Current status of Renal Denervation DRES-Nijkerk, 8 mei 2014

Transcription

1 Current status of Renal Denervation DRES-Nijkerk, 8 mei 2014 Prof. Dr. D.J. van Veldhuisen Afdeling Cardiologie UMC Groningen Agenda! Introduction- risk of hypertension! Clinical evidence overview! Symplicity HTN III, results and remarks! Conclusions and future Renal Denervation 2 1

2 The Problem-hypertension is very common Hypertension affects more than 1 billion people worldwide 1! Today, up to 12.8% of resistant hypertensive patients are on combination drug therapy that is not adequately lowering their BP 2! For every 20 mmhg rise in systolic blood pressure, the risk of cardiovascular death doubles 3, 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

3 5/11/14 Sympathetic Nerve Impact Role of kidney and sympathetic innervation in control of BP! Renal sympathetic nerves play a critical role in the initiation and maintenance of systemic hypertension. Efferent and afferent renal sympathetic nerves form the renal plexus located in the outer wall of the renal artery1! Activation of the efferent renal sympathetic nerves leads to:2! Renal insufficiency by decreasing renal blood flow and function! Hypertension by increasing vasoconstriction, heart rate and heart contractility! Activation of the afferent renal sympathetic nerves leads to:2! Hypertension by increasing the activity of the sympathetic nervous system 5 Afferent Renal Sympathetic Nerves Efferent Renal Sympathetic Nerves 1. Doumas M, Faselis C, Papademetriou V. Renal sympathetic denervation and systemic hypertension. Am J Cardiol. 2010;105(4): Esler MD, The sympathetic system and hypertension. Am J Hypertens. 2000;13(6 Pt 2):99S-105S. Renale sympathicus Zenuwbanen afkomstig van T10-L2 De zenuwen vertakken zich rond de nierarterien en liggen primair in de adventitia Vessel Lumen Media Adven00a Renal Nerves 3

4 Concept Validated by Surgical History Dr. Reginald H. Smithwick Effective, but significant morbidity 7 Surgical Sympathectomy Grimson KS, Orgain ES, Anderson B, et al. Total thoracic and partial to total lumbar sympathectomy, splanchnicectomy and celiac ganglionectomy for hypertension. Ann Surg. 1953;138(4):

5 5/11/14 Renal Denervation Renal sympathetic denervation for control of resistant hypertension1! Renal denervation is a catheterbased ablation procedure in which transmural lesions are delivered along the walls of the renal arteries to disrupt the sympathetic nerve network located within the arterial adventitia Catheter Delivered Lesions 9 1. Esler MD, Symplicity HTN-2 Investigators, et al. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): A randomised controlled trial. Lancet. 2010;376(9756): Symplicity HTN-1 Clinical Trial Catheter-Based Renal Sympathetic Denervation for Resistant Hypertension Durability of Blood Pressure Reduction Out to 24 Months Symplicity HTN-1 Investigators* Lancet. 2009;373: Abstract Renal sympathetic hyperactivity is seminal inhypertension. the maintenance and progression of hypertension. Catheter-based 2011;57: renal sympathetic denervation has been shown to significantly reduce blood pressure (BP) in patients with hypertension. Durability of effect beyond 1 year using this novel technique has never been reported. A cohort of 45 patients with resistant hypertension (systolic BP!160 mm Hg on!3 antihypertension drugs, including a diuretic) has been originally published. Herein, we report longer-term follow-up data on these and a larger group of similar patients subsequently treated with catheter-based renal denervation in a nonrandomized manner. We treated 153 patients with catheter-based renal sympathetic denervation at 19 centers in Australia, Europe, and the United States. Mean age was 57!11 years, 39% were women, 31% were diabetic, and 22% had coronary artery disease. Baseline values included mean office BP of 176/98!17/15 mm Hg, mean of 5 antihypertension medications, and an estimated glomerular filtration rate of 83!20 ml/min per 1.73 m2. The median time from first to last radiofrequency energy ablation was 38 minutes. The procedure was without complication in 97% of patients (149 of 153). The 4 acute procedural complications included 3 groin pseudoaneurysms and 1 renal artery dissection, all managed without further sequelae. Postprocedure office BPs were reduced by 20/10, 24/11, 25/11, 23/11, 26/14, and 32/14 mm Hg at 1, 3, 6, 12, 18, and 24 months, respectively. In conclusion, in patients with resistant hypertension, catheter-based renal sympathetic denervation results in a substantial reduction in BP sustained out to!2 years of follow-up, without significant adverse events. (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) Key Words: hypertension! blood pressure! renal sympathetic denervation - 12-month data \ Expanded Cohort* This Report (SymplicityHHTN-1): - Expanded cohort of patients (n=153) - 36-month follow-up *Expanded ypertension remains a major global public health burafferent and efferent nerves using radiofrequency ablation. den, affecting more than a quarter of adults in developed Initial proof-of-concept studies have demonstrated both resocieties.1 It is the leading attributable cause of mortality ductions in BP (out to 12 months), as well as evidence of worldwide, causing 7.5 million deaths annually. Every 20/ organ-specific sympathetic denervation. Furthermore, the 10-mm Hg increase in blood pressure (BP) is associated with procedure was found to be both simple to perform and safe 2,3 a doubling of cardiovascular mortality. Epidemiological (minimal procedure-related adverse events).8,9 Recently a studies have shown that awareness of the condition is poor, randomized, controlled clinical trial of renal denervation in with approximately half of hypertensives adequately treated patients with treatment-resistant hypertension showed a 33/ 4 6 Furthermore, among patients with to target BP levels. 11-mm Hg reduction of 6-month office BP compared with hypertension, there exists a subgroup who are unable to control.9 An outstanding question with regard to renal denervation achieve adequate BP control despite the use of multiple in general and the radiofrequency approach taken in particumedications and dietary and lifestyle modifications. These lar is the durability of the BP-lowering effect. This is because patients (termed refractory or resistant ) are, by common efferent nerves have been demonstrated to anatomically definition, receiving!3 different classes of antihypertensive regrow over a period of months to years without consistent therapy, with 1 being a diuretic, and at maximal recomdemonstration of functional reinnervation.10,11 Therefore, it is mended or maximal tolerated doses.7 Among such patients, treatment options are few. Addiof great interest and importance to evaluate the long-term tional pharmacological strategies have been proposed. Device safety and the durability of BP reduction that may follow the resultsorpresented at therapies the American College Cardiology Annualprocedure. MeetingAccordingly, 2012 (Krum, procedure-based have also been studiedof recently. denervation the aimh.) of the present One such approach involves a percutaneous, catheter-based analysis was to examine long-term outcomes among the renal sympathetic denervation procedure to disrupt renal entire initial cohort of refractory hypertension patients who Received September 15, 2010; first decision October 6, 2010; revision accepted February 18, *A list of the Symplicity HTN-1 writing committee members and investigators is given in the Appendix. Correspondence to Henry Krum, Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University/Alfred Hospital, Melbourne, Victoria 3004, Australia. henry.krum@med.monash.edu.au 2011 American Heart Association, Inc. Hypertension is available at DOI: /HYPERTENSIONAHA Downloaded from hyper.ahajournals.org 911by NEIL BARMAN on April 25,

6 Symplicity HTN-2 Lancet. 2010;376: Doel: Om de effectiviteit van catheter gebaseerde renale denervatie op reductie van de bloeddruk bij patienten met therapie-resistente hypertensie aan te tonen Patienten: Prospectieve, gecontroleerde en gerandomiseerde studie. 106 patienten, 1:1 gerandomiseerd naar renale denervatie v.s. continueren van medicamenteuze behandeling Clinical Sites: 24 centra in Europe, Australie & Nieuw Zealand Symplicity HTN-2 Investigators. Lancet. 2010;376: Baseline karakteristieken RDN and Controles RDN (n = 52) Control (n = 54) p-value Baseline systolic BP (mmhg) 178 ± ± Baseline diastolic BP (mmhg) 97 ± ± Number anti-htn medications 5.2 ± ± Age 58 ± ± Gender (female) (%) 35% 50% 0.12 Race (Caucasian) (%) 98% 96% >0.99 BMI (kg/m 2 ) 31 ± 5 31 ± Type 2 diabetes 40% 28% 0.22 Coronary artery disease 19% 7% 0.09 Hypercholesterolemia 52% 52% >0.99 egfr (MDRD, ml/min/1.73m 2 ) 77 ± ± Serum creatinine (mg/dl) 1.0 ± ± Urine alb/creat ratio (mg/g) * 128 ± ± Cystatin C (mg/l) 0.9 ± ± Heart rate (bpm) 75 ± ± Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Esler, M.) 6

7 Symplicity HTN-2 Primaire eindpunt en follow-up Primaire eindpunt (6M na randomisatie) Latest Follow-up (12M post Randomisation) 10 RDN (n= 47) 0 from Baseline to 6 Months (mmhg) Diastolic Systolic Diastolic from Baseline to 12 Months (mmhg) Diastolic Systolic p <0.01 for difference between RDN and Control Systolic p <0.01 for Δ from baseline Primaire eindpunt: 84% van RDN patienten had 10 mmhg reductie in SBP 10% van RDN patienten hadden geen reductie in SBP Follow-up: Control crossover (n = 35): -24/-8 mmhg Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Esler, M.) Verschillende devices 7

8 Mean office blood pressure reduction (P-value < 0.001). EnligHTN 1 Trial Worthley S G et al. Eur Heart J 2013;34: Published by Oxford University Press on behalf of the European Society of Cardiology. The Author University Medical Center Groningen 16 8

9 9

10 10

11 11

12 12

13 13

14 14

15 15

16 16

17 17

18 Symplicity HTN 3 remarks The study continues to support that Renal Denervation is safe The trial failed to meet its primary and secondary efficacy endpoints Population Considerations: Sub-group analysis indicates that renal denervation was better than sham for the following sub-groups: non-african Americans, younger patients (those <65 years old) and patients with normal renal function ( 60ml/min/1.73 m 2 ) Medication Considerations: Compliance? 35 Population Considerations: 18

19 Technology considerations 37 Current situation Netherlands Ministery of Health granted conditional reimbursement for Renal Denervation Trial period of 4 years where more clinical evidence will be collected RCT has started recently (Sympathy trial) Currently the trial is executed with MDT system, but possibly other manufacturers can participate once their device has proven safe and effective 19

20 Overall Conclusions and Future Renal Denervation? More Clinical evidence We need to understand the concept of renal denervation Focus on: Patient selection (disease stage, race etc.) Device technology and procedures Develop measurements to monitor success of intervention Outcome 20