- The document discusses sleep disordered breathing (SDB) and its prevalence and consequences in heart failure patients. SDB is highly prevalent in over 50% of HF patients but remains underrecognized. - It presents a new therapeutic concept of using phrenic nerve stimulation to restore normal breathing and eliminate respiratory instability. Unilateral phrenic nerve stimulation improved oxygenation in a HF patient with central sleep apnea. - The remedē® System is an investigational implantable device that uses transvenous phrenic nerve stimulation to improve air exchange and stabilize breathing in patients with central sleep apnea associated with heart failure. Acute feasibility and pilot studies demonstrated reductions in sleep apnea metrics and improvements in oxygen

1. Piotr Ponikowski, MD, PhD, FESC
Medical University, Centre for Heart Disease
Clinical Military Hospital
Wroclaw, Poland
Novel interventions
A rude awakening: sleep­apnoea and heart failureA rude awakening: sleep­apnoea and heart failure

2. Disclosure
Consultancy fees and speaker’s honoraria from:
Coridea and Respicardia

3. Sleep Disordered Breathing and Heart Failure:Sleep Disordered Breathing and Heart Failure:
ConclusionsConclusions
• Highly prevalent (affecting more than 50% of HF
patients), but still under­recognized among cardiologists
• Diagnosis possible in the everyday cardiology practice
• Ominous pathophysiological and clinical consequences
(progression of the disease, increased M&M)
• Attractive therapeutic target

4. A New Therapeutic ConceptA New Therapeutic Concept
Goal: Restore normal breathing at nightGoal: Restore normal breathing at night
• Phrenic nerve stimulation can be used
to modulate diaphragmatic contraction
and affect breathing.
• We hypothesized that stimulation of the
phrenic nerve during a central event
could be used to initiate inspiration or
increase inspiratory time, halting or
preventing the apnea.

5. Elimination of respiratory instability and improvementElimination of respiratory instability and improvement
in oxygenation during unilateral phrenic nerve stimulationin oxygenation during unilateral phrenic nerve stimulation
in a HF patients with central sleep apneain a HF patients with central sleep apnea
Ponikowski P et al. Eur Heart J 2012;33:889-94

6. · The remedē® System improves air exchange by transvenously stimulating
the phrenic nerve to move the diaphragm naturally, resulting in improved
air exchange
· By improving air exchange, CO2 levels stabilize preventing cyclical
disruptive breathing
· The proprietary algorithm can automatically adjust parameters to optimize
therapy and can also be customized to meet the specific requirements of
a patient
Physiology of the remedē® System
*
CAUTION ­­ Investigational device. Limited by Federal (or United States) law
to investigational use.
AVAILABLE FOR SALE IN THE EU/EEA

7. Comparison of Normal Inspiration with CSA Therapies
Normal
Breathing
Mask
Therapies
(ASV, CPAP)
Remedē®
System
Diaphragm pulls air
into the lungs
Ventilation pushes air
into the lungs via
positive intrathoracic
pressure
The remedē® System
pulls air into the lungs
using the same
mechanism of action as
normal breathing

8. · Normal inspiration
» Small increases in afterload
» Small increases in LVEDV
» Increased RV filling
» Decreased RV afterload
·
· Heart rate decreases
· Maintains cardiac output
· Positive pressure ventilation
» Large decreases in afterload
» No change in LVEDV
» Decreased RV filling
» Increased RV afterload
· No change in heart rate
· Could cause large decrease in
cardiac output if volume normal-low
(Frank Starling curve moves to the left)
Physiologic Changes with Normal Inspiration
Compared to Positive Pressure
*

9. · The remedē® System implant takes
place in the EP laboratory by
cardiologists experienced with CRT
· Light sedation is used to keep
patients comfortable
· The device is placed under the skin
in either the right or left chest
· A stimulation lead is placed either
in the left pericardiophrenic or right
brachiocephalic vein
· A second lead to sense respiration
is placed in the azygos vein
How is the remedē® System Implanted?
*
CAUTION ­­ Investigational device. Limited by Federal (or United States) law
to investigational use.
AVAILABLE FOR SALE IN THE EU/EEA

10. §Left Pericardiophrenic Vein
§Right Brachiocephalic Vein
2 stimulation locations
remedē® System Can Provide Unilateral
Stimulation From Two Locations
39CAUTION ­­ Investigational device. Limited by Federal (or United States) law
to investigational use.
AVAILABLE FOR SALE IN THE EU/EEA

11. Demographics (N=16)
Mean ± SD or
% of patients
Age 57 ± 12 years
Male 100%
Heart rate (bpm) 73 ± 17
Atrial fibrillation 19%
BMI 27.5 ± 3.3
NYHA Class I/II/III 19% / 50% / 31%
LVEF 30% ± 12%
Ischemic 44%
ICD/Pacemaker 25%
Medications % of patients
Beta-blockers 94%
ACE-I/ARB 88%
Diuretic 100%
Aldosterone Antagonist 56%
Statin 67%
Digoxin 18%
Anti-coagulant 44%
Anti-Diabetic 25%
Eur Heart J (2012) 33(7): 889­894
Acute Feasibility Study –
Patient Characteristics
Patients on optimal medical therapy
Eur Heart J (2012) 33(7): 889­894

12. ↓ 90%
↓ 50%
↓ 48%
↓ 49%
p≤0.001*
p=0.002*
All values are medians with corresponding inter-quartile ranges and expressed as events/hour.
Acute Feasibility Study - Clinical Results
Therapy shows improvement in standard indices of sleep apnea
*Wilcoxon matched
pair signed ranks test
15/16
patients
had ≥ 70%
reduction
in CAI
Eur Heart J (2012) 33(7): 889­894

13. Purpose
§ To determine the safety and chronic efficacy of remedē® System therapy
on sleep in patients with CSA
Primary Hypothesis
§ The remedē® System will significantly reduce the Apnea/ Hypopnea Index
(AHI) compared to baseline after 3 months of therapy (primary endpoint)
and improve other measures of sleep
Study Design
§ Prospective, multi-center, non-randomized, open-label safety and
efficacy study
§ At least 40 subjects in the US and Europe
§ Follow-up testing at 3 and 6 months
The remedē® System Pilot Study
Overview
*
CAUTION ­­ Investigational device. Limited by Federal (or United States) law
to investigational use.
AVAILABLE FOR SALE IN THE EU/EEAAbraham et al. JACC­HF 2015

14. The remedē® System Pilot Study
Baseline Demographics
Baseline Characteristic
Implanted Subjects
Mean ± SD or % of Subjects
N=47
Age (years) 65.9 ± 9.6 (range 37­83)
AHI (events/hour) 49.5 ± 14.6 (range 22­83)
BMI (kg/m2) 29.3 ± 4.4 (range 21.3­39.2)
Gender (% male) 89%
BP Systolic (mmHg) 123.4 ± 20.8 (range 75­170)
BP Diastolic (mmHg) 73.3 ± 11.4 (range 49­97)
Heart Rate (bpm) 70.2 ± 10.7 (range 51­104)
Resp Rate (breaths/min) 15.7 ± 3.0 (range 11­24)
History of Hypertension 74%
Atrial Fibrillation 30%
Concomitant Device 53%
LVEF (%, core lab) 30.5 ± 11.6 (range 14­61)
NYHA Class I/II/III/IV (NA) 9% / 47% / 21% / 2% (21%)
Abraham et al. JACC­HF 2015

15. Decreased CAI improves oxygenation
and decreases arousals
Decreased AHI is associated with
decreased in both mortality and
ventricular arrhythmias
The remedē® System Pilot Study
Clinically Meaningful Improvements in Sleep Parameters
84% 53%
Abraham et al. JACC­HF 2015

16. Fewer Arousals
decreases
norepinephrine
release and
sympathetic
drive
The remedē® System Pilot Study
Clinically Meaningful Improvements in Sleep Parameters
Improved
Oxygenation
decreases
inflammation,
ischemia and
sympathetic
drive
Sleep
Efficiency
significantly
increased by
the remedē®
System
Increased REM
sleep is
associated with
improved
parasympathetic
control and
decreased
sympathetic
drive
Abraham et al. HFSA 2013
*
*
* * *55%
18%
31%50%
Abraham et al. JACC­HF 2015

17. Parameter N Baseline 6 Month
6 Month
Improvement
HRV (ms) 14 30 51** 21
§ Heart Rate Variability (HRV) is a measure of sympathetic drive
§ Sympathetic drive, over the long term, damages cardiac tissue
leading to arrhythmias and progressive left ventricular dysfunction
Abraham et al. ESC­HF 2014
Adamson et al. Circ 2004;110:2389­2394
The remedē® System Pilot Study
Clinically Meaningful Change in Heart Rate Variability
**p<0.05
By paired student t-test

18. Parameter N Baseline
6
Month
6 Month
Improvement
N Baseline
12
Month
12 Month
Improvement
MLWHF
(score)
36 39 29* 10 30 41 32** 10
*p≤0.01
**p=0.0499
Abraham et al. ESC­HF 2014
Brambatti et al. Europace;2013:15:704­710
Reddy and Dunn Pharmacotherapy 2012;20:679­689.
The remedē® System Pilot Study
Clinically Meaningful Changes in Quality of Life in Patients with Heart Failure
Includes patients with reduced and preserved ejection fraction

19. N=24 Baseline 12 Month Average p value
Ejection Fraction 26.4 ± 7.4 29.7 ± 10.6 0.0123
Diastolic Left Ventricular
4 Chamber Volume
241.6 ± 72.2 222.1 ± 63.8 0.0046
Systolic Left Ventricular
4 Chamber Volume
181.5 ± 68.3 160.8 ± 65.0 0.0008
Abraham et al. ESC­HF 2014
The remedē® System Pilot Study
Echo Changes at 12 Months in Patients with LVEF < 40%

20. · Purpose Evaluate the safety and effectiveness of the therapy
delivered by the remedē® System in subjects with
moderate to severe central sleep apnea (CSA)
1:1 randomization, up to 173 patients enrolled in up to 25 US sites
and 8 European sites
· Primary Endpoints
» Effectiveness Proportion of subjects that achieve a ≥50% reduction in AHI
from baseline to 6 months post randomization (Treatment vs.
Control)
» Safety Freedom from serious adverse events (SAEs) associated with
the implant procedure, The remedē® System, or the delivered
therapy at 12 months
The remedē® System Randomized Controlled Pivotal Trial:
Purpose and Endpoints
*
CAUTION ­­ Investigational device. Limited by Federal (or United States) law
to investigational use.
AVAILABLE FOR SALE IN THE EU/EEA

21. The remedē® System Randomized Controlled Pivotal
Trial Design

22. § CSA confirmed by core lab analysis of PSG within 40 days of
scheduled implant
» AHI greater than or equal to 20
» CAI at least 50% of all apneas, with at least 30 central apnea events
» OAI less than or equal to 20% of the total AHI
*
The remedē® System Randomized Controlled
Pivotal Trial: Inclusion Criteria
CAUTION ­­ Investigational device. Limited by Federal (or United States) law
to investigational use.
AVAILABLE FOR SALE IN THE EU/EEA

23. · The remedē® System therapy, which activates automatically,
is an innovative therapy to treat CSA designed to restore
physiologic breathing
· The remedē® System Pilot Study data show statistically
significant, clinically meaningful long term improvements in:
» Sleep metrics (including AHI, CAI, arousals and REM sleep)
» Oxygen desaturations
» Quality of life (MLWHF, NYHA, Global assessment)
· The remedē® System Pilot Study data show therapeutic benefit
maintained through 12 months
· Future studies will continue to increase understanding of the
remedē® System therapy
Conclusions