sudden death in various populations: is gender a risk factor? 11 th international symposium heart...

SUDDEN DEATH IN VARIOUS SUDDEN DEATH IN VARIOUS POPULATIONS:POPULATIONS:

IS GENDER A RISK FACTOR?IS GENDER A RISK FACTOR?1111thth International Symposium Heart Failure & Co International Symposium Heart Failure & Co

Reggia di Caserta; April 29, 2011; 12:35 P.M.Reggia di Caserta; April 29, 2011; 12:35 P.M.

Maria Rosa Costanzo, M.D., F.A.C.C, F.A.H.AMaria Rosa Costanzo, M.D., F.A.C.C, F.A.H.AMedical Director, Midwest Heart Specialists Heart Failure andMedical Director, Midwest Heart Specialists Heart Failure and

Pulmonary Arterial Hypertension ProgramsPulmonary Arterial Hypertension ProgramsMedical Director, Edward Hospital Center for Advanced Heart FailureMedical Director, Edward Hospital Center for Advanced Heart Failure

Naperville, Illinois, U.S.A.Naperville, Illinois, U.S.A.

Incidence of SCD by Age and GenderIncidence 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.Prospective Study of SCD in Women in the U.S.

Albert CM et al. Circulation 2003;107; 2096-101

Relative Risk of SCD by Age% of Cardiac Deaths Deemed SCD by Age

1st. Cardiac Rhythm Documented Near the Time of Collapse in 109 Sudden Arrhythmic Deaths

70%

6%

14%

10%

VF VT Asystole PEA/Bradycardia

Structural Heart Disease in Structural Heart Disease in Cardiac Arrest SurvivorsCardiac Arrest Survivors

MEN

80%

10%5% 3% 2%

CAD DCM VHD Normal Other

WOMEN

45%

19%

13%

10%

5% 2%2% 2% 2%

CAD DCM VHD

Normal Spasm Congenital

RV Dysplasia Long QT Other

Albert CM et al. Circulation 1998; 93: 1170-6

Factors Associated with PEA vs. VT/VFFactors Associated with PEA vs. VT/VFThe Oregon Sudden Unexpected Death StudyThe Oregon Sudden Unexpected Death Study

63%

37%

74%

26%

58%

42%

0%

10%

20%

30%

40%

50%

60%

70%

80%

PEA VF/VT Asystole

Presenting Arrythmia at TIme of SCD by Gender

Male

Female

OR (95% CI)*OR (95% CI)*

Age (per y Age (per y ↑)↑) 1.02 (1.01-1.04)1.02 (1.01-1.04)

WhiteWhite 1.0 (reference)1.0 (reference)

BlackBlack 2.64 (1.29-5.38)2.64 (1.29-5.38)

HispanicHispanic 0.32 (0.05-2.13)0.32 (0.05-2.13)

AsianAsian 0.88 (0.20-3.98)0.88 (0.20-3.98)

Other RaceOther Race 1.03 (0.23-4.59)1.03 (0.23-4.59)

CADCAD 0.35 (0.23-0.53)0.35 (0.23-0.53)

HyperlipidemiaHyperlipidemia 0.59 (0.38-0.90)0.59 (0.38-0.90)

Hx. SyncopeHx. Syncope 2.64 (1.31-5.32)2.64 (1.31-5.32)

Male, No Pulm. DisMale, No Pulm. Dis 1.0 (reference)1.0 (reference)

Female, No Pulm. DisFemale, No Pulm. Dis 1.68 (1.01-2.82)1.68 (1.01-2.82)

Male, Pulm. Dis.Male, Pulm. Dis. 3.17 (1.86-5.42)3.17 (1.86-5.42)

Female, Pulm. DisFemale, Pulm. Dis 2.11 (1.10-4.04)2.11 (1.10-4.04)

Multivariable Odds Estimates of Factors Associated with PEA vs. VF/VT

Teodorescu C. et al. Circulation 2010; 122: 2116-22

% o

f P

atie

nts

Basic Electrophysiological Variables Basic Electrophysiological Variables Affected by Gender DifferencesAffected by Gender Differences

Cardiac Cycle

QT IntervalHeart Rate

T WaveMorphology

QT-RR Relationship

QT Dispersion

Higher Prevalence in Higher Prevalence in FemalesFemales Higher Prevalence in Higher Prevalence in MalesMales

Congenital Long QT SyndromeCongenital Long QT Syndrome AFAF

Acquired Long QT SyndromeAcquired Long QT Syndrome WPWWPW

AV Nodal Re-Entrant TachycardiaAV Nodal Re-Entrant Tachycardia SCDSCD

Sex-Related Differences in RepolarizationSex-Related Differences in RepolarizationAction Potentials from Isolated

Guinea Pig Ventricular MyocytesBaseline and Ibutilide-Induced

QTc Change in Normal Volunteers

Rodriguez I et al. JAMA 285: 1322-6James MJ et al. Basic Res Cardiol 2004;99: 183-92

Relationship between Relationship between Baseline QT Interval and Cycle LengthBaseline 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 Effects of Dofetilide on APD and Incidence of EADs at a Cycle Length of 1000 ms at a Cycle Length of 1000 ms

in Rabbit RV Endocardial Papillary Musclesin Rabbit RV Endocardial Papillary Muscles

Female

Male

Ovariectomized Females

Orchiectomized Males

Pham TV et al.Circulation 2001; 103:2207-12

Effects of Dihydrotestosterone on Effects of Dihydrotestosterone on Dofelitide-Induced Repolarization Changes Dofelitide-Induced Repolarization Changes in Rabbit RV Endocardial Papillary Musclesin Rabbit RV Endocardial Papillary Muscles

Males

Orchiectomized Males

DHT-Orchiectomized Males

Females

DHT Females

APD EAD

Pham TV et al. Circulation 2002; 106:2132-6

4946

40

65

25

80

5

95

20

85

3

95

21

80

0

10

20

30

40

50

60

70

80

90

100

6-10 11-15 16-20 21-25 26-30 31-35 36-40

Distribution of Probands in Familial LQTS by Age and Sex at Baseline ECG

Males

Females

% P

atie

nts

Age, Y

James AF et al. Prog Biophysics Molecular Biol 2007; 94: 265-319

High Risk Subsets for ACA or ACA by Age GroupsHigh Risk Subsets for ACA or ACA by Age GroupsGoldenberg I et al. Curr Prob Cardiol 2008; 33: 629-94Goldenberg I et al. Curr Prob Cardiol 2008; 33: 629-94

Age Group (Years)Age Group (Years) High Risk SubsetsHigh Risk Subsets BB Effect in High Risk Patients:BB Effect in High Risk Patients:

% Reduction (p value)% Reduction (p value)

ChildhoodChildhood

(1-12)(1-12)

Males Males with prior syncope and/or QTc >500 mswith prior syncope and/or QTc >500 ms

FemalesFemales with prior syncope with prior syncope 73 (0.002)73 (0.002)

AdolescenceAdolescence

(13-20)(13-20)

MalesMales and and Females Females with either one or two or with either one or two or more of the following:more of the following:

QTc QTc ≥ 530 ms≥ 530 ms

≥ ≥ episode of syncope in the past yearepisode of syncope in the past year

≥ ≥ 2 episodes of syncope in the past 2-10 y2 episodes of syncope in the past 2-10 y

64 (0.01)64 (0.01)

AdulthoodAdulthood

(20-40)(20-40) Either one or more of the following:Either one or more of the following:

Female GenderFemale Gender

Interim Syncope after age 18Interim Syncope after age 18


60 (< 0.01)60 (< 0.01)

(41-60)(41-60) Female genderFemale gender

Syncope in the past 10 ySyncope in the past 10 y


LQT3 genotypeLQT3 genotype

42 (0.40)42 (0.40)

(61-75)(61-75) Syncope in the past 10 ySyncope in the past 10 y 86 (0.05)86 (0.05)

Probability of ACA or SCD in 3,774 LQTS PatientsProbability of ACA or SCD in 3,774 LQTS Patientsfrom the International LQTS Registryfrom the International LQTS Registry

0.9%

0.0%

4.5%

1.8%

9.1% 9.0%

0%

1%

2%

3%

4%

5%

6%

7%

8%

9%

10%

Pre-pregnancy Pregnancy Post partum

Influence of Pregnancy on the Risk of Cardiac Events

in Patients with Hereditary Long QT Syndrome% Long QT

% Long QT with new-onset cardiac events

Rashba EJ et al. Circulation 1998; 97: 451-6

% o

f P

atie

nts

320

325

330

335

340

345

350

355

360

365

370

375

Lowest Daily Dose 320 mg/day Highest Daily Dose Max JTc (any dose)

JTc on d, I-sotalol

Women

Men

Lehman MH et al. Am J Cardiol 1999;83: 354-9

JTc

(mse

c)

Lethal Arrhythmias Susceptibility and Lethal Arrhythmias Susceptibility and Myocardial Connexin-43 ExpressionMyocardial Connexin-43 Expression

0

100

200

300

400

500

600

700

800

900

Female Male

Myocardial Connexin-43 Expression

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

Female Male

Susceptibility to VF

Knezl V. et al. Neuroendocrinology Letters 2008; 29: 798-601

Gender Differences in the Gender Differences in the Clinical Manifestations of the Brugada SyndromeClinical Manifestations of the Brugada Syndrome

No EventsNo Events EventsEvents P valueP value No Events No Events EventsEvents P valueP value

Sx. At Dx.Sx. At Dx. 46 (19)46 (19) 20 (64)20 (64) < 0.001< 0.001 15 (15)15 (15) 1 (33)1 (33) NSNS

Previous Previous AF n (%)AF n (%)

18 (7%)18 (7%) 8 (26)8 (26) 0.0050.005 12 (11)12 (11) 2 (67)2 (67) 0.040.04

Spont. Spont. Type -1 Type -1 ECGECG

105 (43)105 (43) 21 (67)21 (67) 0.010.01 23 (21)23 (21) 2 (67)2 (67) 0.040.04

PR (ms)PR (ms) 175 175 ± 30± 30 178 178 ± 40± 40 NSNS 173 173 ± 32± 32 240 240 ± 62± 62 0.0010.001

QRS (ms)QRS (ms) 107 107 ± 17± 17 110 ± 18 110 ± 18 NSNS 97 97 ± 16± 16 130 130 ± 62± 62 NSNS

QTc (ns)QTc (ns) 421 421 ± 48± 48 432 432 ± 42± 42 NSNS 420 420 ± 49± 49 486 486 ± 47± 47 0.0060.006

ST elev.ST elev. 3.6 3.6 ± 2± 2 3 3 ± 1± 1 NSNS 2.4 2.4 ± 1± 1 3.2 3.2 ±1±1 NSNS

VF VF Inducibility Inducibility (%)(%)

2828 7474 < 0.001< 0.001 1111 5050 NSNS

HV IntervalHV Interval 48 48 ± 10± 10 46 46 ± 7± 7 NSNS 46 46 ± 8± 8 60 60 ± 11± 11 0.0020.002

Benito, B. et al. J Am Coll Cardiol 2008;52:1567-1573

Males Females

Benito, B. et al. J Am Coll Cardiol 2008;52:1567-1573

Kaplan-Meier Estimate of Cardiac Event-Free Survival According to Gender

The Brugada Syndrome and Gender

HRHR 95% CI95% CI P P ValueValue

GenderGender 2.822.82 0.64-12.410.64-12.41 NSNS

Previous AFPrevious AF 2.162.16 0.93-5.030.93-5.03 0.0070.007

Syncope at Syncope at Dx.Dx.

1.861.86 0.7-4.970.7-4.97 NSNS

Aborted SCDAborted SCD 8.458.45 3.17-22.553.17-22.55 <0.001<0.001

Spont. Type 1 Spont. Type 1 ECGECG

1.41.4 0.59-3.330.59-3.33 NSNS

VF InducibilityVF Inducibility 2.932.93 1.14-7.551.14-7.55 0.020.02

ICD TrialsICD Trials

Multivariable Predictors of ICD UseMultivariable Predictors of ICD UseVariableVariable HR-Primary Prevention CohortHR-Primary Prevention Cohort HR-Secondary Prevention CohortHR-Secondary Prevention Cohort

Age, per yAge, per y 0.930.93 0.950.95

Male sexMale sex 3.153.15 2.442.44

Black raceBlack race 0.850.85 0.710.71

ComorbiditiesComorbidities

CBVCBV 0.910.91 0.970.97

Chronic Pulm.Chronic Pulm. 0.890.89 0.980.98

CADCAD 3.113.11 5.335.33

DementiaDementia 0.290.29 0.320.32

DMDM 1.021.02 1.101.10

HTNHTN 0.850.85 1.041.04

CancerCancer 0.590.59 0.360.36

RenalRenal 0.980.98 0.900.90

Midwest RegionMidwest Region 1.171.17 1.221.22

NortheastNortheast 1.191.19 1.101.10

Year of ImplantYear of Implant

20002000 1.191.19 1.151.15

20012001 1.571.57 1.381.38

20022002 2.242.24 1.811.81

20032003 2.922.92 1.941.94

20042004 3.593.59 2.042.04

20052005 4.884.88 2.052.05

Adapted from Curtis LH et al. JAMA 2007; 298: 1517-24

1 Year Mortality by ICD Use and Gender 1 Year Mortality by ICD Use and Gender in a Large Medicare Populationin a Large Medicare Population

No. of No. of Pts. At Pts. At RiskRisk

% % MortalityMortality

with ICDwith ICD


without without ICDICD

HRHR

(p value)(p value)

OverallOverall 9699096990 10.410.4 13.413.4 1.011.01

MenMen 4772947729 11.211.2 13.113.1 1.051.05

WomenWomen 4926149261 7.87.8 13.713.7 0.930.93

No. of No. of Pts. At Pts. At RiskRisk


with ICDwith ICD


without without ICDICD

HRHR

(p value)(p value)

OverallOverall 5434254342 10.910.9 16.816.8 0.65 0.65 (0.001)(0.001)

MenMen 2933329333 11.011.0 16.816.8 0.62 0.62 (0.001)(0.001)

WomenWomen 2500925009 10.810.8 16.016.0 0.710.71

(0.001)(0.001)

Primary Prevention Cohort Secondary Prevention Cohort

Adapted from Curtis LH et al. JAMA 2007; 298: 1517-24

Effectiveness of ICD for the Primary Prevention of Effectiveness of ICD for the Primary Prevention of SCD in Women with Advanced HFSCD in Women with Advanced HF

Baseline Characteristics of Patients in Trials Included in the Meta-AnalysisBaseline Characteristics of Patients in Trials Included in the Meta-Analysis

Ghambari H. et al. Arch Intern Med 2009; 169: 1500-6


Sex Differences in Mortality Rates Sex Differences in Mortality Rates Between ICD and Medical Therapy GroupsBetween ICD and Medical Therapy Groups



MEN

WOMEN


161.470 pts, 27% women

Gender Differences in Procedure-Related Adverse Events in Patients Receiving ICD Therapy

Peterson PN et al. Circulation 2009; 119: 1078 - 84

Benefits of ICD in WomenBenefits of ICD in Women

No trial powered to separately examine outcomes in men No trial powered to separately examine outcomes in men and women or test for difference in ICD effectivenessand women or test for difference in ICD effectiveness

Small numbers of women enrolled Small numbers of women enrolled

Limited post-hoc analyses for females do not clearly Limited post-hoc analyses for females do not clearly demonstrate a mortality benefit:demonstrate a mortality benefit:

– SCD-HeFT: benefit not clear (SCD-HeFT: benefit not clear (not powered for gendernot powered for gender))

– MADIT II: nonsignificant trend toward lower mortality in MADIT II: nonsignificant trend toward lower mortality in females but analysis limited by too few female subjectsfemales but analysis limited by too few female subjects

Meta-analysis: 934 females in 5 trials; no difference in Meta-analysis: 934 females in 5 trials; no difference in all-cause mortality for women with ICD vs medical Rxall-cause mortality for women with ICD vs medical Rx

■ Females with lower rates of SCD than Females with lower rates of SCD than malesmales

■ Differences in arrhythmia susceptibilityDifferences in arrhythmia susceptibility

■ 30% of ICDs are implanted in females30% of ICDs are implanted in females

■ Even though the benefit is less, it may Even though the benefit is less, it may represent a clinically significant represent a clinically significant reduction in deathsreduction in deaths

ConclusionsConclusions

ConclusionsConclusions

A trial targeting women is needed

To detect the same ICD benefit in women To detect the same ICD benefit in women as was observed in men with 90% power as was observed in men with 90% power and and αα=0.05, a study larger than SCDHeFT =0.05, a study larger than SCDHeFT would be required (would be required (1.585 women in each 1.585 women in each treatment arm, 3.170 totaltreatment arm, 3.170 total))

It may now even be considered “unethical” It may now even be considered “unethical” to withhold ICD therapy in women meeting to withhold ICD therapy in women meeting the SCD-HeFT enrollment criteria.the SCD-HeFT enrollment criteria.

sudden death in various populations: is gender a risk factor? 11 th international symposium heart...

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