IPERTENSIONE RESISTENTE OLTRE I FARMACI

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1 IPERTENSIONE RESISTENTE OLTRE I FARMACI B.Castiglioni Cardiologia Interventistica U.O. Cardiologia 2 Dipartimento Cardiovascolare Ospedale di Circolo Varese

2 Hypertension Epidemiology Single largest contributor to death worldwide 30% Untreated 35% Treated & Controlled 35% Treated but Uncontrolled Chobanian et al. Hypertension. 2003;42(6): Every 20/10 mmhg increase in BP correlates with a doubling of 10-year cardiovascular mortality Dramatically increases risk of stroke, heart attack, heart failure, & kidney failure Only half of all treated hypertensives are controlled to established BP targets High prevalence: Affects 1 in 3 adults 1B people worldwide 1.6 B by 2025

3 L ipertensione arteriosa viene arbitrariamente definita resistente o refrattaria quando non vengano raggiunti gli obiettivi pressori raccomandati (PA clinica <140/90 mmhg oppure <130/80 mmhg in pazienti con diabete mellito di tipo 2) in presenza di una strategia terapeutica che includa modificazioni dello stile di vita e l assunzione di almeno tre classi di farmaci antipertensivi, tra cui un diuretico, a dosi adeguate. PREVALENZA IPERTENSIONE REFRATTARIA /RESISTENTE tra i pazienti con ipertensione nei paesi industrializzati 10%

4 Documento di Indirizzo 2012 della Società Italiana dell Ipertensione Arteriosa (SIIA) Possibili cause di pseudo-resistenza al trattamento farmacologico antipertensivo.

5 Elevated Morbidity and Mortality Risk Uncontrolled Hypertension Is a Risk Factor for Cardiovascular Morbidity and Mortality Chronic uncontrolled hypertension is related to cardiovascular conditions such as stroke and heart failure 1 The risk of cardiovascular death increases with rising blood pressure, every 20 mmhg rise in SBP doubles the risk of cardiovascular death (See Figure) 2-4 *Measurements taken in individuals aged years, beginning with a blood pressure of 115/75 mmhg, the data in this graph is from Lewington et al References 1. Roger VL, et al. Heart disease and stroke statistics 2011 update: A report from the American Heart Association. Circulation. 2011;123(4):e18-e Lewington S, et al. Age-specific relevance of usual blood pressure to vascular mortality: A meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360: Chobanian AV, et al. The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: The JNC 7 report. JAMA. 2003;289: The graph on this page includes data from sources 2 and 3 and was adapted from

6 Il ruolo della funzione renale e del Sistema Nervoso Simpatico (SNS) nella patogenesi dell ipertensione e documentato da un ampia letteratura scientifica e da numerose sperimentazioni cliniche. I segnali provenienti dal SNS e diretti ai reni aiutano a controllare il flusso sanguigno renale, la ritenzione dei sali e l attivazione del sistema renina angiotensina. A loro volta, i segnali afferenti al SNS provenienti dai reni e diretti al SNC scatenano meccanismi di regolazione globali, ma possono anche causare una stimolazione eccessivamente elevata. L eccessiva attivazione del SNS e strettamente correlata all ipertensione

7 Chronic augmentation of central sympathetic drive is pivotal to the pathophysiology of systemic hypertension. Myat A et al. Circ Cardiovasc Interv. 2013;6: Copyright American Heart Association, Inc. All rights reserved.

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9 Surgical Sympathectomy Grimson, Ann Surg 1941

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14 Renal Nerve Anatomy Allows a Catheter-Based Approach Spacing of e.g. 5 mm. Renal artery access via standard interventional technique 4-6 two-minute treatments per artery Proprietary RF generator Automated Low power Built-in safety algorithms 14

15 Adeguata anatomia arteria renale (calibro lunghezza- tortuosita assenza stenosi) Esperienza operatori Adeguata erogazione energia con contatto parietale ottimale Terapia antiaggregante (ASA) Gestione complicanze (trombosi-spasmo occlusione)

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18 Symplicity HTN-1 Lancet. 2009;373: Hypertension. 2011;57: Initial Cohort Reported in the Lancet, 2009: -First-in-man, non-randomized -Cohort of 45 patients with resistant HTN (SBP 160 mmhg on 3 anti-htn drugs, including a diuretic; egfr 45 ml/min) - 12-month data \ Expanded Cohort* (Symplicity HTN-1) Lancet Expanded cohort of patients (n=153) -36-month follow-up (patients n= 88 )

19 Symplicity HTN-1: BP Reductions through 3 years P<0.01 for from BL for all time points *Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.)

20 Symplicity HTN-1: Percentage Responders Over Time Responder was defined as an office SBP reduction 10 mmhg (n=143) (n=148) (n=144) (n=130) (n=107) (n=59) (n=24) (n=24) *Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.)

21 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Ipertensione arteriosa oltre i farmaci Symplicity HTN-1: Response Rate Among Non-responders at 1 Month (n=45) Responder was defined as an office SBP reduction 10 mmhg Timing rimodellamento vascolare? Ritardo resetting barocettori? Modificata attivita sistema renina-angiotensina? 58% 57% 64% 82% 100% (n=45) (n=45) (n=44) (n=39) (n=17) (n=8) 1 Month 3 Months 6 Months 12 Months 24 Months 36 Months *Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.)

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23 Symplicity HTN-2: Primary Endpoint and Latest Follow-up Primary Endpoint (6M post Randomisation) Latest Follow-up (12M post Randomisation) 10 RDN (n= 47) 0 from Baseline to 6 Months (mmhg) Diastolic Systolic Diastolic from -10 Baseline to Months (mmhg) Diastolic Systolic p <0.01 for difference between RDN and Control Systolic p <0.01 for from baseline Primary Endpoint: 84% of RDN patients had 10 mmhg reduction in SBP 10% of RDN patients had no reduction in SBP Latest Follow-up: Control crossover (n = 35): -24/-8 mmhg (Analysis on patients with SBP 160 mmhg at 6 M)

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26 REINNERVAZIONE? Studi sperimentali suggeriscono dopo denervazione renale analogo meccanismo di reinnervazione come dopo trapianto cardiaco Allo stesso modo non e noto il grado di efficacia funzionale per la perdita del contributo del nervo a mantenere feed back responsabile ipertensione

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28 Safety Event Rate 535 pazienti Safety Measures (%) Renal Denervation (N=364) Sham Procedure (N=171) Difference (95% CI) P Major Adverse Events (-0.9, 2.5) 0.67 To 6 Months 6-Month Composite Safety (-6.0, 2.2) 0.37 Death (-1.4, 1.4) 1.00 Myocardial infarction (-2.4, 2.3) 1.00 New onset ESRD Serum creatinine elevation >50% (-0.8, 2.5) 0.67 Embolic event resulting in end-organ damage (-0.3, 0.8) 1.00 Renal artery intervention Vascular complication requiring treatment (-0.3, 0.8) 1.00 Hypertensive crisis/emergency (-6.4, 1.0) 0.13 Stroke (-2.0, 1.9) 1.00 Hospitalization for new onset heart failure (-1.8, 3.4) 0.76 Hospitalization for atrial fibrillation (-0.8, 2.5) 0.67 New renal artery stenosis >70% (-0.3, 0.9) 1.00 Bhatt DL, Kandzari DE, O Neill WW, et al...bakris GL. N Engl J Med 2014

29 Results: Prespecified Subgroup Analyses * * P value for superiority with margin of 5 mm Hg Bhatt DL, Kandzari DE, O Neill WW, et al...bakris GL. N Engl J Med 2014

30 Potential Limitations Drug adherence not measured by blood levels, but adherence was measured by patient diaries at baseline and 6 months. Medication changes did occur, but results unchanged even when these patients were censored. Duration of primary endpoint may have been too short, but prior studies had found benefit by 6 months. Operator learning curve is always a possibility, but we found no relationship with procedural volume in the trial. Biological confirmation of denervation did not occur, as there is no accepted measure, but appropriate energy delivery was confirmed. Bhatt DL, Kandzari DE, O Neill WW, et al...bakris GL. N Engl J Med 2014

31 The blood pressure lowering effects of renal denervation in a real world population of patients with uncontrolled hypertension: Early outcomes from the Global SYMPLICITY Registry Michael Böhm, on behalf of the Global SYMPLICITY Registry Investigators Universitätskliniken des Saarlandes, Klinik für Innere Medizin III, Homburg/Saar, Germany Long-term safety & effectiveness Real world patient population with: Hypertension and/or Other diseases characterized by elevated sympathetic drive Procedural technique

32 Change in Office BP According to Baseline BP Remember 7mm mean reduction in BP equates to 40% reduction in Stroke!

33 Procedural safety N=1162 Renal artery re-intervention due to dissection Vascular complication Vascular complication, pseudoaneurysm Vascular complication, hematoma 0.09% (n=1) 0.34% (n=4) 0.09% (n=1) Medication Class Change Analysis

34 Event # of events % per patient years Classical CV Events Hospitalization for hypertensive crisis % Death, unrelated to device or procedure % Stroke % MI % Hospitalization for Afib % Hospitalization for new onset HF % Renal Events: Serum creatinine elevations % New onset of end-stage renal disease % (Nephrotoxic overdose) Post-Procedural Events: Renal artery re-intervention % Hematoma %

35 Dal mondo dei trial al mondo reale CRITERI INCLUSIONE ED ESCLUSIONE dei pazienti nei trial TERAPIA FARMACOLOGICA OTTIMALE ADEGUATA ADERENZA TERAPIA BIOMARKER in grado di identificare i pazienti con elevata attivita simpatica (candidati ideali RDN) RISULTATO DELLA PROCEDURA ( non disponibili marker di risultato se non PAS TECNOLOGIA ESPERIENZA OPERATORI FUTURO METODICA E NUOVI CAMPI APPLICAZIONE TEAM MULTIDICIPLINARE

36 Emerging renal enervation technology. Myat A et al. Circ Cardiovasc Interv. 2013;6: Copyright American Heart Association, Inc. All rights reserved.

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38 Ultrasound based Non-focussed high-frequency ultrasound Low pressure balloon with cooled fluid Frictional heating of soft tissues Uniform circumferential denervation

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41 Stime epidemiologiche Attraverso un analisi della letteratura esistente si e stimato che in Italia ci sono circa di pazienti affetti da ipertensione non controllata nonostante l assunzione di una terapia farmacologica. In particolare, di questa popolazione pazienti risultano affetti da ipertensione resistente e non controllata di grado 2 ( / mmhg) e grado 3 ( 180/110 mmhg) nonostante l assunzione concomitante di 4 o piu farmaci antiipertensivi. Secondo quanto riportato nello studio Symplicity HTN 217 e quindi ragionevole stimare che in Italia circa pazienti sono candidabili al trattamento di denervazione renale. E importante sottolineare l opinione di alcuni clinici secondo cui, l indicazione al trattamento di denervazione renale debba invece comprendere anche i pazienti sottoposti al trattamento farmacologico che prevede l assunzione di 3 o piu farmaci. Secondo tale scenario, pertanto, i pazienti candidabili al trattamento in Italia sarebbero circa Attraverso la stessa analisi della letteratura e utilizzando i dati a livello regionale, si e stimato che in Regione Lombardia ci sono circa pazienti affetti da ipertensione resistente non controllata di cui sottoposti a terapia farmacologica con piu di 4 farmaci e affetti da ipertensione di grado 2 ( / mmhg) e 3 ( 180/110 mmhg)18. Di conseguenza, in analogia a quanto precedentemente indicato, si stima che in Regione Lombardia circa pazienti sono candidabili al trattamento di denervazione renale.