Renal denervation in the treatment of Resistant hypertension ACST-2 Collaborators’ Meeting, 4-5th April 2013 Yvonne Bausback, MD Vascular Centre, Park Hospital - Angiology Leipzig, Germany Lancet. 1964 Feb 1;1(7327):235-8. THE ROLE OF BLOOD-PRESSURE CONTROL IN PREVENTING COMPLICATIONS OF HYPERTENSION. HAMILTON M, THOMPSON EM, WISNIEWSKI TK. More than one quarter of adults in developed societies are affected by hypertension1 Japan4 Europe3 44% 45% 81M U.S.2 34% China1 75M 21% 182M India1 21% 118M Latin America1 38% 1Kearney et al. Lancet 2005;365:217-23 et al. Circulation 2010;121:e46–e215 3Wolf-Meier et al. JAMA 2003;289:2363–2369 4Journal of Human Hypertension 2004;18:911-912 2Lloyd-Jones 30M 78M Global burden of hypertension is substantial and growing Global Prevalence (%) Total Hypertensive Population (M) Year Kearney PM: Lancet 2005;365:217–223 Cardiovascular Mortality Risk Hypertension leads to an increased risk of death from stroke and heart disease 8x 4x 2x Systolic BP / Diastolic BP (mmHg) CV mortality risk doubles for every 20 mmHg increase in systolic blood pressure.1,2 1Chobanian 2Lancet et al. Hypertension 2003;42:1206-1252 2002;360:1903-1913 Chronology Of anti-hypertensive treatment Surgical Splanchniectomy  1940s 1950s 1960s Direct Vasodilators Peripheral Sympatholytics Ganglion Blockers Renal Denervation  Thiazide Diuretics 1970s Alpha Blockers Central Alpha2 Agonists Non-DHP CCBs Veratrum Alkaloids Beta Blockers 1980s 1990s ACE Inhibitors ARBs DHP CCBs 2000s DRIs 38% of HTN population remain Uncontrolled 9% of HTN population remain resistant The hyperactive sympathetic nervous system is Activated in arterial hypertension Renal Efferent Nerves Animal experiments Preclinical human trials: • Reduced Norepinephrine spillover (Plasma or kidney tissue) • Muscle nerve activity (MSNA, peroneal nerve) ↑ Renin Release  RAAS activation ↑ Sodium Retention ↓ Renal Blood Flow Patients early in the course of hypertension often have been shown to have increased efferent sympathetic activity to the kidney. Katholi et al., Curr Hypertens Rep 2010 7 Surgical interruption of the sympathetic nervous System (sympathectomy) Used to treat hypertension 75 years ago 200 Blood Pressure Levels, mm/Hg 160 120 80 180 122 103 58 40 1 Operation 99 72 88 64 2 3 110 78 124 88 4 5 6 7 Time in Years 132 80 8 9 Blood pressure levels 10 years after Sympathectomy in 31year-old patient 10 Although effective, this procedure led to many adverse events: •Prolonged hospitalization •Hypotension Smithwick. JAMA. 1953 •Syncope •Impotence •Difficulty walking Renal sympathetic afferent nerves: Effects of renal denervation beside BP- reduction Vasoconstriction Atherosclerosis Sleep Disturbances Insulin Resistance Witkowski et al. Hypertension 2011 Renal Afferent Nerves Hypertrophy Arrhythmia Oxygen Consumption Brandt et al. JACC 2012 Mahfoud et al. Circulation 2011 ↑ Renin Release  RAAS activation ↑ Sodium Retention ↓ Renal Blood Flow Patients with essential hypertension in the later course (with chronic renal disease) have been found to have increased centrally mediated sympathetic activity. Katholi et al., Curr Hypertens Rep 2010 9 Renal nerve anatomy allows a RF catheter – based approach • i.v. sedation and pain management with morphine • 4-6 x two-minute treatments per artery • Proprietary RF Generator − Automated − Low-power − Built-in safety algorithms 11 Evidence for safety and efficacy: Device based FIM studies Study Device Patients (base./FU) Follow up (month) OBP  (mmHg) ABP Responder (mmHg) (%) Simplicity* (Medtronic) 153/ 8 36 - 33/19 -7/-4 (n=11) 54100 ReduceHTN* (BCSI) 44/ 6 6 - 36/-14 n.a n.a. EnligHTN* (St. Jude) 46/46 9 -26/-10 n.a. 76% RAPID* (Covidien) 8/8 6 - 42/15 n.a. n.a Paradise (Recor) 11/11 6 - 32/ -16 n.a n.a (*CE-mark for Europe) Randomized,controlled, but non blinded: Responders after 6 month: 84 % No significant recuction of antihypertensive medication No significant loss of renal function Case report: Renal denervation in resistant HTN • 67 year old woman • Office blood pressure Standard measurement: • Ambulatory blood pressure: 160/ 85 mmHg 163/ 82 mmHg 159/ 83 mmHg 148/ 85 mmHg max daytme 187/110 mmHg non dipping profile mean Case report: Renal denervation in resistant HTN Medication: - Betablocker (hD) - Diuretic (hD) - AT1- Inhibitor (fD); - CA++ Inhibitor (fD), - Direct renin inhibitor (fD), - Centrally acting agent (moxonidine, fD) Case report: Renal denervation in resistant HTN History • Arterial Hypertension for more than ten years, various medication protocols • Diabetes mellitus type 2 • Renal function (eGFR) 60 ml/min • Renal duplex ultrasound: RA – stenosis excluded, RI right 0.74; left 0.72 Renal angiogram: Renal denervation in resistant HTN Procedure: Renal Denervation in resistant HTN 3rd inferior 1st lateral 4th lateral 2nd superior 5th superior Peri – and postinterventional management • i.v. Sedation with Remifentanyl continously during treatment • ECG, BP and oxigen monitoring • 5000 IE Heparin i.v. • 500 - 1000 IE/h i.v. Heparin for 48 hours • ASA 100mg daily for 3 month • BP monitoring 24 h after treatment Follow up Office blood pressure (mmHg) Renal denervation in resistant HTN 180 160 systolic 161 diastolic 140 141 120 100 80 60 40 20 130 • Betablocker (hD) 83• AT1- Inhibitor (hD) 74 71 • Centrally acting agent (moxonidine, hD) 0 Baseline 6 month 1 year Renal artery denervation is effective and safe but ... ...there are still open questions Leipzig REAL World RDN  2011 – 2012, 138 patients included  RR > 140/90 mmHG (office blood pressure)  Ambulatory BP measurement  3 anthypertensive medication (ideally 1 diuretic)  All secondary causes of hypertension were excluded Leipzig REAL World RDN – Results Office Blood pressure 3 Month Sys Dia 6 Month Sys Dia Patient selection? -5 -10.8 -0.7 Responder: 46% -12.5 Leipzig REAL World RDN : Ambulatory BP Ambulatory Blood pressure 3 Month Sys Dia 6 Month Sys Dia Are we measuring a placebo effect? -2.0 - 1,2 -2,7 -4,6 Leipzig Registry BP Distribution Office BP WHO III 44.2 % WHO I 35.51 % Ambulatory BP III° 19.7 % II° 29.1 % normal 18.1 % I° 33.1 % WHO II 20.29 % ⅓ mild Hypertension pseudohypertension ⅓ mild hypertension OBP > 180 mmHg is the only selection criteria for RDN OBP reduction after 6 month Responder: 75% WHO I° WHO WHO WHO I° WHO III° III° II° II° WHO Peri & Postprocedural Complications • Continous i.v. pain management (morphine derivates) • Vasospasm of the renal artery Baseline Immediately after RDN 6 weeks after RDN • Access site complications (6F – 8F) Does it harm the artery? Acute One Month Healthy porcine animal model: •Macroscopic healing after one month •Microscopic intramural fibrosis 10 – 25 % Human studies: •No induced stenosis in clinical trials Rippy et al : Clin Res Cardiol ((2011) 100:1095-1101 No affection of the endothelium after RDN with ultrasound left RA: intravascular ultrasound • Circumferential treatment without endothelial damage after ultrasound based RDN No loss of renal function but improved hemodynamic after RDN • • N = 100 (n=88 pts for RDN group; n=12 controls) GFR (MDRD) > 45 ml/min RDN Group (n=88/100) 3 MFU 6MFU Systolic Blood Pressure (mmHg) - 22,7(-13 %) - 26,6 (-15%) p< 0.001 Diastolic Blood Pressure (mmHg) - 7,7 (-8%) - 9,7 (-10%). P< 0.01 Renal Resistiv Index (RI) - 0.017 (-2%) -0.021 (-3%) p< 0.03 Urine Albumine Creatinine Ratio (mg/mmol) - 0.49 (-31%) - 0.25 (-16%) n. s. -4.2 (-5%) - 4,0 (-5%) n. s. Cystatin C GFR (ml/min) No correlation between BP reduction and change in RI Mahfoud F et al. Hypertension 2012 Renal denervation in moderate to severe chronic kidney disease • • • 2 centres, non randomized, proof of principle study eGFR @ baseline: 31.2± 8.9 ml/min/1,73m2 Creatinin @ baseline 186.7±64.4 mmol/L Individual changes in eGFR N=15 Hering D et al., J am soc nephrol 2012 ESH* Position Paper on renal denervation Schmieder et al. J Hypertension; May 2012 • OBP > 160 (150) mmHg (D.M.) • 3 antihypertenisve drugs (icl. 1 diuretic) • GFR > 45 ml/min • Avoid RDN <  4 mm renal artery stenosis or previous angioplasty/ stenting • Keep to the antihypertensive medication protocol if there is no symptomatic hypotension *European society of hypertension Summary Sympathetic denervation is highly effectiv and safe in reducing BP in refractory hypertension on the background of conclusive preclinical research and initial clincial trials Broad effect range of BP – reduction and a significant rate of non responders especially under daily practice are not yet explained New devices will provide a more predictable procedure and reduce contrast and time