Preventing Sudden Death
Current & Future Role of ICD Therapy
Canada
Research
Chairs
ACC – March 2013
Derek V Exner, MD, MPH, FRCPC, FACC, FAHA, FHRS
Professor, Libin Cardiovascular Institute of Alberta
Canada Research Chair, Cardiovascular Clinical Trials
Choose your
electrician wisely!
Consulting &
Honoraria
Boehringer Ingelheim, GE Healthcare,
Medtronic, Sanofi-Aventis, St Jude Medical
Speakers’ Bureau
Biotronik, Boston Scientific, GE Healthcare,
Medtronic, St Jude Medical
Equipment
donations
AudiCor, Cambridge Heart, GE Healthcare,
Roche Diagnostics, Sorin / ELA
Research
Support
Cambridge Heart, Heart Force Medical, GE
Healthcare, Medtronic, St Jude Medical
Investor Analytics4Life
Salary &
Grants
Alberta AET, CIHR, CRC, HSF Alberta, JC
Anderson Legacy Foundation, WED.
Derek V. Exner - Disclosures
March 2013
Overview
Sudden death
Epidemiology
Risk quantification
ICD Therapy in 2013
Indications
Expectations
Unanswered questions
March 2013
Sudden Death / Sudden Cardiac Arrest
Cardiovascular death < 1 hour of symptoms
March 2013
More deaths than others combined
Magnitude
0
100,000
200,000
300,000
400,000
500,000
Deat
hs p
er y
ear
Breast Lung Stroke Sudden Cancer Cancer Death
March 2013
What Proportion of Sudden Deaths are Arrhythmic?
1. 20%
2. 40%
3. 60%
4. 80%
Sudden Death: Diverse Mechanisms
VF
Rapid
VT
Brady/EM
D
Other
Am J Cardiol 1989;117:151-9
Ambulatory
VT/VF Brady/EMD
Circulation 1989;80:1675-80
Awaiting Transplant
March 2013
Population Subgroups
Rea AJC 2004;93:1455-60.
0 25 50 75
HeartFailure
Prior MI
Population Attributable Risk
% of events (prevalence)
Individual risk (incidence)
0% 25% 50% 75%
March 2013
Who is Indicated for an ICD?
1. Prior cardiac arrest / sustained VT
2. CAD & EF < 35%
3. CAD & EF < 30%
4. 1 & 2
5. 1 & 3
0.2 0.5 1 2
Odds ratio(95% confidence interval)
0.59 (0.43, 0.81)AVID (n = 1,016) 8.2%
CIDS (n = 659) 0.81 (0.57, 1.14) 4.3%
CASH (n = 288) 0.71 (0.43, 1.18) 8.1%
MADIT I (n = 196) 0.30 (0.15, 0.59) 22.8%
CABG-Patch (n = 900) 1.11 (0.81, 1.52)
MUSTT (n = 514) 0.34 (0.22, 0.53) 23.0%
MADIT II (n = 1,232) 0.68 (0.50, 0.92) 5.4%
AMIOVIRT (n = 103) 0.86 (0.27, 2.75) 1.7%
CAT (n = 104) 0.76 (0.33, 1.80) 5.4%
COMPANION (n = 903) 0.64 (0.46, 0.90) 7.3%
SCD-HEFT (n = 1,676) 0.70 (0.56, 0.87) 6.8%
DEFINITE (n = 458) 0.66 (0.39, 1.11) 5.2%
DINAMIT (n = 674) 1.12 (0.76, 1.67)
Overall 0.72 (0.60, 0.86)
Favors ICD
MortalityReduction
Spontaneous or InducibleVentricular Arrhythmias
Heart Failure or LVDysfunction Alone
LV dysfunction inSpecific Circumstances
Risk Groups
BEST-ICD (n = 138) 1.17 (0.39, 3.48)
IRIS (n = 898) 1.01 (0.75, 1.36)
Exner Randomized Trials of ICD Therapy 2011 March 2013
Recommend for history of
hemodynamically significant or
sustained ventricular arrhythmia
(secondary prevention).
For ALL:
Strong
Recommendation
High Quality
Evidence
Consider for primary prevention:
i. Ischemic LVD, NYHA II-III, EF ≤
35%, measured > 1 m post MI, & >
3 m post revascularization ;
ii. Ischemic LVD, NYHA class I, & EF
≤ 30% > 1 m post MI, & < 3 m post
revascularization ;
iii. Nonischemic LVD, NYHA class II-III,
EF ≤ 35%, measured > 9 m after
optimal medical therapy.
Recommendations - Chronic Heart Failure Implantable cardioverter-defibrillator (ICD)
Primary Prevention ICD Therapy Use Is:
1. Too High
2. About Right
3. To Low
ON
152
AB
120
Atlantic 186
QC
170 SK
105
MB
185 BC
122
Territories 125
New ICD Implants per Million
Crysler Industry Data 2010 March 2013
Regarding My Enthusiasm for Primary Prevention ICD Therapy:
1. I am keen
2. I am not keen due to the risk of
shocks
3. I am not keen due to an inability
to predict who will benefit
4. I am not keen due to the risk of
long-term complications (leads,
redo procedures)
5. I am not keen due to poor
accessibility
0
25
50
75
100
Pro
port
ion (
%)
Relying Solely On Low LVEF
Most Identified Are Not At High
Risk
Fails to Identify Most of Those
at Risk
Exner. Curr Opin Cardiol 2009, 24:61–7 March 2013
Clinical Risk Stratification: MADIT II
Predictors of ICD benefit
• age > 70,
• NYHA 3 or 4,
• Elevated urea
(> 26 mg/dl /
(> 9.3 mmol/ L)
• QRSd > 120 ms,
• Atrial fibrillation.
Goldenberg et al., JACC 2008;51:288-96
None of the 5 risk factors
(n = 345; 31%)
HR for ICD therapy 0.96
(95% CI 0.44, 2.07); p = 0.91
> 1 risk factor (n = 786; 69%)
HR for ICD therapy 0.51
(95% CI 0.37, 0.70); p < 0.001
March 2013
Based on data from SCD-HeFT, over the initial 5 years, patients receiving a primary prevention ICD
should expect ?
1. 10% risk of shocks;
95% for VT/VF
2. 25% risk of shocks;
80% for VT/VF
3. 33% risk of shocks;
65% for VT/VF
4. 50% risk of shocks;
50% for VT/VF
Shocks: Necessary & Appropriate ?
VT / VF 65%
OS 12% SVT
20% NSVT 3%
Poole et al. N Engl J Med 2008;359:1009-17
- 1 in 3 ICD recipients
in SCD-HeFT
received shocks
- Inappropriate
2-fold higher
risk of death
- Appropriate
5-fold higher
risk of death
March 2013
Shock Reduction Algorithms
Time to Development of Shocks for VT/VF
Time to Development of Inappropriate Shocks
Reduced from 30.7% to 26.1%
Reduced from 23.5% to 8.4%
99.2% of all VT/VF episodes detected without delay
Volosin, Exner, et al. JCE 2011;22:280-9 March 2013
Range of NID Settings
Original NID = 18/24 Virtual ICD NID = 18/24 NID = 24/32 NID = 30/40
Time to Development of Inappropriate shocks
March 2013 Volosin, Exner, et al. JCE 2011;22:280-9
MADIT-RIT: Shock Reduction
NEJM 2012;367(24):2275-83 March 2013
~ 80% reduction in
inappropriate ICD
therapies
MADIT-RIT: Reduced Mortality
NEJM 2012;367(24):2275-83 March 2013
~ 50% reduction in mortality
(6.6% vs. 3.2%)
ICD Therapy: Recent MI
Exner Randomized Trials of ICD Therapy 2011
0.2 0.5 1 2
Odds ratio(95% confidence interval)
0.59 (0.43, 0.81)AVID (n = 1,016) 8.2%
CIDS (n = 659) 0.81 (0.57, 1.14) 4.3%
CASH (n = 288) 0.71 (0.43, 1.18) 8.1%
MADIT I (n = 196) 0.30 (0.15, 0.59) 22.8%
CABG-Patch (n = 900) 1.11 (0.81, 1.52)
MUSTT (n = 514) 0.34 (0.22, 0.53) 23.0%
MADIT II (n = 1,232) 0.68 (0.50, 0.92) 5.4%
AMIOVIRT (n = 103) 0.86 (0.27, 2.75) 1.7%
CAT (n = 104) 0.76 (0.33, 1.80) 5.4%
COMPANION (n = 903) 0.64 (0.46, 0.90) 7.3%
SCD-HEFT (n = 1,676) 0.70 (0.56, 0.87) 6.8%
DEFINITE (n = 458) 0.66 (0.39, 1.11) 5.2%
DINAMIT (n = 674) 1.12 (0.76, 1.67)
Overall 0.72 (0.60, 0.86)
Favors ICD
MortalityReduction
Spontaneous or InducibleVentricular Arrhythmias
Heart Failure or LVDysfunction Alone
LV dysfunction inSpecific Circumstances
Risk Groups
BEST-ICD (n = 138) 1.17 (0.39, 3.48)
IRIS (n = 898) 1.01 (0.75, 1.36)
0.2 0.5 1 2
Odds ratio(95% confidence interval)
0.59 (0.43, 0.81)AVID (n = 1,016) 8.2%
CIDS (n = 659) 0.81 (0.57, 1.14) 4.3%
CASH (n = 288) 0.71 (0.43, 1.18) 8.1%
MADIT I (n = 196) 0.30 (0.15, 0.59) 22.8%
CABG-Patch (n = 900) 1.11 (0.81, 1.52)
MUSTT (n = 514) 0.34 (0.22, 0.53) 23.0%
MADIT II (n = 1,232) 0.68 (0.50, 0.92) 5.4%
AMIOVIRT (n = 103) 0.86 (0.27, 2.75) 1.7%
CAT (n = 104) 0.76 (0.33, 1.80) 5.4%
COMPANION (n = 903) 0.64 (0.46, 0.90) 7.3%
SCD-HEFT (n = 1,676) 0.70 (0.56, 0.87) 6.8%
DEFINITE (n = 458) 0.66 (0.39, 1.11) 5.2%
DINAMIT (n = 674) 1.12 (0.76, 1.67)
Overall 0.72 (0.60, 0.86)
Favors ICD
MortalityReduction
Spontaneous or InducibleVentricular Arrhythmias
Heart Failure or LVDysfunction Alone
LV dysfunction inSpecific Circumstances
Risk Groups
BEST-ICD (n = 138) 1.17 (0.39, 3.48)
IRIS (n = 898) 1.01 (0.75, 1.36)
0.2 0.5 1 2
Odds ratio(95% confidence interval)
0.59 (0.43, 0.81)AVID (n = 1,016) 8.2%
CIDS (n = 659) 0.81 (0.57, 1.14) 4.3%
CASH (n = 288) 0.71 (0.43, 1.18) 8.1%
MADIT I (n = 196) 0.30 (0.15, 0.59) 22.8%
CABG-Patch (n = 900) 1.11 (0.81, 1.52)
MUSTT (n = 514) 0.34 (0.22, 0.53) 23.0%
MADIT II (n = 1,232) 0.68 (0.50, 0.92) 5.4%
AMIOVIRT (n = 103) 0.86 (0.27, 2.75) 1.7%
CAT (n = 104) 0.76 (0.33, 1.80) 5.4%
COMPANION (n = 903) 0.64 (0.46, 0.90) 7.3%
SCD-HEFT (n = 1,676) 0.70 (0.56, 0.87) 6.8%
DEFINITE (n = 458) 0.66 (0.39, 1.11) 5.2%
DINAMIT (n = 674) 1.12 (0.76, 1.67)
Overall 0.72 (0.60, 0.86)
Favors ICD
MortalityReduction
Spontaneous or InducibleVentricular Arrhythmias
Heart Failure or LVDysfunction Alone
LV dysfunction inSpecific Circumstances
Risk Groups
BEST-ICD (n = 138) 1.17 (0.39, 3.48)
IRIS (n = 898) 1.01 (0.75, 1.36)
0.2 0.5 1 2
Odds ratio(95% confidence interval)
0.59 (0.43, 0.81)AVID (n = 1,016) 8.2%
CIDS (n = 659) 0.81 (0.57, 1.14) 4.3%
CASH (n = 288) 0.71 (0.43, 1.18) 8.1%
MADIT I (n = 196) 0.30 (0.15, 0.59) 22.8%
CABG-Patch (n = 900) 1.11 (0.81, 1.52)
MUSTT (n = 514) 0.34 (0.22, 0.53) 23.0%
MADIT II (n = 1,232) 0.68 (0.50, 0.92) 5.4%
AMIOVIRT (n = 103) 0.86 (0.27, 2.75) 1.7%
CAT (n = 104) 0.76 (0.33, 1.80) 5.4%
COMPANION (n = 903) 0.64 (0.46, 0.90) 7.3%
SCD-HEFT (n = 1,676) 0.70 (0.56, 0.87) 6.8%
DEFINITE (n = 458) 0.66 (0.39, 1.11) 5.2%
DINAMIT (n = 674) 1.12 (0.76, 1.67)
Overall 0.72 (0.60, 0.86)
Favors ICD
MortalityReduction
Spontaneous or InducibleVentricular Arrhythmias
Heart Failure or LVDysfunction Alone
LV dysfunction inSpecific Circumstances
Risk Groups
BEST-ICD (n = 138) 1.17 (0.39, 3.48)
IRIS (n = 898) 1.01 (0.75, 1.36)
0.20.512
Oddsratio(95%confidenceinterval)
0.59(0.43,0.81) AVID(n=1,016)8.2%
CIDS(n=659)0.81(0.57,1.14)4.3%
CASH(n=288)0.71(0.43,1.18)8.1%
MADITI(n=196)0.30(0.15,0.59)22.8%
CABG-Patch(n=900)1.11(0.81,1.52)
MUSTT(n=514)0.34(0.22,0.53)23.0%
MADITII(n=1,232)0.68(0.50,0.92)5.4%
AMIOVIRT(n=103)0.86(0.27,2.75)1.7%
CAT(n=104)0.76(0.33,1.80)5.4%
COMPANION(n=903)0.64(0.46,0.90)7.3%
SCD-HEFT(n=1,676)0.70(0.56,0.87)6.8%
DEFINITE(n=458)0.66(0.39,1.11)5.2%
DINAMIT(n=674)1.12(0.76,1.67)
Overall0.72(0.60,0.86)
FavorsICD
MortalityReduction
SpontaneousorInducibleVentricularArrhythmias
HeartFailureorLVDysfunctionAlone
LVdysfunctioninSpecificCircumstances
RiskGroups
BEST-ICD(n=138)1.17(0.39,3.48)
IRIS(n=898)1.01(0.75,1.36)
March 2013
Use of ICD Therapy Early After MI
Hohnloser et al, NEJM 2004;351:2481-8.
DINAMIT
• N = 674
• EF < 0.35 (6-40 d post-MI)
• Impaired HR variability
Steinbeck et al, NEJM 2009;361:1427-36.
IRIS
• N = 898
• EF < 0.40 (5-31 d post-MI)
• Elevated HR +/- NSVT
Hohnloser. NEJM 2004;351:2481-8. Steinbeck. NEJM 2009;361:1427-36.
March 2013
Hohnloser. NEJM 2004;351:2481-8. Steinbeck. NEJM 2009;361:1427-36.
DINAMIT IRIS
March 2013
Development of a Cardiac Arrest
Moss & Zareba J Electrocardiol 2003;36:101-8
Autonomic Nervous System
Underlying Fixed
Substrate
Dynamic Substrate
March 2013
Holter, Modified Moving Average TWA
J Appl Physiol 2002;92:541-9 J Am Coll Cardiol 2011;58;1309-24 March 2013
Heart Rate Turbulence (HRT)
# of RR interval
RR
inte
rval
(m
s)
PVC
Schmidt et al. Lancet 1999;353:1390-6. Bauer et al. JACC 2008;52:1353-65.
Reflex response to perturbation
1 291 pts (post-MI)
Holter < 14 d
> 3-fold higher risk of death (indep’t)
Validation in multiple studies.
Consistent utility.
March 2013
HRT onset
HRTslope
# of RR interval
RR
inte
rval
(m
s)
PVC
Heart Rate Turbulence (HRT)
Reflex response to perturbation
1 291 pts (post-MI)
Holter < 14 d
> 3-fold higher risk of death (indep’t)
Validation in multiple studies.
Consistent utility.
Schmidt et al. Lancet 1999;353:1390-6. Bauer et al. JACC 2008;52:1353-65. March 2013
Combined Parameter Assessment
Cardiac Death or Cardiac Arrest
Remaining
HRT + TWA & EF < 0.50
322 post-MI patients serial assessment (2-4 & 10-14 weeks) Later testing more accurate
6-fold higher risk with abnormal HRT + TWA
Sensitivity: 55%
Positive PV: 27%
Negative PV: 96%
Exner et al. JACC 2007;50:2275-84. March 2013
Risk Estimation Following Infarction Noninvasive Evaluation: ICD efficacy
EF 0.36 to 0.50
2-15 mo. post-MI
> 3 mo. post-revasc.
< 80 years & without
dialysis, perm AF or AAD
Holter
Abnormal
TWA + HRT
Registry
Usual Care Alone
Usual Care + ICD
Minimum follow-up: 2 years
Mean follow-up: 5 years
1° outcome: mortality
2° outcomes: cost & QoL
March 2013
Summary
March 2013
Sudden death remains an important issue
Post-MI patients are at risk
EF alone is a poor discriminator
The recommendations for ICD therapy are
based on many large randomized trials
Clinical risk scores exist to maximize
benefit
Shock reduction is here to stay
Unanswered questions persist (post-MI)