Renal Sympathetic Denervation Beyond Hypertension: Therapy for Arrhythmias and for Autonomic Nervous System Dysfunction?

Transcription

1 Renal Sympathetic Denervation Beyond Hypertension: Therapy for Arrhythmias and for Autonomic Nervous System Dysfunction? Vivek Y. Reddy, MD Helmsley Trust Professor of Medicine Director, Cardiac Arrhythmia Service The Mount Sinai Hospital

2 Disclosures Ablative Solutions: grant support Biosense-Webster: grant support, consultant Boston Scientific: grant support, consultant Cibiem: consultant, equity* Medtronic: grant support, consultant Perseus: consultant, equity* St Jude Medical: grant support, consultant I will be discussing off-label use of catheter ablation devices, as well as non-fda approved devices. [* I will not be discussing products from these companies]

3 The Excitement Builds

4 The Excitement Abruptly Ends

5 Can HTN be treated by an intervention? Role of Sympathetic Nerves in HTN Thoracolumbar Surgical Sympathectomy Smithwick et al. JAMA 1953;152(16); Schlaich, W. Presented at ESH 2010

6 Placebo Controlled Trial of RSDN Symplicity HTN-3: No Significant Effect over Placebo Bhatt et al. NEJM 2014; DOI: /NEJMoa

7 Symplicity HTN-3 Why was it a negative study? Clinical Trial Issues: eg, not adequate roll-in period Technical issues: perhaps the catheter was not properly employed Technical Expertise vs Design Flaw Refractory hypertension is not primarily sympathetically-driven (as modifiable by RSDN)

8 Symplicity HTN-3 Why was it a negative study? Clinical Trial Issues: eg, not adequate roll-in period Technical issues: perhaps the catheter was not properly employed Technical Expertise vs Design Flaw Refractory hypertension is not primarily sympathetically-driven (as modifiable by RSDN)

9 Does Technique Matter? Pre-Clinical Data: Symplicity Flex & Spyral Medtronic Investor Briefing (March 2014)

10 Case: Autopsy in a RSDN Patient Limited Destruction of the Nerves Vink et al, Nephrol Dial Transplant (2014) 29:

11 Case: Autopsy in a RSDN Patient Limited Destruction of the Nerves Sakakura,et al, J Am Coll Cardiol (2014) 64:635

12 Symplicity HTN-3 Procedural Variable: No. of Ablation Lesions Kandzari et al. EuroPCR (2014)

13 Catheter/Energy Technologies for RSDN

14 RSDN: Chemical & Ultrasound Minimal Effect on the Arterial Wall T.Fischell et al. Eurointervention 9:140 (2013) K.Sakakura et al. Eurointervention (2014)

15 RSDN Using External Ultrasound Energy Minimal Effect on the Arterial Wall Courtesy: P.Neuzil (Homolka/Prague)

16 Symplicity HTN-3 Why was it a negative study? Clinical Trial Issues: eg, not adequate roll-in period Technical issues: perhaps the catheter was not properly employed Technical Expertise vs Design Flaw Refractory hypertension is not primarily sympathetically-driven (as modifiable by RSDN)

17 Does Renal Denervation Do Anything? Effect on Neurohormones Schlaich et al. NEJM 36: (2009) Schlaich et al, ExpBiol (2009) Ahmed H / Neuzil P / Reddy VY: JACC-CV Interv 5: (2012).

18 Blinded-Placebo Controlled Trial of RSDN Single-Center RCT of Mild-Resistant HTN Design: Sham vs RSDN (Symplicity Catheter) Inclusion: 4-6 ablations / vessel 1 Center / Experienced Operators Daytime ABPM: SBP= or DBP=90-94mmHg Stable Drugs 3 including diuretic (No change for 4 wks pre-random) Primary Endpoint: SBP at 6mo Patient Demographics Mean SBP (ABPM): 144 mmhg No. anti-htn Drugs: 4.3 Analysis: (71 pts Randomized) ITT: 32 (RSDN) vs 35 (Placebo) Per-P: 29 (RSDN) vs 34 (Placebo) S,Desch et al. Presented at TCT 2014

19 Does Renal Denervation Do Anything? RSDN in ESRD/HD: Case Example Renal Denervation Case: 70 yo woman w/ CKD/HD x 7yrs, L-nephrectomy 20 yrs ago (cancer), Refractory HTN (Hydal / Nifed / Coreg / Aldac / ARB) Office BP: 208/68 Difficulty with HD b/c hypotension At 6 weeks, stopped 2 meds No need to stop HD b/c hypotension Office BP: 208/68 148/75

20 Is Hypertension the best Target for RSDN?

21 HTN and AF: Progressive Atrial Remodeling in an Ovine Model Heart Rhythm 2010;7: Increasing Interstitial Collagen over Time Remodeling at Different Time Domains.

22 Predictors of Recurrence After AF Ablation Retrospective Analysis of 292 patients undergoing PVI for AF Non-Dilated LA (<40mm) = 178 pts vs Dilated LA (>40mm) = 114 pts Non-Dilated LA Dilated LA Takigawa et al. JRAS, DOI: / (2012)

23 Cardiac SNS Overactivity Predicts AF Recurrences Following Ablation Patients undergoing PVI (n=88) underwent 123 I-mIBG imaging (cardiac neuronal imaging) 5 days post-ablation The only multivariate predictor of AF recurrence was a high 123 I-mIB washout rate (excessive SNS activation). Arimoto et al. JCE (2011)

24 OSA-Related Atrial Arrhythmias Effect of RSDN Porcine model of Obstructive Sleep Apnea Tracheostomy and application of negative tracheal/thoracic pressure (NTP) NTP (4 times per hour) x 4 hours D. Linz, Clin Res Cardiol, DOI /s (2014)

25 OSA-Related Atrial Arrhythmias Effect of RSDN Porcine model of Obstructive Sleep Apnea Tracheostomy and application of negative tracheal/thoracic pressure (NTP) NTP (4 times per hour) x 4 hours Linz et al, Hypertension 62:767 (2013) D. Linz, Clin Res Cardiol, DOI /s (2014)

26 Pathogenesis of Atrial Fibrillation Potential Modulation by RSDN D. Linz, Clin Res Cardiol, DOI /s (2014)

27 Refractory HTN Patients with AF RSDN as Adjunctive Therapy to AF Ablation-1 Pokushalov et al, JACC (2012) 60:

28 Refractory HTN Patients with AF RSDN as Adjunctive Therapy to AF Ablation-2 Of course, most AF pts don t have refractory hypertension. Could RSDN might be beneficial in the majority of our AF ablation patients (who typically have milder/controlled hypertension)? Pokushalov et al, Heart Rhythm (2014)

29 RSDN as Upstream Therapy in AF? HFIB Study AF + HTN population: AF ablation vs AF ablation+rsdn Single-Blind (Sham-RSDN), Randomized-Controlled Trial FDA Approval: IDE# G Primary Endpoint: AF Recurrence PI: V.Reddy / Mount Sinai H-FIB AF + Hypertension AF Ablation Renal Angiogram Pilot (Enrollment of 50 pts): Renal Artery Dissection 3 pts Renal Artery Stenosis 3 pts Placebo R RSDN Plan for Full Study: Dedicated RSDN Catheter Follow-Up AF Recurrences H Ahmed / MA Miller / VY Reddy, JCE 25:503-9 (2013)

30 RSDN for Refractory VT Storm Clinical Case Series 4 Patients / 3 Centers 2-NICM / 2-Isch Dz Prior Ablations in all 2 Endo Only 2 Endo/Epi RSDN Performed in all EP catheter (Irrigated or nonirrigated) Follow-Up 8.8 ± 2.6 months (range 5 11 mo) No hemodynamic deterioriation No change in renal function Decrease in VT Episodes 11±4 episodes 0.3 ±0.1 episodes Remo et al. Heart Rhythm 11:541 (2014)

31 RSDN for Ventricular Arrhythmias: Preventing Shocks in High-Risk ICD Patients ICD recipients: Scar-Related VT Secondary Prevention or Inducible Primary Prevention Populations Primary Endpoint: ICD Therapy Single-Blind (Sham-RSDN), Randomized-Controlled Trial FDA Approval: IDE# G PI: V.Reddy / Mount Sinai Protocol Design: Pilot Phase: 20 Patients (Done) Full Study: ~450 Patients Trial Design Details: Funding by Boston Scientific, Inc. RSDN Catheter: Vessix System RESCUE-VT 2º Prevention 1º Prevention + Inducible VT Placebo ICD Implantation Renal Angiogram R Follow-Up ICD Therapy RSDN

32 RSDN and AF Multiple Clinical Trials are Ongoing D. Linz, Clin Res Cardiol, DOI /s (2014)

33 Is this a fool s errand?

34 Upstream Therapy for AF? RCT: Intensive Weight Reduction Plan vs General Lifestyle Advice Abed et al, JAMA, 310:2050 (2013)

35 Improving the Success of AF Ablation Role of Adjunctive Sympathetic Inhibition 12-mo AF Recurrence Moxonidine 20% Placebo 37% (p=0.007) G.Giannopoulos et al, Circulation (in press)

36 Final Thoughts-1 What is the right technique? Technology vs Physiology Need Outcome data with new ablation approaches Efficacy: Only Blinded RCTs matter Who is the right patient? Hypertension: Refractory HTN What design? Moderate HTN RSDN as replacement for Drugs? Endpoint: ABPM vs Office BP? Arrhythmias? Adjunctive to AF Ablation? Reducing ICD shocks? Congestive Heart Failure?

37 Final Thoughts-2 Irrational Exuberance vs Irrational Nihilism The Autonomic Nervous System and Cardiovascular Disease Need to explore means to modulate the sympathetic (& parasympathetic) nervous systems RSDN is one of several novel approaches to modulate the autonomic nervous system Other Approaches being tested: Vagal Stimulation Baroreceptor Stimulation Spinal Cord Stimulation Carotid Body Ablation Celiac Ganglion Ablation

38