Download SUDDEN DEATH IN VARIOUS POPULATIONS: IS GENDER A RISK

SUDDEN DEATH IN VARIOUS
POPULATIONS:
IS GENDER A RISK FACTOR?
11th International Symposium Heart Failure & Co
Reggia di Caserta; April 29, 2011; 12:35 P.M.
Maria Rosa Costanzo, M.D., F.A.C.C, F.A.H.A
Medical Director, Midwest Heart Specialists Heart Failure and
Pulmonary Arterial Hypertension Programs
Medical Director, Edward Hospital Center for Advanced Heart Failure
Naperville, Illinois, U.S.A.
Incidence of SCD by Age and Gender
Kannel WB et al. Am Heart J 1998; 136:205
Prospective Study of SCD in Women in the U.S.
% of Cardiac Deaths Deemed SCD by Age
Relative Risk of SCD by Age
1st. Cardiac Rhythm Documented Near the Time of
Collapse in 109 Sudden Arrhythmic Deaths
10%
14%
6%
70%
VF
VT
Asystole
PEA/Bradycardia
Albert CM et al. Circulation 2003;107; 2096-101
Structural Heart Disease in
Cardiac Arrest Survivors
MEN
5%
WOMEN
3% 2%
2% 2%
5% 2% 2%
10%
10%
45%
13%
80%
CAD
DCM
VHD
Normal
Other
19%
CAD
DCM
Normal
Spasm
RV Dysplasia Long QT
Albert CM et al. Circulation 1998; 93: 1170-6
VHD
Congenital
Other
Factors Associated with PEA vs. VT/VF
The Oregon Sudden Unexpected Death Study
Multivariable Odds Estimates of
Factors Associated with PEA vs. VF/VT
Presenting Arrythmia
at TIme of SCD by Gender
Age (per y ↑)
1.02 (1.01-1.04)
White
1.0 (reference)
Black
2.64 (1.29-5.38)
Hispanic
0.32 (0.05-2.13)
Asian
0.88 (0.20-3.98)
30%
Other Race
1.03 (0.23-4.59)
20%
CAD
0.35 (0.23-0.53)
Hyperlipidemia
0.59 (0.38-0.90)
Hx. Syncope
2.64 (1.31-5.32)
Male, No Pulm. Dis
1.0 (reference)
Female, No Pulm. Dis
1.68 (1.01-2.82)
Male, Pulm. Dis.
3.17 (1.86-5.42)
Female, Pulm. Dis
2.11 (1.10-4.04)
74%
80%
70%
% of Patients
OR (95% CI)*
Male
Female
63%
58%
60%
42%
50%
37%
40%
26%
10%
0%
PEA
VF/VT
Asystole
Teodorescu C. et al. Circulation 2010; 122: 2116-22
Basic Electrophysiological Variables
Affected by Gender Differences
Cardiac Cycle
Heart Rate
QT
Dispersion
QT Interval
QT-RR
Relationship
T Wave
Morphology
Higher Prevalence in Females
Higher Prevalence in Males
Congenital Long QT Syndrome
AF
Acquired Long QT Syndrome
WPW
AV Nodal Re-Entrant Tachycardia
SCD
Sex-Related Differences in Repolarization
Action Potentials from Isolated
Guinea Pig Ventricular Myocytes
James MJ et al. Basic Res Cardiol 2004;99: 183-92
Baseline and Ibutilide-Induced
QTc Change in Normal Volunteers
Rodriguez I et al. JAMA 285: 1322-6
Relationship between
Baseline QT Interval and Cycle Length
Orchiectomy (Placebo)
Orchiectomy
+
Dihydrotestosterone
Liu XK et al. Cardiovasc Res 2003; 57:28-36
Effects of Dofetilide on APD and Incidence of EADs
at a Cycle Length of 1000 ms
in Rabbit RV Endocardial Papillary Muscles
Female
Ovariectomized
Females
Male
Orchiectomized
Males
Pham TV et al.
Circulation
2001; 103:2207-12
Effects of Dihydrotestosterone on
Dofelitide-Induced Repolarization Changes
in Rabbit RV Endocardial Papillary Muscles
APD
EAD
Orchiectomized
Males
Females
Males
DHT-Orchiectomized
Males
DHT Females
Pham TV et al. Circulation 2002; 106:2132-6
Distribution of Probands in Familial LQTS
by Age and Sex at Baseline ECG
100
90
95
95
Males
Females
85
80
80
80
% Patients
70
65
60
49
50
46
40
40
30
25
21
20
20
5
10
3
0
6-10
11-15
16-20
21-25
26-30
31-35
36-40
James AF et al. Prog Biophysics Molecular Biol 2007; 94: 265-319
Age, Y
High Risk Subsets for ACA or ACA by Age Groups
Goldenberg I et al. Curr Prob Cardiol 2008; 33: 629-94
Age Group (Years)
High Risk Subsets
Childhood
(1-12)
Males with prior syncope and/or QTc >500 ms
Females with prior syncope
Adolescence
(13-20)
Males and Females with either one or two or
more of the following:
QTc ≥ 530 ms
≥ episode of syncope in the past year
≥ 2 episodes of syncope in the past 2-10 y
Adulthood
(20-40)
BB Effect in High Risk Patients:
% Reduction (p value)
73 (0.002)
64 (0.01)
60 (< 0.01)
Either one or more of the following:
Female Gender
Interim Syncope after age 18
QTc ≥ 500 ms
(41-60)
Female gender
Syncope in the past 10 y
QTc ≥ 500 ms
LQT3 genotype
42 (0.40)
(61-75)
Syncope in the past 10 y
86 (0.05)
Probability of ACA or SCD in 3,774 LQTS Patients
from the International LQTS Registry
Influence of Pregnancy
on the Risk of Cardiac Events
in Patients with Hereditary Long QT Syndrome
10%
9%
% Long QT
9.1% 9.0%
% Long QT with new-onset cardiac events
% of Patients
8%
7%
6%
4.5%
5%
4%
3%
2%
1%
1.8%
0.9%
0.0%
0%
Pre-pregnancy
Pregnancy
Post partum
Rashba EJ et al. Circulation 1998; 97: 451-6
JTc on d, I-sotalol
375
370
Women
Men
365
JTc (msec)
360
355
350
345
340
335
330
325
320
Lowest Daily Dose
320 mg/day
Highest Daily Dose Max JTc (any dose)
Lehman MH et al. Am J Cardiol 1999;83: 354-9
Lethal Arrhythmias Susceptibility and
Myocardial Connexin-43 Expression
Myocardial Connexin-43 Expression
Susceptibility to VF
900
90%
800
80%
700
70%
600
60%
500
50%
400
40%
300
30%
200
20%
100
10%
0
Female
Male
0%
Female
Male
Knezl V. et al. Neuroendocrinology Letters 2008; 29: 798-601
Gender Differences in the
Clinical Manifestations of the Brugada Syndrome
Males
Females
No Events
Events
P value
No Events
Events
P value
Sx. At Dx.
46 (19)
20 (64)
< 0.001
15 (15)
1 (33)
NS
Previous
AF n (%)
18 (7%)
8 (26)
0.005
12 (11)
2 (67)
0.04
Spont.
Type -1
ECG
105 (43)
21 (67)
0.01
23 (21)
2 (67)
0.04
PR (ms)
175 ± 30
178 ± 40
NS
173 ± 32
240 ± 62
0.001
QRS (ms)
107 ± 17
110 ± 18
NS
97 ± 16
130 ± 62
NS
QTc (ns)
421 ± 48
432 ± 42
NS
420 ± 49
486 ± 47
0.006
ST elev.
3.6 ± 2
3±1
NS
2.4 ± 1
3.2 ±1
NS
VF
Inducibility
(%)
28
74
< 0.001
11
50
NS
HV Interval
48 ± 10
46 ± 7
NS
46 ± 8
60 ± 11
0.002
Benito, B. et al. J Am Coll Cardiol 2008;52:1567-1573
The Brugada Syndrome and Gender
Kaplan-Meier Estimate of
Cardiac Event-Free Survival According to Gender
HR
95% CI
P Value
Gender
2.82
0.64-12.41
NS
Previous AF
2.16
0.93-5.03
0.007
Syncope at
Dx.
1.86
0.7-4.97
NS
Aborted SCD
8.45
3.17-22.55
<0.001
Spont. Type 1
ECG
1.4
0.59-3.33
NS
VF Inducibility
2.93
1.14-7.55
0.02
Benito, B. et al. J Am Coll Cardiol 2008;52:1567-1573
ICD Trials
Multivariable Predictors of ICD Use
Variable
HR-Primary Prevention Cohort
HR-Secondary Prevention Cohort
Age, per y
0.93
0.95
Male sex
3.15
2.44
Black race
0.85
0.71
CBV
0.91
0.97
Chronic Pulm.
0.89
0.98
CAD
3.11
5.33
Dementia
0.29
0.32
DM
1.02
1.10
HTN
0.85
1.04
Cancer
0.59
0.36
Renal
0.98
0.90
Midwest Region
1.17
1.22
Northeast
1.19
1.10
2000
1.19
1.15
2001
1.57
1.38
2002
2.24
1.81
2003
2.92
1.94
2004
3.59
2.04
2005
4.88
2.05
Comorbidities
Year of Implant
Adapted from Curtis LH et al. JAMA 2007; 298: 1517-24
1 Year Mortality by ICD Use and Gender
in a Large Medicare Population
Primary Prevention Cohort
No. of
Pts. At
Risk
%
Mortality
with ICD
%
Mortality
without
ICD
Overall
96990
10.4
13.4
1.01
Men
47729
11.2
13.1
Women
49261
7.8
13.7
Secondary Prevention Cohort
HR
No. of
Pts. At
Risk
%
Mortality
with ICD
%
Mortality
without
ICD
Overall
54342
10.9
16.8
0.65
(0.001)
1.05
Men
29333
11.0
16.8
0.62
(0.001)
0.93
Women
25009
10.8
16.0
0.71
(0.001)
(p value)
Adapted from Curtis LH et al. JAMA 2007; 298: 1517-24
HR
(p value)
Effectiveness of ICD for the Primary Prevention of
SCD in Women with Advanced HF
Baseline Characteristics of Patients in Trials Included in the Meta-Analysis
Ghambari H. et al. Arch Intern Med 2009; 169: 1500-6
Effectiveness of ICD for the Primary Prevention of
SCD in Women with Advanced HF
Sex Differences in Mortality Rates
Between ICD and Medical Therapy Groups
Ghambari H. et al. Arch Intern Med 2009; 169: 1500-6
Effectiveness of ICD for the Primary Prevention of
SCD in Women with Advanced HF
MEN
WOMEN
Ghambari H. et al. Arch Intern Med 2009; 169: 1500-6
Gender Differences in Procedure-Related Adverse Events
in Patients Receiving ICD Therapy
161.470 pts, 27% women
Peterson PN et al. Circulation 2009; 119: 1078 - 84
Benefits of ICD in Women
No trial powered to separately examine outcomes in men
and women or test for difference in ICD effectiveness
Small numbers of women enrolled
Limited post-hoc analyses for females do not clearly
demonstrate a mortality benefit:
– SCD-HeFT: benefit not clear (not powered for gender)
– MADIT II: nonsignificant trend toward lower mortality in
females but analysis limited by too few female subjects
Meta-analysis: 934 females in 5 trials; no difference in
all-cause mortality for women with ICD vs medical Rx
Conclusions
■ Females with lower rates of SCD than
males
■ Differences in arrhythmia susceptibility
■ 30% of ICDs are implanted in females
■ Even though the benefit is less, it may
represent a clinically significant
reduction in deaths
Conclusions
A trial targeting women is needed
To detect the same ICD benefit in women
as was observed in men with 90% power
and α=0.05, a study larger than SCDHeFT
would be required (1.585 women in each
treatment arm, 3.170 total)
It may now even be considered “unethical”
to withhold ICD therapy in women meeting
the SCD-HeFT enrollment criteria.