Καινοτόμες θεραπείες στον υπερτασικό ασθενή: SPYRAL project

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1 Καινοτόμες θεραπείες στον υπερτασικό ασθενή: SPYRAL project Κων/νος Τσιούφης Αναπληρωτής Καθηγητής Καρδιολογίας ΕΚΠΑ Πρόεδρος Ελληνικής Καρδιολογικής Εταιρείας President of European Society of Hypertension (ESH)

2 Δήλωση σύγκρουσης συμφερόντων Έχω λάβει υποστήριξη συμμετοχής σε συνέδρια ή ερευνητική υποστήριξη ή τιμητική αμοιβή ομιλίας από Medtronic, St. Jude Medical, Bayer, Novartis, Astra-Zeneca, Boehringer In, Pfizer, Chiesi, Pharmanel, Sanofi, Vianex, Win-Medica, Elpen, Menarini.

3 Percentage of global deaths for males in 2010 by cause and age Globally, CVD is the most common non-communicable cause of death CV disease Cancer War and disaster Intentional injuries Unintentional injuries Transport injuries Other non-communicable diseases Musculoskeletal disorders Diabetes, urogenital, blood, and endocrine Mental and behavioural disorders Neurological disorders Cirrhosis Chronic respiratory diseases Cardiovascular and circulatory diseases Cancer Other communicable diseases Nutritional deficiencies Neonatal disorders Maternal disorders Neglected tropical diseases and malaria Diarrhoea, lower respiratory infections, and other common infectious diseases HIV/AIDS and tuberculosis Lozano et al. Lancet 2012;380:

4 Hypertension: A Global Health Crisis Chow et al. JAMA 2013;310:959-68

5 ΕΘΝΙΚΟ & ΚΑΠΟΔΙΣΤΡΙΑΚΟ ΠΑΝΕΠΙΣΤΗΜΙΟ ΑΘΗΝΩΝ ΙΑΤΡΙΚΗ ΣΧΟΛΗ ΠΡΟΓΡΑΜΜΑ ΜΕΤΑΠΤΥΧΙΑΚΩΝ ΣΠΟΥΔΩΝ «ΑΡΤΗΡΙΑΚH ΥΠEΡΤΑΣΗ ΚΑΙ ΚΑΡΔΙΑΓΓΕΙΑΚA- ΝΕΦΡΙΚA ΝΟΣHΜΑΤΑ» «To Πρόγραμμα στοχεύει στην παροχή υψηλού επιπέδου εκπαίδευσης και εξειδίκευσης στο αναπτυσσόμενο αντικείμενο της Υπέρτασης και των συνοδών καρδιαγγειακών και νεφρικών νοσημάτων, στην πρακτική εξάσκηση και στην προαγωγή της έρευνας σε αυτά τα γνωστικά αντικείμενα.» Ακαδημαϊκά Έτη & Οι ενδιαφερόμενοι καλούνται να υποβάλλουν αίτηση από την 21 η Μαΐου 2018 μέχρι την 25 η Ιουνίου 2018 Υποψήφιοι Μεταπτυχιακοί Φοιτητές Πτυχιούχοι Τμημάτων Ιατρικής Πτυχιούχοι Χαροκόπειου Πανεπιστημίου Πτυχιούχοι Φαρμακευτικής Σχολής Πτυχιούχοι Οδοντιατρικής Σχολής Πτυχιούχοι Νοσηλευτικής ΑΕΙ Πτυχιούχοι Τμήματος Βιολογικού

6 Blood Pressure Control in ESH Excellence Centers Blopresh study Research Project of the European Society of Hypertension To determine 1. average BP values in different ESH Excellent Centers, countries and European regions (attended and unattended BP) 2. Prevalence of uncontrolled hypertensive patients and analyze the most important factors/predictors for treatment failure in ESH Excellence Centers. 3. Preparation of strategies aiming to increase hypertension control globally but with specificities for particular countries/regions Timeframe: December 2017-December 2019

7 187 ESH Centres of Excellence

8 NEW ESC/ESH HTN guidelines June Annual Meeting Barcelona

9 Interventional therapy for (Resistant) Hypertension 2009-Renal Denervation Carotid Baroreceptor Stimulation Iliac A-V anastomosis

10 RDN: Strong pathophysiological background Papademetriou V, Tsioufis C, Doumas M. Circulation 2014

11 Renal Anatomy Allows a Catheter-Based Approach RENAL DENERVATION Deliver Energy to the Renal Nerves that Help Control Blood Pressure Vessel lumen Media Adventi tia Renal nerves

12 RDN trials: Safety profile Symplicity HTN-1 Symplicity HTN-2 Symplicity HTN-3 EnligHTN 1 Reduce-HTN Global Symplicity Registry Hypotension, n Hypertensive emergency, n Renal artery stenosis >70% or in need of stent, n Significant worsening of renal function, n egfr at baseline, ml/min/1.73m ± ± ± ± ± (60-92) egfr at follow-up, ml/min/1.73m ± ± ± ± ± (57-89)

13 RDN: Efficacy to lower BP 2009 RDN Amazing Easy Anyone can DO! HTN-3 Data on intermediate end points New Clinical Trials 2017 RDN Works DENER Subanalyses of HTN : RDN Doesn t Work Animal Data

14 SPYRAL HTN Clinical Program Addressing Confounding Factors 1 Identified from SYMPLICITY HTN-3 Superior Anterior Inferior Posterior Medications Patients Procedure SYMPLICITY HTN- 3 Drug changes and variable patient adherence Heterogenous study population Procedural experience and variability SPYRAL HTN Off and On Med studies with drug compliance testing Excluding isolated systolic hypertension patients Spyral catheter, branch treatment, case proctoring

15 Renal Nerve Distribution Renal nerves may have a positional bias on radial distance from arterial lumen; distal nerves are closer Distal Proximal Prior concept uniform radial distribution Distal Proximal Current concept nonuniform radial distribution Sakakura K, et al. J Amer Coll Cardiol. 2014;64:

16 IVY Pre Clinical Trial: Combined Treatment in Main Artery and Branch Vessels in Porcine Model %NE Change ± SD -71 ± 27% -83 ± 21% -92 ± 9% Pre-clinical porcine data show significantly greater reductions in renal sympathetic activity with combined proximal and distal therapy application. Mahfoud et al. J Am Coll Cardiol. 2015;66:

17 SPYRAL HTN ON MED Study Office BP Office BP ABPM Office SBP >150 and <180 mm Hg on 1,2 or 3 meds for 6 weeks Confirmed on meds Thiazide-type diuretic Calcium channel blocker ACE/ARB Beta Blocker Stable meds 1st screening Office SBP 2 4 weeks 2nd screening Urinalysis Observed drug intake Office SBP ABPM ABPM 140 to <170 Office 150 and <180 DBP 90 N<50 Renal denervation + meds Randomisation/ Procedure Sham procedure + meds N<50 Drug testing 1 Mo 3 Mo 6 Mo 1 Mo 3 Mo 6 Mo Mo Unblinding 12 Mo

18 SPYRAL HTN OFF MED Study Follow-up every 2 weeks (through 3 mo) Med titration every 2 weeks if uncontrolled 3 Mo 6 Mo 12 Mo Patients with HTN Screening visit 1 Office SBP Taken off medications 2-week safety check 3-week washout SBP>180 Screen failure Screening visit 2 Baseline ABPM Office SBP ABPM 140 to 170 mm Hg Office 150 to <180 mm Hg DBP 90 mm Hg 4-week washout N<60 Renal denervation Randomisation/ procedure Sham procedure N<60 Follow-up every 2 weeks (through 3 mo) 3 Mo 6 Mo Unblinding Mo Represents study safety measures Drug testing to confirm washout at Screening visit 2 and 3 mo; drug testing at 6 mo and 12 mo

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21 Mean ± SD SPYRAL HTN OFF MED Baseline Blood Pressure RDN Sham Control Office measurements N = 38 N = 42 Office SBP (mm Hg) ± ± 6.4 Office DBP (mm Hg) 99.9 ± ± 7.5 Office heart rate (bpm) 71.1 ± ± hour measurements N = 37 N = 42 Mean 24-hour SBP (mm Hg) ± ± 7.4 Mean 24-hour DBP (mm Hg) 99.1 ± ± 8.2 Mean 24-hour heart rate (bpm) 72.3 ± ± 11.5 P = NS for differences in all baseline characteristics R. Townsend.. C. Tsioufis, D. Tousoulis...M. Bohm, Lancet 2017

22 Mean ± SD SPYRAL HTN OFF MED Baseline Blood Pressure RDN Sham Control Office measurements N = 38 N = 42 Office SBP (mm Hg) ± ± 6.4 Office DBP (mm Hg) 99.9 ± ± 7.5 Office heart rate (bpm) 71.1 ± ± 9.8! 24-hour measurements N = 37 N = 42 Mean 24-hour SBP (mm Hg) ± ± 7.4 Mean 24-hour DBP (mm Hg) 99.1 ± ± 8.2 Mean 24-hour heart rate (bpm) 72.3 ± ± 11.5! P = NS for differences in all baseline characteristics R. Townsend.. C. Tsioufis, D. Tousoulis...M.Bohm, Lancet 2017

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28 SPYRAL HTN OFF MED Procedural Details Mean ± SD RDN (N = 38) Sham Control (N = 42) Number of main renal arteries treated per patient 2.2 ± 0.5 NA Number of branches treated per patient 5.2 ± 2.5 NA Total number of ablations per patient 43.8 ± 13.1 NA Main artery ablations 17.9 ± 10.5 NA Branch ablations 25.9 ± 12.8 NA Treatment time (min) 57.1 ± 19.7 NA Contrast volume used (cc) ± ± 38.5 R. Townsend.. C. Tsioufis, D. Tousoulis...M. Bohm, Lancet 2017

29 SPYRAL HTN OFF MED Laboratory Values at Baseline and 3 Months Mean ± SD Baseline Change at 3 months RDN Sham RDN Sham Plasma Renin Activity (ng/ml/h) 0.93 ± ± ± ± 0.80 Aldosterone (ng/dl) 7.54 ± ± ± ± 6.24 Serum Creatinine (mg/dl) 0.93 ± ± ± ± 0.09 egfr (ml/min/1 73 m 2 ) ± ± ± ± Glucose (mmol/l) 5.50 ± ± ± ± 1.34 Potassium (mmol/l) 4.17 ± ± ± ± 0.44 Sodium (mmol/l) ± ± ± ± 2.70 R. Townsend.. C. Tsioufis, D. Tousoulis...M. Bohm, Lancet 2017

30 BP Change from baseline to 3 months (mmhg) SPYRAL HTN OFF MED Blood Pressure Change from Baseline to 3 Months: Office BP (-15.1, -4.9) P<0.001 Systolic -2.3 (-6.1, 1.6) P=0.24 Chart Title -5.3 (-7.8, -2.7) P<0.001 Diastolic Baseline BP (mmhg) n=37 n=41 n=37 n=41 Δ -7.7 mmhg (-14.0, -1.5) P=0.02 R. Townsend.. C. Tsioufis, D. Tousoulis...M. Bohm, Lancet 2017 Δ -4.9 mmhg (-8.5, -1.4) P= (-2.9, 2.2) P=0.81 RDN

31 BP Change from baseline to 3 months (mmhg) SPYRAL HTN OFF MED Blood Pressure Change from Baseline to 3 Months: 24-Hr ABPM (-9.1, -2.0) P=0.003 Systolic -0.5 (-3.9, 2.9) P=0.76 Chart Title -4.8 (-7.0, -2.6) P<0.001 Diastolic Baseline BP (mmhg) n=35 n=36 n=35 n=36 Δ -5.0 mmhg (-9.9, -0.2) P=0.04 Δ -4.4 mmhg (-7.2, -1.6) P= (-2.2, 1.4) P=0.65 R. Townsend.. C. Tsioufis, D. Tousoulis...M. Bohm, Lancet 2017 RDN

32 BP Change from baseline to 3 months (mmhg) SPYRAL HTN OFF MED Blood Pressure Change at 3 Months hr SBP 24-hr DBP Office SBP Office DBP Baseline BP (mmhg) (-9.1, -2.0) P= (-3.9, 2.9) P=0.76 Chart Title n=35 n=36 n=35 n=36 n=37 n=41 n=37 n=41 Δ -5.0 mmhg (-9.9, -0.2) P= (-2.2, 1.4) P= (-6.1, 1.6) -4.8 P=0.24 (-7.0, -2.6) P<0.001 Δ -4.4 mmhg (-7.2, -1.6) P= (-15.1, -4.9) P<0.001 Δ -7.7 mmhg (-14.0, -1.5) P=0.02 R. Townsend.. C. Tsioufis, D. Tousoulis...M. Bohm, Lancet (-7.8, -2.7) P< (-2.9, 2.2) P=0.81 Δ -4.9 mmhg (-8.5, -1.4) P=0.008 RDN

33 SPYRAL HTN OFF MED Perspective: Extrapolated Risk Reduction 20% reduction in relative risk for cardiovascular events with the presently observed OSBP 7.7 mm Hg difference between treatment groups Ettehad D, Emdin CA, Kiran A, et al. Lancet. 2016; 387:

34 SPYRAL HTN OFF MED Biologic proof of principle for the efficacy of renal denervation, not powered for statistical significance Clinically significant blood pressure reductions at 3 months In mild to moderate hypertensive patients treated with RDN In the absence of anti-hypertensive medications compared to sham control No major safety events Conclusions Despite a more complete denervation procedure that extended into renal artery branch vessels The results of this feasibility study will inform the design of a larger pivotal trial R. Townsend.. C. Tsioufis, D. Tousoulis...M. Bohm, Lancet 2017

35 SPYRAL HTN-OFF MED study: Renal denervation in the spiral orbits of current results and future studies Costas Tsioufis, Kyriakos Dimitriadis, Vasilios Papademetriou, Dimitrios Tousoulis

36 How to test for and validate achieved RDN? Mapping Ablation Verification Start Electrical stimulation Electrical stimulation Physiological markers Hot spots Ablation Physiological markers Determine Hot/Cold spot Verify efficient ablation System Tsioufis et al. Euro PCR 2017

37 Catheter Multi-electrode Flexible design Adjustable basket size System 8F GC/ GW compatible Femoral access approach Console Multi channel generator Real time physiological signals analysis using a proprietary algorithm Configurable outputs Tsioufis et al. Euro PCR 2017

38 Large variation in response per patient and per location

39 Take Home Message Confirm the diagnosis of HTN by appropriate BP measurements Sustained strict control of BP (BP<140/90mmHg) is mandatory for all hypertensive patients For those with high CV risk systolic goal BP should be close to 130 mmhg, if tolerated Avoid diastolic BP below 70 mmhg The lower the better (only in some cases) The earlier the better (always) Let s treat the patient and not only the BP number!

40 ΕΘΝΙΚΟ & ΚΑΠΟΔΙΣΤΡΙΑΚΟ ΠΑΝΕΠΙΣΤΗΜΙΟ ΑΘΗΝΩΝ ΙΑΤΡΙΚΗ ΣΧΟΛΗ ΠΡΟΓΡΑΜΜΑ ΜΕΤΑΠΤΥΧΙΑΚΩΝ ΣΠΟΥΔΩΝ «ΑΡΤΗΡΙΑΚH ΥΠEΡΤΑΣΗ ΚΑΙ ΚΑΡΔΙΑΓΓΕΙΑΚA- ΝΕΦΡΙΚA ΝΟΣHΜΑΤΑ» «To Πρόγραμμα στοχεύει στην παροχή υψηλού επιπέδου εκπαίδευσης και εξειδίκευσης στο αναπτυσσόμενο αντικείμενο της Υπέρτασης και των συνοδών καρδιαγγειακών και νεφρικών νοσημάτων, στην πρακτική εξάσκηση και στην προαγωγή της έρευνας σε αυτά τα γνωστικά αντικείμενα.» Ακαδημαϊκά Έτη & Οι ενδιαφερόμενοι καλούνται να υποβάλλουν αίτηση από την 21 η Μαΐου 2018 μέχρι την 25 η Ιουνίου 2018 Υποψήφιοι Μεταπτυχιακοί Φοιτητές Πτυχιούχοι Τμημάτων Ιατρικής Πτυχιούχοι Χαροκόπειου Πανεπιστημίου Πτυχιούχοι Φαρμακευτικής Σχολής Πτυχιούχοι Οδοντιατρικής Σχολής Πτυχιούχοι Νοσηλευτικής ΑΕΙ Πτυχιούχοι Τμήματος Βιολογικού