Autonomic regulation therapy for heart failure

Transcription

1 Autonomic regulation therapy for heart failure Pre-clinical and Clinical Evidence Supporting Vagus Nerve Stimulation For Treatment of Heart Failure Inder Anand, MD, FRCP, D Phil, (Oxon.) Professor of Medicine, Cardiovascular Division University of Minnesota Medical School and VA Medical Center Minneapolis, Minnesota

2 Disclosure Information I have the following financial relationships to disclose: I have consulted for and/or received research support from Amgen, Critical Diagnostics, Cyberonics, Novartis, Zensun

3 Pathophysiology ANTHEM-HF Study of Heart Failure with Reduced Ejection Fraction Autonomic imbalance in HF is characterized by increased sympathetic activity and withdrawal of parasympathetic activity Autonomic imbalance and the related RAAS activation is associated with progression of HF and worse outcomes Blocking the SNS and RAAS has resulted in a remarkable improvement in outcomes of patients with HF. However, improving parasympathetic activity in HF has received little attention 3

4 Direct Measures of Assessing Vagal Activity Not Available Surrogates Used Heart Rate response to blockade of muscarinic cholinergic receptors - Parasympathetic tone Heart Rate variability - Parasympathetic modulation Post Exercise HR Recovery - Parasympathetic reactivation Baroreceptor sensitivity slope - Reflex Parasympathetic activity No Drugs Approved Enhance Vagal Tone

5 Pre-Clinical Evidence Supporting VNS in Heart Failure VNS has been tested in three Animals Models Rat Post-MI model of HF Canine model of pacing induced HF Canine model of microembolization induced HF

6 Vagal Nerve Stimulation Markedly Improves Long-Term Survival After Chronic Heart Failure in Rats Li et al, Circulation 2004,109: Male Sprague-Dawley rats Post MI heart failure Post MI heart failure + vagal nerve stimulation Right vagal nerve stimulation 6 weeks of treatment, 14 days post-mi 20 Hz stimulation, 10 sec ON, 50 sec OFF Intensity of stimulation adjusted to decrease HR by bpm

7 VNS Improved Hemodynamics and Neurohormones in Rats with Post-MI Heart Failure Li et al, Circulation 2004,109:

8 VNS Improved Survival in Rats with Post-MI HF Li et al, Circulation 2004,109:

9 VNS improved LV Function and Attenuated Systemic inflammation and Neuro-hormonal Activation in Dogs with Pacing-induced Heart Failure 15 mongrel dogs (VNS (n=8) and control (n=7)) Rapid pacing-induced heart failure At 220 bpm for 4 weeks for induction of HF At 180 bpm 4 weeks HF for maintenance of HF Implanted with Cyberonics VNS system, without an RV lead for feedback HR control Right VNS continuously, duty cycle, 14s on and 12s off, 20 Hz and 0.5 ms pulse width, at an intensity to reduce sinus rate by ~ 20 bpm Zhang et al, Circ Heart Fail 2009; 2:

10 VNS improved LV Function and Attenuated Systemic inflammation and Neuro-hormonal Activation in Dogs with Pacing-induced Heart Failure Zhang et al, Circ Heart Fail 2009; 2:

11 Vagus Nerve Stimulation in Microembolization Induced Heart Failure Dogs with heart failure (n=13) Active therapy (n=7) Control (n=6) Vagal nerve stimulation (CardioFit System, BioControl) Stimulation synchronized to cardiac cycle Basal heart rate reduced by 10% by feedback control of resting(average in HR 10 bpm; range 1-28 bpm) Data collected at baseline and 3 month follow-up Sabbah et al, Heart Failure Rev 2011;16:171-8

12 Vagus Nerve Stimulation in Experimental HF Sabbah et al, Heart Failure Rev 2011;16:171-8

13 VNS Improved LV Structure and Function in Micro-embolization Dogs with HF Sabbah et al, Heart Failure Rev 2011;16:171-8

14 VNS Attenuates Release of Plasma Proinflammatory Cytokines in Dogs with HF Sabbah et al, Heart Failure Rev 2011;16:171-8

15 Improved Cellular and Structural Markers of LV Remodeling HF-VNS Treatment HF Control VNS decreased interstitial fibrosis Interstitial Fibrosis VNS increased capillary density Capillary Density Sabbah H. Cleve Clin J of Med. 2011;78(Suppl. 1):S24-S29

16 Favorable Effects of VNS in Animal Models of HF Improved LV Structure & Function Improved Cytokine & NH Profile Vagus Nerve Stimulation in Experimental Heart Failure Decreased Interstitial Fibrosis Improved Survival

17 VNS In Patients With Heart Failure: First-In-Man Experience 32-patient, multi-center study in Europe Patient population: NYHA Class II-IV; LVEF 35%; SR Medically stable for 3 months, including -blockers Primary endpoints: Device safety and side effects Secondary endpoints measured at 6 months: Objective: EF, EDV, ESV Subjective: NYHA, 6 min walk, Quality Of Life (MLHFQ ) HR variability indirect measure of parasympathetic tones De Ferrari GM, Peter Swartz et al. Eur Heart J. 2011;32:847-55

18 VNS In Patients With Heart Failure: First-In-Man Experience Right cervical VNS (CardioFit, BioControl) Stimulation titration started 2 4 weeks after implant at 1-2 Hz, synchronized to cardiac cycle, target current: 5.5 ma, HR reduction of 5 10 bpm, or onset of sideeffects. Patients followed at 3 and 6 months 1-year optional follow-up. De Ferrari GM, et al. Eur Heart J. 2011;32(7):847-55

19 Baseline Characteristics Male 30/32 (94%) Age 56 ± 11 years Ischemic heart failure 20/32 (62%) NYHA II/III/IV 15/15/2 HF duration prior to enrollment 4.3 ± 2.8 years Left ventricular ejection fraction 23.1 ± 7.6% Treatment with: ACE-I or ARB 31/32 (97%) β-blockers 31/32 (97%) Loop diuretics 31/32 (97%) Anti-aldosterone agents 17/32 (53%) Digoxin 9/32 (28%) Previous ICD implantation 19/32 (59%) De Ferrari GM, et al. Eur Heart J. 2011;32(7):847-55

20 Safety Data 100% implant success rate Device or Procedure Related Adverse events: 1 acute pulmonary edema: resolved with IV lasix 1 patient needed surgical revision Anticipated side effects all resolved Cough (5 patients) Dysphonia (4 patients) Mandibular pain (3 patients) De Ferrari GM, et al. Eur Heart J. 2011;32(7):847-55

21 Increased LV Ejection Fraction De Ferrari GM, et al. Eur Heart J. 2011;32(7):847-55

22 Sustained Improvement in NYHA Class De Ferrari GM, et al. Eur Heart J. 2011;32(7):847-55

23 Increased Exercise Capacity P-values are versus paired baseline De Ferrari GM, et al. Eur Heart J. 2011;32(7):847-55

24 Improved Quality of Life De Ferrari GM, et al. Eur Heart J. 2011;32(7):847-55

25 Conclusions Chronic VNS in HF patients is safe. Chronic VNS may improve symptoms, LV structure and function, quality of life and exercise capacity. Several questions remain unanswered: Site of VNS right vs left Intensity and protocol of stimulation Synchronous or independent of cardiac cycle Duration of on vs off cycle Role of HR reduction Ideal patient likely to benefit most Mechanisms of such a remarkable effect on HF

26 Hot Line: Heart Failure: devices and interventions Autonomic Regulation Therapy for the Improvement of Left Ventricular Function and Heart Failure Symptoms: The ANTHEM-HF Study

27 Objectives Evaluate a new autonomic regulation therapy (ART) with left or right VNS, for the treatment of chronic symptomatic heart failure with reduced ejection fraction Feasibility and Tolerability of the ART system Primary safety endpoint: Incidence of procedure and devicerelated adverse events during the 9-month duration of the study Primary efficacy endpoint: Changes in left ventricular ejection fraction (LVEF) and end-systolic volume (LVESV) at 6 months

28 ANTHEM-HF Study Secondary Endpoints Changes at 6 months in: Left ventricular end-systolic diameter (LVESD) 6-minute walk distance Quality of life (Minnesota Living with HF Questionnaire) NYHA Class Heart rate variability (HRV) Blood biomarkers (NT-proBNP and hs-crp)

29 Inclusion and Exclusion Criteria Key Inclusion Criteria Stable symptomatic heart failure NYHA class II / III Left ventricular ejection fraction (EF) 40% Left ventricular end diastolic diameter (LVEDD) 50 to 80 mm QRS width < 150 ms Optimal pharmacologic therapy for at least 3 months Key Exclusion Criteria Prior cardiac transplant 1 st, 2 nd, or 3 rd -degree heart block Primary autonomic dysfunction Refractory symptomatic hypotension Severe obstructive or restrictive lung disease

30 ANTHEM-HF Study Study Design Randomization Informed Consent Baseline Assessment Left side Right side VNS Device Implant VNS System Activated Titration 2 weeks 10 weeks Titration Complete Cyclic VNS Therapy (6 months) 3 months Outcome Measures 6 months Outcome Measures Safety and adverse events Assessment (9 months) Premchand et al, J Card Fail 2014; 20:

31 ANTHEM-HF Study Autonomic Regulation Therapy VNS Therapy System (Cyberonics, Houston, USA) 100,000+ left-sided implants in epilepsy patients Implanted on L or R vagus nerve by surgeon Without RV sensing lead Chronic intermittent stimulation delivered to vagus 10 Hz (natural frequency), 250 µsec pulse width VNS intensity titrated over 10 wks to max tolerable current; below the of threshold of side effects or HR change ECG monitored continuously to confirm no acute HR change Over time the threshold for side-effects gradually increased Average stimulation current: 2.0 ± 0.6 ma 10 Hz, 250 µsec pulses ON OFF 14 sec 66 sec

32 ANTHEM-HF Study Screening, Enrollment and Follow-up Screening n=78 Randomization n=60 Inc / Exc failure (n=12) Withdrawal (n=4) Brady arrest (n=1) Sudden death (n=1) Right-Sided Implantation n=29 Titration n=29 3-month F/U n=29 Left-Sided Implantation n=31 Titration n=30 3-month F/U n=28 Death 1 n=1 Death 2 n=2 6-month F/U n=29 6-month F/U n=28 1. Embolic stroke (implant-related) 2. HF death (unrelated) and sudden death (unrelated)

33 ANTHEM-HF Study Baseline Characteristics Left (n=31) Right (n=29) Pooled (n=60) Age (years) 51.2 ± ± ± 12.2 Male (%) Heart failure Etiology, Ischemic (%) NYHA Class II/III 18 / / / 26 Body mass index (kg/m 2 ) 24.0 ± ± ± 4.1 LVEF (%) 32.8 ± ± ± 7.2 LVESV (ml) ± ± ± 40.1 LVESD (mm) 51.5 ± ± ± 7.9 LVEDD (mm) 61.7 ± ± ± 6.7 HR (bpm) 78 ± ± ± 10 Systolic blood pressure (mmhg) 114 ± ± ± 15 Diastolic blood pressure (mmhg) 73 ± 8 74 ± ± 9 38

34 ANTHEM-HF Study Baseline Characteristics HF Drug Treatment Left (n=31) Right (n=29) Pooled (n=60) -blocker (%) ACE-I or ARB (%) Aldosterone antagonist (%) Digoxin (%) Loop diuretics (%) Premchand et al, J Card Fail 2014; 20:

35 Primary Safety Outcomes Left Right Pooled SAEs Related 1 0 1* Unrelated Most Common Related Non-Serious AEs Voice alternation, hoarseness Cough Oropharyngeal pain Implant-Related Infections System Malfunctions Therapy discontinuation by Pts or PI * Post-surgical embolic stroke Including 1 unrelated HF death and 1 unrelated sudden death

36 Primary Efficacy Endpoints Echocardiographic Indices of LV Function Pooled: n=57; Left: n=28; Right: n=29 Mean 95% Confidence Interval Premchand et al, J Card Fail 2014; 20:

37 ANTHEM-HF Study Secondary Efficacy Endpoints Baseline 6 Months Change p-value LVESD (mm) 52 ± 8 49 ± < NYHA Class (I/II/III/IV) 0 / 33 / 24 / 0 30 / 24 / 3 / 0 < MWD (m) 287 ± ± < MLHFQ score 40 ± 1 21 ± < HRV (SDNN, ms) 93 ± ± <0.01 HR (bpm) 78 ± ± <0.005 NT-proBNP, IQR (pg/ml) 864 [ ] 888 [ ] 24 NS CRP, IQR (mg/l) 1.7 [ ] 1.3 [ ] -0.4 <0.025

38 Limitations The study was uncontrolled and open-label; placebo effects may have contributed to the observed changes Although no significant differences were observed in any outcome between left and right-sided ART, the confidence intervals of most measurements were wide, some differences cannot be ruled out The study was conducted in India, and results may not generalize to other populations

39 Conclusions The ANTHEM-HF approach to ART (chronic, low-amplitude, natural frequency), on either the left or right side, was feasible and welltolerated Safety assessment did not raise concerns Both left and right-sided ART were associated with improvements in cardiac function (LVEF, LVESD, HRV) and heart failure symptoms (NYHA class, 6-minute walk distance, quality of life) Further investigation of ART in a controlled clinical study is warranted

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41 96 Eligible Patients, All Implanted with Device 95 Randomized 1 Death Lost Paired Data (n=4) Deceased (n=1) Safety FU Only (n=2) Lost to FU (n=1) 59 Therapy Patients with paired data sets 63 ON therapy 32 OFF therapy 28 Control Patients with paired data sets Modified intention to treat analysis Lost Paired Data (n=4) Deceased (n=2) Safety FU Only (n=1) No Echo Data (n=1)

42 Primary Endpoint LVESD LVESD (cm) Baseline 6 Months Baseline 6 Months Therapy Control

43 Secondary Endpoints LVEDV (ml) Baseline 6 Months Baseline 6 Months LVESV (ml) Baseline 6 Months Baseline 6 Months Therapy Control Therapy Control LVEF (%) Baseline 6 Months Baseline 6 Months Therapy Control

44 Blinding Primary echo endpoint was blinded However, many patients felt the stimulation (slight tickling/vibration in the neck) At the 6-month follow-up visit, patients were asked to which group they believed they were randomized Blinding index 0 means blinding was perfect Blinding index 1 would be completely un-blinded

45 Clinical Studies in Heart Failure Company Dev Stage Geography Target Population Study Name Subjects Completion Status BioControl CE-Mark EU Systolic HF CardioFit Completed Boston Scientific Phase II EU Systolic HF NECTAR- HF Completed Cyberonics CE-Mark EU Systolic HF ANTHEM- HF Completed BioControl (Medtronic) IDE US Systolic HF INOVATE- HF Enrolling

46 INOVATE-HF (BioControl) Enrollment 650 (3:2) Patient Population Therapy Primary Efficacy Endpoints Class III HF, EF<40% Right cervical VNS, Synchronized to cardiac cycle All-cause mortality and HF hospitalization Start Date Feb 2011

47 Comparison of ART Trials ANTHEM-HF CardioFit Study NECTAR-HF Patient Population Class II-III, EF 40% Class II-III, EF 35% Class II-III, EF 35% Number of Patients Trial Design Open Label, Randomized L and R Open Label, R VNS Randomized, Sham- Controlled, R VNS Stimulator Cyberonics VNS Therapy System BioControl CardioFit System Boston Scientific Precision System Stimulation Frequency 10 Hz 1-2 Hz (synchronized to cardiac cycle) 20 Hz Stimulation Amplitude 2.0 ± 0.6 ma 4.1 ± 1.2 ma 1.2 ± 0.7 ma LV Performance Assessment LVEF and LVESV LVEF and LVESVI LVESD Duration of Follow-up 6 months 6 months 6 months Therapy-related SAEs 1 (2%) 7 (22%) 9 (9%) Primary Finding Improvement in cardiac function and HF symptoms Improvement in cardiac function and HF symptoms No change in cardiac function