why microvolt t-wave alternans? l ~10 million patients at elevated risk of scd l 450,000 sudden...
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Why Microvolt T-Wave Why Microvolt T-Wave Alternans?Alternans?
~10 million patients at elevated risk of SCD
450,000 sudden deaths per year1
~ONLY 100,000 patients receive life saving ICD therapy per year2
A need for a cost effective, efficient, tool for assessing risk of SCD.
1AHA 2003 Statistics
2IIndustry Sources
Sudden Cardiac DeathSudden Cardiac DeathA Major Public Health ProblemA Major Public Health Problem
10 million patients at elevated risk for SCD
400,000 deaths
1/7 of all deaths
FDA Cleared IndicationsFDA Cleared Indications
“FDA cleared indications support testing a wide spectrum of patients the physician suspects are at risk of ventricular tachyarrhythmias. “The presence of Microvolt T-Wave Alternans as measured by the Analytic Spectral Method of the [Heartwave System] in patients with known, suspected or at risk of ventricular tachyarrhythmia predicts increased risk of a cardiac event (ventricular tachyarrhythmia or sudden death).”1
1 FDA 510(k) K013564, November 21, 2001
Clinical ApplicationsClinical Applications History indicating increased risk of sustained ventricular arrhythmias
– Syncope, Pre-syncope, Palpitations
– Non-sustained VT
– Family History
– VT or VF associated with transient or reversible cause
Left Ventricular Dysfunction
– Heart failure
– Cardiomyopathy (Ischemic or Non-Ischemic)
– Ejection Fraction 0.40
Prior Myocardial Infarction
High Risk Groups for SCDHigh Risk Groups for SCD
High Coronary High Coronary RiskRisk
Post M IPost M I
Heart Failure/Heart Failure/E F < 35%)E F < 35%)
Previous Previous VF / VTVF / VT
Syncope /Syncope /Heart DiseaseHeart Disease
00 100100 200200 3003005050
(thousands)(thousands)(millions)(millions)
Population SizePopulation Size
00 1010 2020 505011 22 55
SCD Percent / YearSCD Percent / Year Total SCD / YearTotal SCD / Year
00 101011 22 55 2020
(percent)(percent)
Adapted from Myerburg
Clinical EvidenceClinical Evidence
Rosenbaum, Jackson, Smith, Garan, Ruskin, Cohen. NEJM 1994;330:235-41
Design83 consecutive patients referred for EP studyAlternans compared to EP as a predictor of
arrhythmia- free survivalAtrial pacing @ 100 BPMFollow -up 20 months
Results
Patient Characteristics Value Prediction of EPS Events
Male / Female 59 / 24 Sensitivity 81% 89%
Age (±SD) 57±16 Specificity 84% 89%
PPV 76% 80%
Indication for study NPV 88% 94%
Sustained VT 31% Relative Risk 5.2 13.3
Syncope 22%
Cardiac arrest 20%
Supraventricular arrhythmias 18%
Symptomatic ventricular ectopy 7%
Palpitations 1%
Type of heart disease
Coronary artery disease 64%
Dilated cardiomyopathy 8%
Mitral-valve prolapse 4%
No organic heart disease 24%
MGH/MIT Clinical Study
MGH / MIT StudyMGH / MIT Study
EP StudyAlternans Test
0
20
40
60
80
100
0 4 8 12 16 20
Months
Arr
hyth
mia
-free
Sur
viva
l (%
)
Negative
Positive
0
20
40
60
80
100
0 4 8 12 16 20
Months
Arr
hyth
mia
-free
Sur
viva
l (%
)
Negative
Positive
Rosenbaum, Jackson, Smith, Garan, Ruskin and Rosenbaum, Jackson, Smith, Garan, Ruskin and Cohen Cohen N Engl J Med N Engl J Med 1994;330:235-2411994;330:235-241
RR =13.3P<0.001
RR =5.2P<0.001
Frankfurt ICD Study
Design95 consecutive patients receiving ICD’sRisk stratification prior to implant:
TWA, EPS, LVEF, BRS, SAECG, HRV, QT Dispersion, QTVI, Mean RR, NSVT
Endpoint: First appropriate ICD firingFollow -up 18 months
Patient Characteristics Value% Male 81%Age (±SD) 60±10EF (±SD) 36 ±14
Index ArrhythmiaVentricular fibrillation (VF) 38 (40%)VF/VT 4 (4%)Ventricular tachycardia (VT) 45 (48%)Nonsustained VT w/ syncope 8 (8%)
Type of Heart DiseaseCoronary artery disease 71 (75%)Dilated cardiomyopathy 16 (17%)Hypertrophic cardiomyopathy 2 (2%)Other 1 ( 1%)None 5 (5%)
Hohnloser, Klingenheben, Li, Zabel, Peetermans, and Cohen. J Cardiovasc Electrophysiol 1998; 9:1258-1268
Results
Follow-up 442±210 days
41 first appropriate ICD firings (34 for VT, 7 for VF)
TWA (relative risk 2.5, p < 0.006) and LVEF (relative risk 1.4, p < 0.04) were the only statistically significant univariate predictors of appropriate ICD firing during follow-up.
Cox regression analysis revealed that TWA was the only statistically significant independent predictor of appropriate ICD firing.
TWA was highly predictive in the CAD subgroup as well.
Frankfurt ICD Study ResultsFrankfurt ICD Study Results
EP Study
0102030405060708090
100
0 2 4 6 8 10 12 14 16 18
Months
Eve
nt
Fre
e S
urv
ival
TWA +
TWA -
Alternans Test
P<0.006Relative Risk 2.5
0102030405060708090
100
0 2 4 6 8 10 12 14 16 18
Months
Eve
nt
Fre
e S
urv
ival
EP +
EP -
P<0.23Relative Risk 1.0
Hohnloser, Klingenheben, Li, Zabel, Peetermans, and Cohen. J Cardiovasc Electrophysiol 1998; 9:1258-1268
Multi-Center Regulatory Study
Design 337 patients referred for EP study 9 US Centers Objective: Compare TWA predictive accuracy to EPS Follow- up on 290 patients for 297 + 103 days Endpoints: Ventricular tachyarrhythmic events(VTE), VTE plus Total Mortality
Patient Characteristics Value Results% Male 64%Age (±SD) 56±16EF (±SD) 44 ±18%
Indication for EPSyncope or Presyncope 41%Cardiac Arrest 5%Sustained VT 14%Non-Sustained VT 4%SVT 31%Other 5%
Type of Heart DiseaseCoronary artery disease 46%Dilated cardiomyopathy 10%Valvular heart disease 11%Other structural abnormality 4%No structural heart disease 30%
Gold MR, et al. JACC 2000: 36, 2247-53.
Number of Events
Relative Risk
Probability of Event
(Positive)
Probability of Event
(Negative)VT Events
TWA 12 10.92 18.9% 1.7%
EPS 16 7.07 23.6% 3.3%
VT Events or Death
TWA 15 13.93 23.2% 1.7%
EPS 20 4.69 24.9% 5.3%
Multi-Center Regulatory Study Multi-Center Regulatory Study
Gold MR, et al. JACC 2000: 36, 2247-53.
50
60
70
80
90
100
0 2 4 6 8 10 12 14
Alternans Test
RR =13.9P<0.001
Months
Eve
nt
Fre
e S
urv
ival
TWA +
TWA -
50
60
70
80
90
100
0 2 4 6 8 10 12 14
EP Study
RR=4.7P=0.001
MonthsE
ve
nt
Fre
e S
urv
iva
l
EP +
EP -
Syncope Study
DesignMulticenter study of patients undergoing EPS using standard protocolsSubstudy of 121 pts referred for evaluation of unexplained syncopeFollow-up 12 months
Patient Characteristics
Results
In patients with unexplained syncope undergoing electrophysiology testing, 11% will have an arrhythmic event or death in 12 months
TWA was a better predictor of arrhythmic events and death than inducible VT during EPS
AllN=313
SyncopeN=121
Age 56 ± 15 years 61± 15 years*
Gender 64% male 74% male*
EF 0.40 45% 49%
CAD 46% 56%
Bloomfield DM, Gold MR, Anderson KP, Wilber DJ, El-Sherif N, Estes NAM, Groh WJ, Kaufman ES, Greenberg ML, Rosenbaum DS, Dabbous O, Cohen RJ. AHA, 1999.
Syncope SubstudySyncope Substudy
Bloomfield DM, Gold MR, Anderson KP, Wilber DJ, El-Sherif N, Estes NAM, Groh WJ, Kaufman ES, Greenberg ML, Rosenbaum DS, Dabbous O, Cohen RJ. AHA, 1999.
50
60
70
80
90
100
0 1 2 3 4 5 6 7 8 9 10 11 12
TWA -
TWA +
RR = 4.4; P< 0.05
Eve
nt
Fre
e S
urv
i val
Months
EP -
EP +
Eve
nt
Fr e
e S
urv
i val
Months
50
60
70
80
90
100
0 1 2 3 4 5 6 7 8 9 10 11 12
Design
107 consecutive CHF patients
Excluded recent MI and VT/VF patients
Tested for TWA, EF, SAECG, Mean RR, HRV, NSVT, BRS test performed
Endpoint: VT/VF, SCD
Patient Characteristics Value Results
% Male 80% Sensitivity 100%
Age (±SD) 56±10 PPV 21%
EF (±SD) 28 ±7 TWA only significant predictor
TWA independent of EF
Heart Disease
Coronary artery disease 67%
Dilated cardiomyopathy 33%
Klingenheben T, Zabel M, D’Agostino RB, Cohen RJ, Hohnloser SH. The Lancet 2000; 356: 651-652.
Frankfurt CHF Study
Frankfurt CHF Study Frankfurt CHF Study
Klingenheben T, Zabel M, D’Agostino RB, Cohen RJ, Hohnloser SH. The Lancet 2000; 356: 651-652.
50
60
70
80
90
100
0 4 8 12 16 20 24
Alternans Test
TWA +
TWA -
Months
Eve
nt
Fre
e S
urv
ival
P<0.001
Ikeda Post MI Study
Design119 consecutive patients with acute MIMTWA test at 20±6 (7 to 30 days) post-MIDeterminate results for TWA, SAECG and EF in
102 patientsEndpoints: sustained VT, VF, sudden deathFollow-up: 13 ± 6 months
Patient Characteristics ValueMale
83Female 19Age (±SD) 60±9Ejection fraction (±SD) 49 ±9%
Primary PTCA 98%w/ Stent 58%
Anterior wall MI 49%Inferior wall MI 34%Lateral wall MI 17%
Patients receiving thrombolitic therapy
Results
MTWA had the highest univariate relative risk (16.8) compared to SAECG (5.7) and EF (4.7)
MTWA had the highest sensitivity (93%) compared to SAECG (53%) and EF (60%).
MTWA negative patients had the lowest event rate (2%) compared to SAECG (9%) and EF (8%).
MTWA alone had a PPV of 28%; combining TWA with
SAECG yielded the highest PPV (50%).
Ikeda T, Sakata T, Takami M et al. JACC 1999; 35:722-729.
Ikeda Post-MI StudyIkeda Post-MI Study
0
20
40
60
80
100
0 2 4 6 8 10 12
P = 0.0002
TWA -
TWA +
Eve
nt
Fre
e (%
)
Months
Ikeda T, Sakata T, Takami M et al. JACC 1999; 35:722-729.
Design126 non-ischemic DCM patients Endpoints: VT, VF, SCDFollow-up: 11.9 + 6.3 monthsRisk Stratifiers: TWA, LVEF baroreceptor sensitivity, RR interval, HRV
Patient Characteristics Value Results% Male 77% 7.6% event rate in MTWA negative Age (±SD) 55±11 30% event rate in MTWA positive EF (±SD) 28.8 ± 11.5
ICD recipients 32
Conclusions: MTWA was the only statistically significant predictor of events.
Klingenheben T, Cohen RJ, Peetermans JA, Hohnloser SH. AHA, 1998.
Non-Ischemic DCM Study
Kllingenheben T, Bloomfield, D, Cohen, R, Hohnloser, S; Circ Vol. 104 No. 17, abstract #3689, 2002
Non-Ischemic DCM StudyNon-Ischemic DCM StudyPreliminary Results in 126 patientsPreliminary Results in 126 patients
Kllingenheben T, Bloomfield, D, Cohen, R, Hohnloser, S; Circ Vol. 104 No. 17, abstract #3689, 2002
31 30 24 19 17 15 12 TWA-
62 53 43 37 35 27 20 TWA+
0 3 6 9 12 15 18
50
60
70
80
90
100
TWA-
TWA+P=0.05
Months
Arr
hyt
hm
ia-F
ree
Su
rviv
al
Ikeda Post MI (Large Multicenter Prospective Study)
Ikeda, T, Amer J Card, Vol. 89, 2002
Design Results
850 consecutive post MI patients PPV: 18%
Endpoints: SCD & VT NPV: 98%
Follow-up: 25 + 13 months RR: 10
Risk Stratifiers: TWA, LP, EF, NSVT
Patient Characteristics Value
# Male 711
Age 63 + 11
Conclusions:
MTWA measured in the late phase of MI is a strong risk stratifier for SCD in infarct survivors.
Ikeda Post MI (Large Ikeda Post MI (Large Multicenter Prospective Multicenter Prospective Study)Study)
1
.9
.8
.7
.6
0 4 8 12 16 20 24
Follow-Up in Months
Event F
ree Survival
TWA +
TWA -
Ikeda, T, Amer J Card, Vol. 89, 2002
MTWA in MADIT II PatientsMTWA in MADIT II Patients
MADIT II may radically change our approach to identifying which patients need an ICD
– Patients with an ischemic cardiomyopathy and EF 0.30
– There was a 31% reduction in mortality in patients randomized to ICD
Many physicians want to further risk-stratify this population to identify
– A high-risk group likely to benefit from ICD therapy
– A low risk group who may not benefit from ICD therapy
Bloomfield MADIT II substudy (Large Multicenter Prospective Study)
Bloomfield, Circulation, 2004; 110: 1885-1889
Design Results
177 post MI patients with EF< 30% Mortality Rate amongst MTWA Negatives: 2.1%
Endpoints: All cause mortality RR: 7.4
Follow-up: 16.2 + 7.0 months
Conclusions:• MTWA positive patients had a substantially higher mortality (18.9%)compared to
MTWA negative group (7%)• One-third of MADIT II patients had negative MTWA tests, had an excellent 2-year
survival, and therefore may not require ICD therapy.
Bloomfield MADIT II PatientsBloomfield MADIT II Patients
Bloomfield, Circulation, 2004; 110: 1885-1889
Hohnloser MADIT II Patients
Design
129 post MI patients with EF< 30%
Primary endpoints: Sudden cardiac Death & resuscitated cardiac arrest
Secondary endpoint: Primary endpoint plus sustained ventricular arrhythmia
Follow-up: 16.0 + 8.0 months
Hohnloser et al. Lancet, Vol. 362 July 2003
Results
Event rate amongst MTWA Negatives (primary endpoint): 0 %
RR =
Event rate amongst MTWA Negatives (secondary endpoint): 5.7%
RR = 5.5
Conclusions:
In MADIT II population patients with negative MTWA had an extremely low 2-years mortality rate
MTWAMTWA
Relative Risk =
0 6 12 18 24
70
80
90
100
35 34 26 24 19 TWA Neg
TWA Neg
94 80 62 44 34 TWA Not Neg
TWA Not Neg
P = 0.023
Months
Eve
nt-
Fre
e S
urv
ival
(%
)
Relative Risk at 24 months = 1.1
QRS WidthQRS Width
0 6 12 18 24
70
80
90
100
80 73 59 45 35 QRS <= 120 ms
QRS <= 120 ms
37 32 24 19 15 QRS > 120 ms
QRS > 120 ms
P = 0.78
MonthsE
ven
t-F
ree
Su
rviv
al (
%)
Hohnloser, Lancet, Vol. 362, July 2003
Hohnloser MADIT II Patients Hohnloser MADIT II Patients (primary end point)(primary end point)
0 6 12 18 24
50
60
70
80
90
100
35 32 24 22 19 TWA Neg
TWA Neg
94 73 53 37 28 TWA Not Neg
TWA Not NegP = 0.01
Months
Eve
nt-
Fre
e S
urv
ival
(%
)
0 6 12 18 24
50
60
70
80
90
100
80 69 54 43 34 QRS <= 120 ms
QRS <= 120 ms
37 27 18 12 10 QRS > 120 ms
QRS > 120 ms P = 0.023
Months
Eve
nt-
Fre
e S
urv
ival
(%
)
MTWAMTWA QRS WidthQRS Width
Relative Risk = 5.5 Relative Risk = 2.0
Hohnloser MADIT II Patients Hohnloser MADIT II Patients (secondary end point)(secondary end point)
Hohnloser, Lancet, Vol. 362, July 2003
Baravelli : Predictive Significance for SCD of Microvolt level Baravelli : Predictive Significance for SCD of Microvolt level T wave Alternans in NYHA class II CHF patients: A T wave Alternans in NYHA class II CHF patients: A Prospective studyProspective study
Design
73 patients in NYHA class II with LVEF of <45%
Ischemic and Non-ischemic Cardiomyopathy
Primary endpoint was SCD, documented sustained VT/VF and appropriate ICD shock
Follow-up 17.1±7.4 months
Baravelli et al, International Journal of Cardiology, March 2005
Results
MTWA was positive in 30 (41%) patients, Negative in 26 (36%)
7 arrhythmic events in the MTWA positive group
No events in the MTWA negative group
Sensitivity 100%Specificity 53%NPV 100%PPV 24%
Conclusions:
Data suggests that MTWA is a promising predictor of arrhythmic events in NYHA class II CHF patients.
Baravelli : Predictive Significance for SCD of Baravelli : Predictive Significance for SCD of Microvolt level T wave Alternans in NYHA Microvolt level T wave Alternans in NYHA class II CHF patients: A Prospective studyclass II CHF patients: A Prospective study
Baravelli et al, International Journal of Cardiology, March 2005
Baravelli : Predictive Significance for SCD of Baravelli : Predictive Significance for SCD of Microvolt level T wave Alternans in NYHA Microvolt level T wave Alternans in NYHA class II CHF patients: A Prospective studyclass II CHF patients: A Prospective study
Baravelli et al, International Journal of Cardiology, March 2005
Bloomfield Patients with Ischemic Heart Disease and Left Ventricular Dysfunction
DesignStudy conducted at 11 clinical centers in U.S.
587 ischemic heart disease patients with LVEF≤40
Primary endpoint all cause mortality or non-fatal sustained ventricular arrhythmias
20 ± 6 month follow-up
Bloomfield et al, Journal of the American College of Cardiology, January 2006
Results
66% had abnormal MTWA test
51 end points (40 deaths, and 11 non-fatal sustained ventricular arrhythmias
HR was 6.5 at 2 years(95% confidence interval, p<0.001)
Survival of -patients with normal MTWA was 97.5% at 2 years
Conclusions:
Among patients with heart disease and LVEF ≤ 40, MTWA can identify not only a high-risk group, but also a low-risk group unlikely to benefit for ICD prophylaxis.
Bloomfield Patients with Left Bloomfield Patients with Left Ventricular DysfunctionVentricular Dysfunction
Bloomfield et al, Journal of the American College of Cardiology, January 2006
Recent Clinical Review PapersRecent Clinical Review Papers
“T-Wave Alternans and the Susceptibility to Ventricular
Arrhythmias”, Sanjiv Narayan, MB. MD, Journal of the American College of Cardiology, January 2006
“Can Microvolt T-wave Alternans Testing reduce unnecessary defibrillator implantation?”, Antonis A. Armoundas, Stefan H. Hohnloser, Takanori Ikeda, Richard Cohen, Nature in Clinical Practice, October 2005
MTWA is a Powerful Arrhythmic MTWA is a Powerful Arrhythmic Risk StratifierRisk Stratifier
Annual Spontaneous Ventricular Tachyarrhythmic Event Rates These rates were observed in prospective natural history MTWA studies in patients similar to patients in
MADIT-II and SCD-HeFT. Study Population N Follow-
Up (months)
MTWA+ MTWA- HR
Klingenheben, 2000
CHF (Prior MI and DCM)
107 18 16% 0%
Hohnloser, 2003 DCM 137 18 17% 4% 4 Kitamura, 2002 DCM 83 21 16% 2% 9 Adachi, 2001 DCM 82 40 11% 1% 12 Grimm, 2003 DCM
LVEF 0.45 263 72 3% 2% 1.5
Ikeda, 2000 Prior MI 102 13 30% 2% 16 Ikeda, 2002 Prior MI 834 24 4% 0.5% 8 Hohnloser et al, 2003
Prior MI LVEF 0.30
129 24
9%* 19%
0%* 3%
6
Chow, 2003 Prior MI LVEF 0.30
203 18 8% 1% 6
All All 1,811 8.4% 1.2% 7
*SCD and Cardiac Arrest only
Antonis A. Armoundas, Stefan Hohnloser, Takanori Ikeda, Richard J. Cohen, Nature Clinical Practice, October 2005
All Cause Mortality is Lower in MTWA Negative Patients All Cause Mortality is Lower in MTWA Negative Patients Who Did Not Receive ICDs than in Comparable Patients Who Did Not Receive ICDs than in Comparable Patients in the MADIT-II and SCD-HeFT Trials who Did Receive in the MADIT-II and SCD-HeFT Trials who Did Receive ICDsICDs
Annual All Cause Mortality Rates Upper portion of table involves prospective ICD studies. Lower part of table involves prospective MTWA studies in non-ICD patients with reported mortality endpoint analyses.
Study Population N Follow-Up
(months) No ICD ICD
MADIT II2, 2002 Prior MI LVEF 0.30
1,232 20 13.2% 9.2%
SCDHeFT3, 2004 CHF LVEF 0.35
2,521 60 9.0% 6.5%
All 3,753 10.4% 7.4%
Study Population N Follow-Up (months)
Entire Population
MTWA-
Bloomfield9, 2003 Prior MI LVEF 0.30
177 24 7% 2%
Hohnloser et al17, 2003
Prior MI LVEF 0.30
129 24 10% 7%
Costantini et al, 2004
DCM LVEF 0.40
282 24 3% 0%
Grimm et al14, 2003
DCM LVEF 0.45
263 72 4% 2%
All 851 5.3% 2.0%
Antonis A. Armoundas, Stefan Hohnloser, Takanori Ikeda, Richard J. Cohen, Nature Clinical Practice, October 2005