Brief History of Major
Advancements in Cardiac Pacing
Mark D. Carlson, MD, MA
2
3
Pacing System Component
pulse generator
•
•
•
•
Casing (can)
• Titanium (biocompatible,
lightweight, stronger than
steel)
Connector (header)
• Leads plug into ports in the
clear epoxy header
Components
• Diodes, resistors, oscillator,
microchips
Battery
• The largest single component
inside the pulse generator
• Lithium iodide
2. Leads
3. Programmer/Remote
monitor
Path to Medical Device Innovation and
Improved Patient Care
 Problem/Opportunity
 Population
 Therapy (Current and Innovative)
 Outcomes
5
Path to Medical Device Innovation and Improved
Patient Care
 Problem/Opportunity
 Etiology and Mechanism
 Therapy (Current or Innovative)
 Mechanism of action
 Population
 Risk
 Prevalence
 Incidence
 Outcomes (Clinical/Regulatory/Health Economic)
 Measurements
 Surrogates
 Short/Long Term
6
Problem: Sudden Cardiac Death (1960s and Now)
 SCD: the most common cause of death in the U.S.
 Incidence: 300,000 to 400,000 each year (U.S.)
 Only 2% – 15% reach the hospital
 Half of these early survivors die before discharge
Therapy: SCD prevention the1960s, 70s, and 80s
 Frequent PVCs post MI associated with increased
mortality (SCD)
 Assumptions:
 PVCs trigger life-threatening sustained ventricular arrhythmias
 Suppression of PVCs with AAD improves survival
 SCD is increased in post-MI patients with low EF
 Assumptions:
 Induction of sustained VT during EP study identifies patientss
at increased risk
 Suppression of inducibility by AADs improves survival
8
Population: Sudden Cardiac Deaths – Incidence and
Prevalence
Incidence (%/Year)
Total Events (#/Year)
Overall Incidence
in Adult Population
High Coronary
Risk Sub-Group
Any Prior
Coronary Event
EF < 30%
Heart Failure
Out-of-Hospital
Cardiac Arrest Survivors
Convalescent Phase
VT/VF After MI
0
1
2
5 10 20 30
(%)
Source: Myerburg RJ. Circulation. 1992;85(suppl I):I-2 – I-10.
0
100
200
(x 1000)
300
Innovative Therapy: Automatic Implantable Defibrillator)
10
Timeline
 1966, Dr. Harry Heller died of
SCD in Israel
 1969, Michel Mirowski and
Morton Mower performed the
first canine transvenous
defibrillation at Sinai Hospital,
Baltimore
 1975, First canine implants
 February 4,1980, First human
implant at Johns Hopkins
Early AIDs
 1980-1985 clinical trial of first
ICDs
 1985 FDA approved first ICD
for human use
 First pulse generators were
140 cc (similar to a pack of
cigarettes)
 Abdominal implant
 Thoracotomy patch lead
implant
 Considered tx of last resort
 Patients had failed drugs and
survived two episodes of SCD
Landmark ICD Clinical Trials
1991: CAST
•AADs
suppressed
PVCs but
increased
mortality
1996:
MADIT
•ICDs
reduced
mortality
by 54% vs
AADs
13
1997/98:
AVID, CASH,
CIDS
•ICDs
improved
mortality in
secondary
prevention
2002: DAVID I
• Dual-chamber
pacing (70ppm)
vs ventricular
back-up pacing
(40 ppm)
increased
mortality in ICD
pts.
2002:
MADIT II
•ICDs
reduced
mortality
by 31%
vs AADs
2004:
DINAMITE
•ICDs
reduced SD
but not
mortality
early after
MI
2004:
DEFINITE
• ICDs
reduced
SAD and allcause
mortality in
NICM by an
amount that
bordered
significance
2005: SCDHeFT
• ICDs
reduced
mortality vs
amiodarone
or placebo
Advances in ICD Therapy
Lead Implant
Procedure
Implanting Physician
Device size
Procedure time
Perioperative
mortality
Post-implant
hospitalization
Battery longevity
Programmability
Pacing
Monitoring
Sensors
Then
Thoracotomy
Median sternotomy
Lateral thoracotomy
Cardiac surgeon
120 - 140 cc
2 - 4 hours
2.5%
Now
Tranvenous
Skin incision
3 - 5 days
1 day
18 months
None/Defib
None
In clinic
HR
Up to 9 years
Multiple/ATP
DDDR
Remote
Multiple physilogic
EP or surgeon
< 40 cc
1 hour
< 0.5%
Advances in ICD Therapy
Then
Now
Rhythm discrimination
none
Tx Programmability
Pacing
Stored Electrograms
None/Defib
None
None
Monitoring
Sensors
In clinic
HR
MRI compatability
unproven
QRS morphology
Onset
Rate Stability
Multiple/ATP
DDDR
Atrial and Ventricular
At high rates and with therapy
Remote
Activity
Posture
Intrathoracic impedance
Intracardiac ST segment
Intravascular pressure
Validated through clinical
studies
DAVID
 Dual chamber atrial based pacing could be beneficial by
allowing for
 Optimal medical management
 Increased heart rate and cardiac output
 Reduced incidence of AF
 Hypothesis: Dual chamber pacing (70 bpm) decreases
mortality and HF hospitalization for heart failure compared
to ventricular backup pacing (40 bpm).
16
DAVID – Results
Death or First Hospitalization for
New or Worsened CHF
Cumulative Probability
Dual-Chamber Rate-Responsive Pacing (DDDR)
Ventricular Backup Pacing (VVI)
0.4
Relative Hazard (95% CI), 1.61 (1.06-2.44)
0.3
0.2
0.1
0
No. at Risk
DDDR
VVI
0
6
250
256
159
158
Time, mo
12
18
76
90
21
25
The DAVID Trial Investigators. Dual-chamber pacing or ventricular backup pacing in
patients with an implantable defibrillator. JAMA. 2002;288(24):3115-3123.
SCD-HeFT Hypothesis
 Determine if amiodarone or ICD* will decrease the
risk of death from any cause in patients with mild-tomoderate heart failure
Bardy GH. N Engl J Med. 2005;352:225-237.
SCD-HeFT Results
HF Prevalence
U.S.




5.8 M heart failure patients in 2006 in the US1
Prevalence: 2.6%1
670,000 people are newly diagnosed each year.1
30% will die in the first year
(US and EU)3-5
 60% will die within 5 years (US)5
 1.1M HF hospitalizations annually; readmission rate is 25% and
50% at 30 days and 6 months
 Annual Medicare costs of ~$37B for hospitalizations with
~$17.4B of costs for readmissions within 30 days
Europe
 15 M heart failure patients in the ESC 51 member countries2
 Overall 2-3% prevalence2
1.
2.
3.
4.
5.
AHA 2010 Statistics at a Glance, 2010
The European Society of Cardiology, ESC HF Guideline, 2008
Curtis et al, Arch Intern Med, 2008.
Roger et al. JAMA, 2004.
Cowie et al, EHJ, 2002.
x
Evolution of CRT Pacing
1st Generation
 Unipolar or bipolar
simultaneous BiV pacing
2nd Generation
 Unipolar or bipolar sequential
BiV pacing (V-V Timing)
25
Cumulative Patients
Cardiac Resynchronization Randomized Trials
4000
CARE HF
MIRACLE ICD
3000
2000
1000
MIRACLE
MUSTIC AF
MIRACLE ICD II
MUSTIC SR
COMPANION
PATH CHF
PATH CHF II
CONTAK CD
0
1999
2000
2001
2002
2003
Results Presented
• Actual •
Projected
Doug Smith:
2004
2005
COMPANION All-Cause Death Results
Event-Free Survival (%)
100
OPT
CRT
CRT-D
90
(CRT vs. OPT) P = 0.059
(CRT-D vs. OPT) P = 0.003
80
70
60
50
0
90
180
270
360 450 540
630
720
810 900 990 1080
Days from Randomization
No. at Risk
OPT
CRT
CRT-D
308
617
595
284
579
555
255
520
517
217
488
470
Bristow M. N Engl J Med. 2004;350:2140-2150.
186
439
420
141
355
331
94
251
219
57
164
148
45
104
95
25
60
47
4
25
21
2
5
1
CRT Challenges
 CRT pacing complications at implant and follow-up
 Phrenic nerve stimulation 1
 High pacing thresholds2
 Lead dislodgement3
 Surgical lead revision increases risks5-7
 Tradeoff: Lead stability vs optimal pacing location4
 Efficacy
1.
2.
3.
4.
5.
6.
28 7.
Biffi M, et al. CICEP, 2009.
Gurevitz O, et al. PACE, 2005.
Leon AR, et al. J Am Coll Cardiol, 2005.
Duray, et al. J of Cardio Electro, 2008.
Klug et al. Circulation, 2007.
Poole JE, et al. Circulation, 2010.
Romeyer-Bouchard et al. EHJ, 2010.
CRT Pacing Challenges: PNS
Up to 37% of CRT patients experience PNS at implant or follow-up
29
 Biffi M, et al. CICEP, 2009.
Evolution of CRT Pacing
1st Generation
 Unipolar or bipolar
simultaneous BiV pacing
2nd Generation
 Unipolar or bipolar sequential
BiV pacing (V-V Timing)
Prox 4
3rd Generation
 Quadripolar selected LV site
BiV pacing
30
Mid 3
Mid 2
Distal 1
Evolution of CRT Pacing
1st Generation
 Unipolar or bipolar simultaneous BiV
pacing
2nd Generation
 Unipolar or bipolar sequential BiV pacing
(V-V Timing)
3rd Generation
 Quadripolar selected LV site BiV pacing
4th Generation
 Quadripolar multisite LV and RV
pacing
31
P4
M3
M2
D1
The Path to Heart Failure Decompensation
Pressure Changes
Autonomic
Adaptation
Impedance
Changes
Weight Changes,
BP, HF
Symptoms
Decompensation
Stable
Time
* Graph adapted from Adamson PB, et al. Curr Heart Fail Reports, 2009.
Hospitalization
Implanted LAP Systems
Standalone LAP and Combination CRT/D/LAP
CAUTION: Investigational Device, Limited
by Federal (or United States) Law to
Investigational Use
LAP System: Physician Directed, Patient SelfManagement Paradigm
Jack
PAM
Powers implant by RF
Atmospheric reference
Stores waveform
telemetry
Alerts patient to monitor
 DynamicRX®
 Internet connectivity
CAUTION: Investigational Device, Limited
by Federal (or United States) Law to
Investigational Use
Cardiomems Heart Failure Sensor
Verdejo, H. E. et al. J Am Coll Cardiol 2007;50:2375-2382
CAUTION: Investigational Device, Limited
by Federal (or United States) Law to
35
Investigational Use
Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply.
CardioMems PAP Sensor Deployment and Data
Collection
CAUTION: Investigational Device, Limited
by Federal (or United States) Law to
Investigational Use
Cumulative HF Hospitalizations Reduced
At 6 Months and Full Duration
Cumulative Number of HFR Hospitalizations
260
Treatment
240
Control
220
37% reduction
Full Duration
200
180
160
140
120
100
80
60
28% reduction
6 Months
40
20
0
0
90
180
270
360
450
540
630
720
810
900
82
67
29
25
5
10
1
0
Days from Implant
No. at Risk
Treatment 270
Control
280
262
267
244
252
210
215
169
179
131
137
108
105
Caution: Investigational Device. Limited by U.S. law to investigational use only.
St. Jude Medical – Sponsored Landmark Clinical Trial
Highlights
ADOPT-A (Atrial Dynamic Overdrive Pacing
Trial)
DAVID - (Dual-chamber
RethinQ -
(REsynchronization THerapy
In Normal QRS)
pAcing or Ventricular backup
–
CRT-D and V-V Timing
pacing in patients with an
JACC 2003
NEJM 2007
(Post AV Nodal Ablation
Implantable Defibrillator) - [DDDR
Chest 2007
Evaluation)
vs. VVIR]
JAMA 2002
JCE 2005
Manuscript published –
(Dual-chamber pAcing
JACC in 2009
or Ventricular backup pacing in patients
(DEFIbrillators in Non-Ischemic
with an Implantable Defibrillator) - [AAIR
Cardiomyopathy Treatment
vs. VVIR]
Evaluation)
- (Fractional flow
– (DefibrillatorManuscript in preparation
NEJM 2004
reserve (FFR) vs. Angiography
– (Optimal
IN Acute Myocardial Infarction
in Multivessel Evaluation)
Pharmacological Therapy in
Trial)
ANALYZE ST NEJM 2009
ICD Patients)
Intracardiac ST segment
NEJM
2004
JAMA
RHYTHM ICD
PAVE
DEFINITE
DAVID II -
FAME
DINAMIT
OPTIC
monitoring to detect ACS
Enrolling
ASSERT – (ASymptomatic
AF Stroke Evaluation in Pacemaker
Patients and the AF Reduction
Atrial Pacing Trial)
NEJM, 2011
FREEDOM - Impact of
CABANA - (Catheter ABlation
Versus ANti-Arrhythmic Drug Therapy for
AF)
Enrolling
BROADEN (BROdmann Area 25 DEep Brain Neurostim
Study)
Enrolling
Frequent QuickOpt CRT
optimization
SCD-HeFT (Sudden Cardiac Death in HEart
Failure Trial)
10-Year Follow-up Study
HRS 2012
FAME II - (Fractional flow
reserve (FFR) vs. Angiography
in Multivessel Evaluation)
LAPTOP HF -
Left Atrial
Pressure to Optimize HF
therapy
Enrolling
NEJM 2010
AF Business Area
CRM Business Area
CV Business Area
38
FOR INTERNAL USE ONLY. DO NOT DISTRIBUTE.
NM Business Area
Medical Technology Innovation Cycle
Bench Testing
and Preclinical
Studies
Feasibility and
Pivotal
Clinical Trials
Therapy
Development
FDA
Post Market
Studies
Identify the
Population
Understand
Etiology
Fine tune
therapy
Device
performance
Problem or
Opportunity
to Improve
therapy
39
Thank You
40