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© © CM Gibson 2006CM Gibson 2006
Cross-sections of left ventricle after experimentalcoronary artery occlusion
Reimer KA, et al. Circulation. 1977;56:786-794.
Time Dependence of Reperfusion Therapy:Time Dependence of Reperfusion Therapy:“Wavefront” Phenomenon of Necrosis in Dogs“Wavefront” Phenomenon of Necrosis in Dogs
Duration of occlusion 3 h
Area supplied byoccluded artery
x xx
xx
x
xxx x
xxx
x xx
x
xx x x
xx
xx x xx
xx
x
XXXXNecrosis Ischemic but viable Nonischemic
24 h40 min
© © CM Gibson 2006CM Gibson 2006
Time is Muscle: Delays in Symptom to Door Time are Associated Time is Muscle: Delays in Symptom to Door Time are Associated with Poorer Flow in the Muscle Independent of Flow in Arterywith Poorer Flow in the Muscle Independent of Flow in Artery
16% rise in risk of a closed muscle for every hour of delay in STEMI (p=0.0005) Gibson, JACC 2004
Normal LargeCapillary Lumen
Clinical Picture: Clinical Picture:
Open ArteryOpen Artery
Closed MuscleClosed Muscle
Blistering of CapillariesBlistering of Capillaries
& Endothelium& Endothelium
“Blistered” / Swollen Endothelium /wall of the capillary
Normal non-infarctedwall without edema
Infarcted wall with edema (white areas)
Interstitial Edema Interstitial Edema EHJ (2004) 25, 794–803EHJ (2004) 25, 794–803
© © CM Gibson 2006CM Gibson 2006
0
1
2
3
GUSTO I90-93
2.8
Med
ian
Tim
e (h
rs) B
etw
een
Sym
ptom
O
nset
and
Tre
atm
ent
GUSTO III95-97
InTIME II97-99
ASSENT 300-01
ASSENT II97-98
GUSTO V99-01
Time from Symptom Onset to Study Treatment in Large Scale Thrombolytic Trials
2.8 2.7 2.72.7 2.9
Gibson CM, Circulation 2001;104:2632-2634
© © CM Gibson 2006CM Gibson 2006
Adapted from Tiefenbrunn AJ, Sobel BE. Circulation. 1992;85:2311-2315.
Time-Dependent Benefit of Reperfusion TherapyTime-Dependent Benefit of Reperfusion Therapy
0
20
40
60
80
100
0 2 4 6 8 10 12
Reperfusion Time (hours)
% B
enef
it
Reimer/Jennings 1977Bergmann 1982GISSI-I 1986
© © CM Gibson 2006CM Gibson 2006Adapted from Timm TC, et al. Circulation. 1991;84(suppl II):II-230.
6.2
3.23.7
5.2
01234567
1 2 3 4
Time From Symptom Onset (hours)
Mor
talit
y R
ate
(%)
PP=0.05=0.05
TIMI 2: 6-Week MortalityTIMI 2: 6-Week Mortality
© © CM Gibson 2006CM Gibson 2006
Adapted from Lee KL, et al. Circulation. 1995;91:1659-1668.
Importance of Time-to-Treatment: Results of GUSTO-IImportance of Time-to-Treatment: Results of GUSTO-I
0
2
4
6
8
10
12
0 1 2 3 4 5 6 7 8 9 10 11 12
Time From Onset of Symptoms to Treatment (hours)
2=149 (1 df )
30-D
ay M
orta
lity
( %)
© © CM Gibson 2006CM Gibson 2006
Rapid Treatment Is Associated Rapid Treatment Is Associated With Decreased MortalityWith Decreased Mortality
Data source: Boersma E, et al. Lancet. 1996;348:771-775.
Number of lives saved per 1,000 patients treated with fibrinolytics (based on 35-day mortality)
65
37
2629
0
10
20
30
40
50
60
70
0-1 h 1-2 h 2-3 h 3-6 h
Live
s sa
ved
(No.
)
Time from symptom onset to thrombolysis
50,246 pt meta-analysis1983-93
© © CM Gibson 2006CM Gibson 2006Adapted from Weaver WD, et al. JAMA. 1993;270:1211-1216.
1.2
8.7
4.9
11.2
0.0
2.0
4.0
6.0
8.0
10.0
12.0
Mortality Infarct Size
Tx <70 minutesfrom onset
Tx >70 minutesfrom onset
PP=0.04=0.04 PP<0.001<0.001
Perc
ent
MITI: Mortality, Infarct Size, and TimeMITI: Mortality, Infarct Size, and Time
© © CM Gibson 2006CM Gibson 2006
1.0
3.7 4.06.4
14.1
0
5
10
15
20
25
60 61-75 76-90 91
Berger PB, et al. Circulation. 1999;100:14-20.
PP=0.001=0.001
Door-to-Balloon Time (minutes)
Importance of Door-to-Balloon Time: Importance of Door-to-Balloon Time: 30-Day Mortality in the GUSTO-IIb Cohort30-Day Mortality in the GUSTO-IIb Cohort
Mor
talit
y (%
)
>< PTCA not performed
© © CM Gibson 2006CM Gibson 2006
11.14 1.15
1.411.62 1.61
0.6
0.8
1
1.2
1.4
1.6
1.8
2
0-60
61-9
0
91-1
20
121-
150
151-
180
>180MV
Adju
sted
Odd
s of
Dea
th
Cannon CP, Gibson CM et al, JAMA 2000
© © CM Gibson 2006CM Gibson 2006
Patency and Mode of ReperfusionPatency and Mode of Reperfusion
0
20
40
60
80
100
0 30 45 60 75 90 120 150
Pate
ncy
Rat
e (%
)
Fibrinolysis
PTCA at 75minutes
PTCA at 120minutes
Time (minutes)
90-minutepatency
ED
arrival
Drug
administration
Adapted from Gibson CM. Ann Intern Med. 1999;130:841-847.
© © CM Gibson 2006CM Gibson 2006
Hypothetical Relationship Between Early Reperfusion, Hypothetical Relationship Between Early Reperfusion, Mortality Reduction, and Extent of Myocardial Salvage Mortality Reduction, and Extent of Myocardial Salvage
Gersh BJ, et al. Gersh BJ, et al. JAMAJAMA. 2005;293:979-986.. 2005;293:979-986.
00
2020
4040
6060
8080
100100
1212 2424Time From Symptom Onset to Reperfusion TherapyTime From Symptom Onset to Reperfusion Therapy
(hours)(hours)
Mor
talit
y Re
duct
ion,
(%
)M
orta
lity
Redu
ctio
n, (
%) Mortality Reduction (%)Mortality Reduction (%)
Extent of SalvageExtent of Salvage(% of area at risk)(% of area at risk)
Critical Time-dependent Critical Time-dependent PeriodPeriodGoal: Myocardial SalvageGoal: Myocardial Salvage
D-B – HarmD-B – Harm
A-B – No BenefitA-B – No Benefit
Shifts in Shifts in Potential Potential OutcomesOutcomes
A-C – BenefitA-C – BenefitB-C – BenefitB-C – Benefit
D-C – HarmD-C – Harm
00
Time-independent PeriodTime-independent PeriodGoal: Open Infarct-related Goal: Open Infarct-related ArteryArtery
44
DD
CC
BB AA
88 1616 2020
© © CM Gibson 2006CM Gibson 2006
Door to Balloon Time
<60 min(44 min ± 12)
n=183
60-90 min(75 min ± 9)
n=296
90-120 min (103 min ± 8)n=304
>120min(156 min ± 30)
n=403p-value
Onset-to-Door (mins) 197 ± 182 140 ± 140 141 ± 151 113 ± 124 <0.0001
Onset-to-Balloon (mins) 235 ± 180 216 ± 140 244 ± 150 269 ± 126 <0.0001
Death 30-days 0.6% 0.7% 4.7% 2.5% 0.0037
MACE 30-days 1.6% 2.4% 7.6% 5.5% 0.0034
Infarct Size (% LV) 14.2 ± 15.8 13.2 ± 14.6 18.0 ± 18.0 17.4 ± 18.0 0.0023
Does a 90-Minute Door-to-Balloon Time Matter? Observations From Four Current Does a 90-Minute Door-to-Balloon Time Matter? Observations From Four Current Reperfusion TrialsReperfusion Trials
EMERALD, COOL MI, AMIHOT, ICE-ITEMERALD, COOL MI, AMIHOT, ICE-IT
O’Neill, et al. JACC,2005:Suppl A:45:225A.
© © CM Gibson 2006CM Gibson 2006
Time from Symptom Onset to TreatmentTime from Symptom Onset to TreatmentPredicts 1-year Mortality after Primary PCIPredicts 1-year Mortality after Primary PCI
De Luca et al, Circulation 2004
The relative risk of 1-year mortality increases by7.5% for each 30-minute delay
n=1791
© © CM Gibson 2006CM Gibson 2006
Time from Symptom Onset to TreatmentTime from Symptom Onset to TreatmentPredicts One-year MortalityPredicts One-year Mortality
4.4
1.5
5.74.7
1.2
6.3
8.5
0.8
11.9
9.7
0.0
13.0
0
3
6
9
12
15 p = 0.006
<2 hrs 2-4 hrs 4-6 hrs
p = 0.02
De Luca at al, JACC 2003
>6 hrs
All Patients Low-Risk
p = NS
High-Risk
© © CM Gibson 2006CM Gibson 2006
Time from Symptom Onset to Treatment Predicts One-year Mortality Time from Symptom Onset to Treatment Predicts One-year Mortality Among Patients with Occluded Epicardial ArteriesAmong Patients with Occluded Epicardial Arteries
5.34.1
2.7
5.55.9
9.2
0
12.7
0
3
6
9
12
15 p = 0.013
<2 hrs 2-4 hrs 4-6 hrs
p = NS
De Luca at al, JACC 2003
>6 hrs
Pre-PCI TIMI 2/3 Flow Pre-PCI TIMI 0/1 Flow
© © CM Gibson 2006CM Gibson 2006
Predictors of Door-to-Balloon Delay in Primary Predictors of Door-to-Balloon Delay in Primary AngioplastyAngioplasty
3.7
3.2
2.7
2.2
1.7
Mea
n D
o or -
to-b
allo
on t i
me
(hou
rs)
Mea
n D
o or -
to-b
allo
on t i
me
(hou
rs)
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 230 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
Time of hospital arrival (24 hour clock)Time of hospital arrival (24 hour clock)
n=40,017
Angeja BG, et al. Angeja BG, et al. Am J CardiolAm J Cardiol 2002;89:1156-1161) 2002;89:1156-1161)
© © CM Gibson 2006CM Gibson 2006
What is Primary Angioplasty ?What is Primary Angioplasty ?
• Primary Angioplasty: Door to balloon time <1 hour
• Secondary Angioplasty: Door to balloon time 1 - 2 hours
• Tertiary Angioplasty: Door to balloon time 2 - 3 hours
• Post MI Care: Door to balloon time 3 - 4 hours
• Elective Case: > 4 hours
CM Gibson 2006
© © CM Gibson 2006CM Gibson 2006
PCI-Related Time Delay vs Mortality Benefitin 22 Randomized Studies of PCI vs Fibrinolytic Therapy
-5
0
5
10
15
Abso
lute
Ris
k Di
ffere
nce
In D
eath
(%)
0 20 40 60 80 100PCI-Related Time Delay (min)
Nallamothu and Bates, AJC 2003
23 RCTs For every 10 min delay to PCI: 1 % reduction in Mortality Difference
Between PCI & LysisN= 7419
p=0.006
DANAMI: on site PCI90 DB – 50 DN = 40 min delay
DANAMI: with transfer110 DB – 50 DN = 60 min delay
“USA AMI” with transfer:171 DB – 32 DN =139 min delay
© © CM Gibson 2006CM Gibson 2006
NRMI 2,3,4
452,544 Reperfusion Eligible
STEMI Patients
1,963 Hospitals
Transfer Out Patients
n=119,235
Missing Time Intervalsn=13,137
Did Not Receive PCIor Fibrinolytic Therapyas Initial Reperfusion
n=89,524
Study Population192,509 Patients
645 Hospitals230,648 Patients1,860 Hospitals
≥20 STEMI Patients Treated
Treatment of ≥10 patients with Primary PCI and ≥10 patients with Fibrinolytic Therapy
Pinto DS … Gibson CM, Circulation 2006Pinto DS … Gibson CM, Circulation 2006
© © CM Gibson 2006CM Gibson 2006
Mortality Increases with Increasing PCI Related DelayMortality Increases with Increasing PCI Related Delay
PCI Related Delay (DB-DN) (min)
In H
ospi
tal M
orta
lity
(%) For every 30 minute delay,For every 30 minute delay,
mortality increases 10%mortality increases 10%
Pinto DS … Gibson CM, Circulation 2006Pinto DS … Gibson CM, Circulation 2006
© © CM Gibson 2006CM Gibson 2006
0.8
1.25
1.5
Estimated Treatment Effect and 95% Confidence IntervalsConditional on PCI Related Delay (DB-DN)(min)
After Adjusting for CovariatesEs
timate
d Trea
tmen
t Effe
ct
0.5
1.0
2.0
PCI Related Delay (DB-DN) (min)60 75 90 105 120 135 150 165 180114
Odd
s of
Dea
th w
ith
Fibr
inol
ysis
PCI Related Delay (DB-DN) (min)
PCI B
ette
rFi
brin
olys
is B
ette
r
The Advantage of PCI Compared with Fibrinolyisis Decreases as the PCI Related The Advantage of PCI Compared with Fibrinolyisis Decreases as the PCI Related Delay IncreasesDelay Increases
Pinto DS … Gibson CM, Circulation 2006Pinto DS … Gibson CM, Circulation 2006
0.8
1.25
1.5
Estimated Treatment Effect and 95% Confidence IntervalsConditional on PCI Related Delay (DB-DN)(min)
After Adjusting for CovariatesEs
timate
d Trea
tmen
t Effe
ct
0.5
1.0
2.0
PCI Related Delay (DB-DN) (min)60 75 90 105 120 135 150 165 180114
Odd
s of
Dea
th w
ith
Fibr
inol
ysis
PCI Related Delay (DB-DN) (min)
PCI B
ette
rFi
brin
olys
is B
ette
r
Pinto DS … Gibson CM. Circulation. 2006Pinto DS … Gibson CM. Circulation. 2006 *Betriu A. Am J Cardiol. 2005; 95:100-101.*Betriu A. Am J Cardiol. 2005; 95:100-101.
Randomized Studies*
© © CM Gibson 2006CM Gibson 2006
Prehospital Delay & Timing of Reperfusion Strategy Prehospital Delay & Timing of Reperfusion Strategy EquivalenceEquivalence
0-120
121+NonAnt MI65+ YRS Ant MI 65+
YRS NonAnt MI<65 YRS Ant MI <65
YRS
179
168 148
107 103
58 43
400
60
120
180
Prehospital Delay (min)
19,517
5,296
9,812
41,774
16,119
20,424
10,614
PCI R
elat
ed D
elay
(DB
-DN
) Whe
re
PCI a
nd F
ibrin
olyt
ic M
orta
lity
Are
Equ
al (M
in)
3,739
Pinto DS … Gibson CM, Circulation 2006Pinto DS … Gibson CM, Circulation 2006
© © CM Gibson 2006CM Gibson 2006
Pre-hospital Delay (Min)
Age <65 years & Anterior Infarction
(n=patients, n=hospitals)
Age <65 years & Non-anterior Infarction
(n=patients, n=hospitals)
Age ≥65 years & Anterior Infarction
(n=patients, n=hospitals)
Age ≥65 years & Non-anterior Infarction
(n=patients, n=hospitals)
0-120 39 minMet goal without transfer: 2.6%
Met goal with transfer: 3.6%
(n=19,517 pts; n=269 hospitals)
56 minMet goal without transfer:
20.2%Met goal with transfer:
17.3%(n=41,774 pts; n=385 hospitals)
109 minMet goal without transfer: 94.1%
Met goal with transfer: 92.8%
(n=9,812 pts; n=180 hospitals)
154 minMet goal without transfer: 99.8%Met goal with transfer: 100.0%(n=20,424 pts; n=271 hospitals)
121+ 50 minMet goal without transfer: 7.9%Met goal with transfer: 11.9% (n=5,296 pts; n=117 hospitals)
103 minMet goal without transfer: 89.1%
Met goal with transfer: 82.2%(n=16,119 pts; n=244 hospitals)
142 minMet goal without transfer: 98.1%
Met goal with transfer: 97.1%
(n=3,739 pts; n=91 hospitals)
183 minMet goal without transfer: 100.0%
Met goal with transfer: 100.0%(n=10,614 pts; n=191 hospitals)
Time At Which PCI Looses Superiority In Survival Over Time At Which PCI Looses Superiority In Survival Over Fibrinolysis Varies Depending Upon Patient Risk Fibrinolysis Varies Depending Upon Patient Risk
Pinto DS … Gibson CM, Circulation Pinto DS … Gibson CM, Circulation 20062006
© © CM Gibson 2006CM Gibson 2006
Time of OnsetTime of Onset
ED Time Point 1: ED Time Point 1: DOORDOOR
ED Time Point 2: ED Time Point 2: DATADATA
ED Time Point 3: ED Time Point 3: DECISIONDECISION
ED Time Point 4: ED Time Point 4: DRUGDRUG
Time Interval IIIDecision to drug
Time Interval IIECG to decision to treat
Time Interval IDoor to ECG
NHAAP Recommendations. U.S. Department of Health NIH Publication: 1997:97-3787.
The Four DsThe Four Ds
© © CM Gibson 2006CM Gibson 2006
75
105
135
165
195
225
255
1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003
Min
utes
(Med
ian)
Min
utes
(Med
ian)
NRMI 1NRMI 1 NRMI 2NRMI 2 NRMI 3NRMI 3 NRMI 4NRMI 4
NRMI Non-Transfer-In PatientsNRMI Non-Transfer-In Patients
NRMI Transfer-In PatientsNRMI Transfer-In Patients
Door to Balloon Times By Transfer Status, Primary PTCA PatientsDoor to Balloon Times By Transfer Status, Primary PTCA Patients
228
111
171
100110: DANAMI Transfer
90: DANAMI On Site
© © CM Gibson 2006CM Gibson 2006
05
1015202530354045
1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003
Perc
ent o
f Pat
ient
sPe
rcen
t of P
atie
nts
NRMI 1NRMI 1 NRMI 2NRMI 2 NRMI 3NRMI 3 NRMI 4NRMI 4
Non-Transfer-In PatientsNon-Transfer-In Patients
Transfer-In PatientsTransfer-In Patients
Door to Balloon Times Door to Balloon Times <<90 Minutes By Transfer Status, Primary 90 Minutes By Transfer Status, Primary PTCA PatientsPTCA Patients
3.8
33.6
39.1
5.3
© © CM Gibson 2006CM Gibson 2006
20
25
30
35
40
1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003
Perc
ent o
f Pat
ient
sPe
rcen
t of P
atie
nts
NRMI 1NRMI 1 NRMI 2NRMI 2 NRMI 3NRMI 3 NRMI 4NRMI 4
All Patients
Door to Balloon Times Door to Balloon Times <<90 Minutes90 Minutes
34.5 %
29.4 %
© © CM Gibson 2006CM Gibson 2006
National Trends in AMI Management:National Trends in AMI Management:Door to Drug Time with ThrombolysisDoor to Drug Time with Thrombolysis
0102030405060708090
100
1990 1991 1992 1993 1994 1995 1996 1997 1998 1999
Med
ian
time,
min
utes
NRMI 1 NRMI 2 NRMI 3 (Activase only) (All lytics) (All lytics)
60
91
34 39
NRMI 1: Includes patients where initial ECG was the method of MI diagnosis NRMI 2 and 3: Includes patients with ST on 1st 12-lead ECG results, where 1st 12-lead ECG date/time = 1st 12-lead ECG with ST and/or BBB date/time
Non-transfer-in patients
75th percentile, 52
25th percentile, 22
© © CM Gibson 2006CM Gibson 2006
National Trends in AMI Management:National Trends in AMI Management:Door to Balloon Time in PPTCADoor to Balloon Time in PPTCA
80
90
100
110
120
1994 1995 1996 1997 1998 1999
Med
ian
time,
min
utes NRMI 2 NRMI 3
116
108
Includes patients with ST on 1st 12-lead ECG results, where 1st 12-lead ECG date/time = 1st 12-lead ECG with ST and/or BBB date/time (non-transfer-in patients)