83, 1.96) * ITT population, 5 mm Hg superiority margin test mm Hg RDN Better Control Better Bhatt et al. NEJM DOI: /NEJMoa

13 HTN-3: Different Control Response in African American Population Bhatt et al. NEJM DOI: /NEJMoa

14 Multiple Unblinded Trials Show RDN Lowers Blood Pressure Medtronic EnligHTN/St Jude Vessix/Boston Sci. Maya/Covidien Recor Published Sources: 1. Lancet Lancet TCT Journal of Human Hypertension Circulation Clin Res Cardiol J Am Soc Nephrol Eur Heart J TCT Eurointervention EuroIntervention 2013

15 The French DENERHTN study: an open label multicenter RCT Azizi M. et al. The Lancet 2015

16 Schéma de DENERHTN RDN No RDN

17 BP results of DENERHTN

18 Azizi M. et al

19 Resistant hypertension? Assessment of adherence by toxicological urine analysis. Juoh, Omjver et am Jpuroam pg Hyqerteosjpo. 31(4) ,2013 2

20 Mesures des taux urinaires chez 57 patients avec HTA résistante Ratjp = opnbre de tests urjoajres ofhatjgs/opnbres de tests nfdjcaneoteux tptaux

21 Monitoring of drug levels improve BP control in follow-up visits Brjoler et am, JACC, Marci 2014

22 What is the exact location of renal sympathetic nerves? Sakakura K et al. J Am Coll Cardiol 2014;64:635 43

23 Density of SN according to localisation Number of nerves (n) Sakakura K et al. JACC 2014;64: Mahfoud F. et al. JACC, 64, Issue 7, 2014, Pages

24 Position du cathéter de dénervation et réduction des catécholamines

25 In sheeps, renal sympathetic nerve activity and the response to electrical stimulation is back to normal 11 months after RDN Booth LC et a. Hypertension. 2015;65: DOI: /HYPERTENSIONAHA

26 Nouveau programme de développement de la dénervation rénale: SPYRAL HTN Global Clinical Trial Program Approximately 100 patients with moderate- to high-risk hypertension. These studies will be conducted at approximately 20 centers. The SPYRAL HTN-OFF MED study is designed to isolate the effect of renal denervation on blood pressure reduction. The SPYRAL HTN-ON MED study will evaluate the effect of renal denervation on blood pressure in the presence of antihypertensive medication. the SPYRAL HTN-ON MED study requires patients who, despite use of drugs from three of the most common classes of medications prescribed for hypertension, do not achieve adequate blood pressure control. Additionally, patient medication adherence will be closely monitored and there will be a focus on ambulatory blood pressure monitoring (ABPM) to ensure consistency between both arms of the on- and off-medication studies. Medtronic press release, April 2015

27 B. Williams, ESC meeting London 2015

28 An historical perspective on our understanding of baroreceptor physiology Victor, R. G. (2015) Carotid baroreflex activation therapy for resistant hypertension Nat. Rev. Cardiol. doi: /nrcardio

29 Regulation of blood pressure via the baroreflex Courand PY et al. Archives of Cardiovascular Diseases, Volume 107, Issue 12, 2014,

30 The old and the new

31 Barostim neo Improved Technology Platform Procedural Improvements Sjohme emectrpde (vs. twp numtj-qrpohed emectrpdes) Patjeot qpsjtjpojoh Siprter qrpcedure tjne aod ipsqjtam stay (1 ipur aod 1 day vs. 3 ipurs aod 2 days) Substaotjammy jnqrpved sagety qrpgjme Product Improvements Sjhojgjcaotmy snammer mead desjho Lpoher battery mjge MRI cpnqatjbme 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 2nd Generation neo +4x improvement 1st Generation Rheos Months from Implant 31

32 The Barostim neo-system From CVRx site

33 Response repeatability of arterial blood pressure and relative total MSNA over time in a patient Karsten Heusser et al. Hypertension. 2010;55:

34 Effect of chronic electric baroreceptor stimulation on LF and HF power during chronic carotid receptor stimulation Wustmann K et al. Hypertension. 2009;54:

35 Correlation between the systolic BP difference and the LF:HF ratio Wustmann K et al. Hypertension. 2009;54:

36 Changes in systolic and diastolic BP after unilateral or bilateral baroreceptor activation therapy. de Leeuw P W et al. Hypertension. 2015;65:

37 Relationship between changes in resting heart rate and resting systolic BP with baroreceptor activation therapy on the left side (A) or on the right side (B). de Leeuw P W et al. Hypertension. 2015;65:

38 Clinical studies with baroreceptor activation in resistant hypertension Zannad F et al. Hypertension. 2015;65:5-15.

39 Effect of chronic baroreceptor activation in DeBut-HT Jan Menne et al. Nephrol. Dial. Transplant. 2013;28:

40 Long-term BP effects of baroreceptor stimulation: the DEBuT-HT study 0 Systolic (Baseline = 193 ± 36 mmhg) Diastolic (Baseline= 111 ± 20 mmhg) Heart Rate (Baseline= 74 ± 12.8 mmhg) N = year 2 years Anti-hypertensive Medications Changes Baseline year years 4 years 5 years 2 years years years Scheffers et al., J. Am. Coll. Cardiol. 2010;56; Kroon et al, ASH years

41 Sustained reduction in 24-hour ABPM in DEBuT-HT 0 Systolic (Baseline: 176 mmhg) Diastolic (Baseline: 107 mmhg) Heart Rate (Baseline: 80 bpm) * -6^ * -13^ -11* ^ *All p values < ^All p values < year (n=15) 2 years (n=8) Scheffers et al., J Am Coll Cardiol 2010;56:1254 8

42 Schematic representation of the Rheos pivotal trial. John D. Bisognano, et al Baroreflex Activation Therapy Lowers Blood Pressure in Patients With Resistant Hypertension : Results From the Double- Blind, Randomized, Placebo-Controlled Rheos Pivotal Trial Journal of the American College of Cardiology, Volume 58, Issue 7, 2011,

43 Long term results from the Rheos trials Part a reprinted from Bisognano, J. D. et al. J. Am. Coll. Cardiol. 58, (2011), Part b adapted from Bakris, G. L. et al. J. Am. Soc. Hypertens. 6, (2012), Victor, R. G. (2015) Carotid baroreflex activation therapy for resistant hypertension Nat. Rev. Cardiol. doi: /nrcardio

44 Rheos Pivotal Trial Extended Follow-up SBP No BAT BAT Goal N=322 Baseline N=294 1 Year N=255 2 Year N=238 3 Year N=214 4 Year N=114 5 Year N=34 6 Year de Leeuw et al., ESH p<

45 Rheos Study Barostim Demonstrated Pivotal Left Ventricular Trial LV Remodeling Reverse Remodeling with BAT 60 Patjeots grpn Rieps study eorpmmed jo ecipcardjphraqiy substudy SEVERELY ABNORMAL Study assessed ciaohes jo megt veotrjcumar nass jodex (LVMI) agter 12 npotis pg actjve tieraqy MODERATELY ABNORMAL 100 LVMI reductjpo js a strpoh jodjcatpr pg eggectjve ieart gajmure tieraqy At 12 npotis pg BAT, averahe reductjpo pg LVMI was 15 h/n 2 (q < 0.01) tp oprnam raohe n=60 n=60 Baseline 12 Months NORMAL Bisognano, et al, J Am Coll Cardiol

46 Effects of Barostim on Kidney Function N=23 Wallbach, et al., Am J Nephrol 2014

47 Long Term Safety of Rheos Implant 10% 8% 6% 4% 3.28% Safety Events Years 2-5 System/Procedure 0.037% Stroke 0.014% Myocardial Infarction % Rate per Patient Year 2% 0% 1.18% 1.25% 0.23% 0.55% 0.23% Baseline Year 1 Year 2 Year 3 Year 4 Year 5 > 60% Carotid Stenosis (%) de Leeuw et al., ESH/ISH 2014

48 Effet du coupleur artério-veineux (ROX coupler) sur la pression artérielle dans l hypertension résistante Lobo et al, Lancet 2015; 385:

49 Conclusions Renal denervation works in some patients with resistant hypertension but more evidence needs to be acquired. Baroreceptor stimulation appears to be effective and safe in patients with resistant hypertension Preliminary data suggest that the BP changes induced by baroreceptor stimulation are associated with a regression of target organ damages (LVH, albuminuria). However, a larger clinical experience is needed and a larger endpoint trial with morbidity and mortality data should be performed. The ROX device may be effective but is associated to too many side effects and long term risks have not been assessed.