Time Is Myocardium and the Wavefront of Necrosis
CM Gibson 2002
The DANAMI-2 Trial
Danish Trial in Acute Myocardial Infarction-2
Presented at the American College of Cardiology
51st Annual Scientific Session
Atlanta, GA
Dr. Henning Rud Andersen
for the DANAMI-2 investigators
DANAMI-2: Study Design
High-risk ST elevation MI patients (>4 mm elevation), Sx < 12 hrs
5 PCI centers (n=443) and 22 referring hospitals (n=1,129), transfer in < 3 hrs
Lytic therapy
Primary PCI
Primary PCI
Front-loaded tPA 100
mg
with transfer
without transfer
(n=567)
(n=223)
(n=782)
Death / MI / Stroke at 30 Days
Stopped early by safety and efficacy committee
DANAMI-2: Centers
DANAMI-2: Primary Results
P=0.0003
16%
14%
Death / MI / Stroke (%)
P=0.048
P=0.002
16%
RRR
45%
12%
Non-Transfer Sites
Transfer Sites
Combined
16%
14%
RRR
40%
12%
12%
12%
9%
8%
8%
8%
8%
4%
4%
4%
0%
0%
0%
Lytic
Primary PCI
RRR
45%
Lytic
Primary PCI
7%
Lytic
Primary PCI
Composite Outcome (%)
Trials Comparing Primary PTCA With Fibrinolytic Therapy:
GUSTO-IIb Cohort
18
16
14
12
10
8
6
4
2
0
16.1
13.7
14.1
PTCA
t-PA
9.6
30 days
6 months
P=0.033
P=NS
GUSTO-IIb Angioplasty Substudy Investigators. N Engl J Med. 1997;336:1621-1628.
DANAMI-2: Results
8%
Death
Recurrent MI
Stroke
P=0.35
P<0.0001
P=0.15
7.6%
8%
6.6%
8%
6.3%
6%
6%
6%
4%
4%
4%
2%
2%
1.6%
2.0%
2%
1.1%
0%
0%
Lytic
Primary PCI
0%
Lytic
Primary PCI
Lytic
Primary PCI
DANAMI-2: Commentary on Low Rate of
Rescue/Adjunctive PCI
• The benefit in the primary composite endpoint result is
driven predominantly by a lower rate of recurrent MI among
patients treated with fibrinolysis compared with primary PCI
• Rescue PTCA for failed fibrinolysis was carried out
infrequently in DANAMI 2, in only 2.5% of cases.
• The trial confirms what has been observed in the past:
fibrinolytic monotherapy when administered with
unfractionated heparin is associated with a significant rate
of recurrent myocardial infarction if not accompanied by
either rescue, facilitated or delayed PCI.
• It could be speculated that the incidence of recurrent MI
may be reduced with a more aggressive strategy of
performing rescue or adjunctive PCI soon after fibrinolytic
administration.
Gibson CM, 2002
DANAMI-2: Commentary on Biases Inherent in the
Assessment of the Recurrent MI Endpoint
Among patients treated with fibrinolysis:
Recurrent MI may be secondary to reocclusion of a patent
infarct vessel following thrombolysis or may occur following
delayed PCI after thrombolytic administration
Among patients treated with primary PCI:
Recurrent MI may be secondary to stent thrombosis or late
vessel occlusion several days following the procedure
Because of the inability to detect recurrent MI during the
index primary PCI (unlike during the performance of a later
delayed PCI), this limits the number of post PCI CK MIs
detected in this strategy
Gibson CM, 2002
DANAMI-2: Commentary on Low Rate of
Rescue/Adjunctive PCI
• Thus, the detection of post PCI CK elevations may be
limited to only those patients enrolled in the fibrinolytic arm
of the study
• Determination of the timing of the recurrent MI is critical:
did the recurrent MI occur before or after the PCI
• Lower rates of GP 2b3a inhibitor use may be associated
with higher rates of post PCI CK elevations, and it is critical
to understand the proportion of patients treated with
adjunctive GP 2b3a inhibition during elective or late PCI
Gibson CM, 2002
Thrombus Remains Following Thrombolysis
Van Belle et al. Circulation. 1998;97:26-33.
Clinical Impact of Reocclusion:
Data from the TAMI trials:
• 810 patients, cath 90 min & 7 days later:
• 12.4% reocclude
• 58% symptomatic
• In-hospital mortality 11.0% vs 4.5% (P=0.01).
Ohman et al. Circulation. 1990;82:781-791.
Recent Efforts to Reduce Reocclusion / Reinfarction
• In order to reduce the risk of reocclusion, several
strategies have been employed in recent
thrombolytic trials
– Mechanical
• Adjunctive / Rescue / and delayed
PCI
– Pharmacologic
• GP 2b3a inhibition
• Treatment with the antithrombotic
agent enoxaparin
CM Gibson 2002
2 Year Survival Following Rescue PCI
1.00
Rescue PCI
Survival
Survival was
Improved in
patients with 90
minute TIMI Grade
0/1 Flow after TNK
who underwent
rescue PCI in the
TIMI 10B trial
Log rank p=0.006
0.75
No PCI
0.50
0.25
0.00
0
.5
1
1.5
2
Years
CM Gibson, AHA 2001
DANAMI 2: Commentary on Low Rate of
Rescue / Adjunctive PCI Use
• In recent large scale thrombolytic trials in which rescue /
adjunctive PCI has been performed more aggressively,
lower rates of recurrent MI have been observed
• In the setting of ST segment elevation MI treated with
thrombolytic monotherapy, the administration of
enoxaparin has been associated with a reduced rate of
reinfarction when compared to unfractionated heparin.
• Would the use of Rescue / Adjunctive PCI and
enoxaparin have been associated with a lower rate of
reinfarction in the DANAMI 2 study?
Gibson CM, 2002
Rate of Rescue / Adjunctive PCI Use in DANAMI 2 Compared with Other Recent
Trials
7%
6.3%
% Recurrent MI
6%
5%
4.2%
4%
3.5%
3%
2.3%
2.7%
2.2%
1.8%
2%
1%
0%
DANAMI
tPA + Hep
Urgent PCI
Non-Urgent
PCI
2.5%
ASSENT 3
TNK + Hep
14.4%
GUSTO V
rPA + Hep
GUSTO V
rPA + Abx
ASSENT 3
TNK + Abx
ASSENT 3
TNK + Enox
8.6%
5.6%
9.1%
11.9%
19.4%
17.4%
16.5%
CM Gibson 2002
ENTIRE
TNK + Enox
44.4%*
* Urgent & non-urgent combined
ENTIRE TIMI 23: 30 Day Death/MI
12
8
20
FULL Dose TNK
15.9
HALF Dose TNK
+ Abx
P=0.005
15
11.3
P=0.01
4.9
8.2
P=0.002
4
3.1
3.1
UFH
ENOX
0
% Pts
159
10
12.2
6.5
4.4
5
P=0.003
3.7
1.9
2.5
UFH
ENOX
0
N=
82
160
1.8
77
5.5
3.9
1.8
MI
2.6
3.7
Death
UFH
ENOX
164
324
ENTIRE TIMI 23: Recurrent MI
In Patients NOT Undergoing PCI (N=259)
FULL Dose TNK
9.8
10
HALF Dose TNK
+ Abx
10
8
7.6
6
4
1.1
2
8
0
UFH
% Pts
79
6
5.3
4
1.9
2
0.0
0
UFH
N=
41
ENOX
103
UFH
ENOX
38
77
ENOX
180
DANAMI-2 Commentary on Door to Balloon Times
• In DANAMI 2, door-to-balloon times were approximately
114 minutes for those patients transferred to another
facility
• Based upon the data presented by Cannon et al, a doorto-balloon time of 114 minutes was not associated with a
significant increase in mortality in the NRMI 2 database
when compared to a door-to-balloon time of < one hour
• If transfer for primary PCI is elected, then door to balloon
times should be similar to those observed in DANAMI 2
• In NRMI 4, the current median door to balloon time
among patients transferred to another facility in the US for
primary PCI is much longer at 198 minutes
Gibson CM, 2002
DANAMI 2: Door to Balloon Times
Community Hospital
Thrombolysis
(n=782)
PCI, non-transported
patients
(n=223)
PCI, transported
patients
(n=567)
P=0.0007 P=0.0003
N=27,080
1.8
P=0.01
1.6
P=NS
1 .1 4
1 .1 5
2,230
5,734
6,616
4,461
2,627
5,412
121-150
151-180
>180
1 .4 1
91-120
1.2
1 .6 1
61-90
1.4
P=NS
1 .6 2
0-60
M V Adjusted Odds of Death
2
1
1
0.8
0.6
Door-to-Balloon Time (mins)
Cannon CP et al, JAMA 2000
NRMI-2: Primary PCI Door-to-Balloon time vs. Mortality
10
N=27,080
P < 0.00001
8.5
Mortality (%)
8
7.9
6.7
6
4.2
4.6
5.1
4
2
0
0-60
61-90
91-120
121-150
151-180
Door-to-Balloon Time (minutes)
>180
Door to Balloon Times Among Patients Transferred in NRMI 4
Door to
Data to
Cath Lab to
Data:
Cath Lab Arrival:
Balloon:
50th: 8 Min.
50th: 137 Min.
50th: 39 Min.
25th: 4 Min.
25th: 87 Min.
25th: 29 Min
75th: 16 Min.
75th: 220 Min.
75th: 53 Min.
8
137
39
Total Door to Balloon Time: 198 minutes
(25th: 137; 75th: 281)
Percent of Patients with Door to Balloon Time < 90 Min.: 4.8%
Sample Size: 1,292; Time Period: October 2000 – September 2001
Gibson CM, 2002
NRMI 4 Transfer-In Annual Data Report 2002
Importance of Operator Experience and Volume in Primary PCI
Outcomes
• A significant proportion of the DANAMI operators had
little prior experience with primary PCI.
• Is operator and hospital volume associated with PCI
outcomes in larger series?
Gibson CM, 2002
NRMI 2-3: Primary PCI vs. Thrombolysis: 1996-2000
N=62,000 Patients
In-hospital Mortality
Volume
< 16 /yr
17-48/yr
>48/yr
% Hosp
25%
50%
25%
Non-fatal stroke
Magid et al. JAMA 2000
Tlysis
5.9
5.9
5.4
Prim PCI
6.2
4.5
3.4
P value
NS
<0.001
<0.001
1.1
0.4
<0.001
NRMI-2: Primary PCI
Institutional Volume vs. Mortality
10
N=27,080
P < 0.00001
8.0
Mortality (%)
8
6.2
6
4.7
4
2
0
<1
1-3
>3
Institutional Monthly Volume of Primary Angioplasty Cases
Primary PCI: Door-to-Balloon time vs. Mortality
Stratified by Institutional Volume
<1 / month
N=4,740
P = 0.0008
1-3 / month
N=14,078
P < 0.0001
Door-to-Balloon Time (minutes)
>3 / month
N=14,078
P < 0.0001
MV Adjusted Odds of Death
Hospital Volume of Primary PTCA vs. Mortality
1.2
1
0.8
0.87
0.6
0.4
0.2
0
0.83
0.72
P value for trend < 0.001
N: Pt = 2,825
Hosp =113
5 to 11
5,245
112
12 to 20
9,303
113
19,162
112
21 to 33
>33
Hospital Volume of Primary Angioplasty per Year
Canto. NEJM 2000
Randomized Trial Results Versus Community-Setting Results:
NRMI-2 Cohort
n=2,958, lytic eligible, no shock at presentation
PTCA
Percent
8
6
5.4
5.2
t-PA
6.2
5.6
4
2
0
In-hospital mortality
P=NS
In-hospital mortality or
nonfatal stroke
P=NS
Tiefenbrunn AJ, et al. J Am Coll Cardiol. 1998;31:1240-1245.
Trials Comparing Primary PTCA With Fibrinolytic Therapy: MITI
Cohort
100
Survival (%)
95
Thrombolytic therapy
90
85
80
Primary angioplasty
75
P=0.80
70
0
0.5
1
1.5
2
2.5
Time After Discharge (years)
Every NR, et al. N Engl J Med. 1996;335:1253-1260.
3
3.5
4
DANAMI-2 Commentary: Facilitated PCI Not
Evaluated
• This trial tested the efficacy of thrombolytic therapy with
very little use of rescue/adjunctive PCI (2.5%) versus
“primary PCI” without significant pharmacologic therapy
before the PCI
• The trial provides no data regarding the efficacy of
“facilitated PCI” in which a thrombolytic agent or GP 2b3a
inhibitor would be administered prior to rescue or
adjunctive PCI.
• The concept of “facilitated PCI” will be tested in
upcoming trials.
Gibson CM, 2002
Relative Speed and Magnitude of Patency
Pre Hospital Lytic
+ 2b3a
Lytic + 2b3a:
94% by 60 min.
100
80
Lytic
2 hour
60
Door to
Balloon
40
20
0
0

Pre Hospital Drug
administration
30


ED
Drug
arrival administration
45
60
75
90
120
150
Time (minutes)
Adapted from Gibson CM. Am Interm Med. 1999;130:841-847.
Fibrinolytic Therapy Pre-PCI
PRAGUE*
PACT
* Patients transferred for PCI
50
70
60
50
40
30
20
10
0
40
28
TIMI 3
TIMI 2
19
33
20
10
15
Placebo
tPA
Adapted from Ross AM, et al. J Am Coll Cardiol.
1999;34:1954-1962.
30
30
0
TIMI 3
TIMI 2
12
15
17
Placebo
SK
Adapted from Widimsky P, et al. J Eur Heart J.
2000;21:823-831.
Convalescent LV Function by Patency Group: Global Ejection
Fraction
TIMI 3 on cath lab arrival
62.4
% Convalescent LVEF
Never had TIMI 3
P=0.004
80
60
TIMI 3 after leaving cath lab
57.9
54.7
40
20
0
Adapted from Ross AM, et al. J Am Coll Cardiol. 1999;34:1954-1962.
Relationship of TIMI 3 Flow Before PCI to 6 Month
Survival
Stone et al. Circ 2001; 104: 636-641
Preliminary Designs of Upcoming Facilitated PCI Trials
ASSENT 4
TNK
Heparin / ASA
ADVANCE
TNK + Integrilin
Integrilin
TIGER
TNK
TNK + Integrilin
TITAN
Integrilin in ER
FINESSE
rPA
Integrilin in Cath
Lab
rPA + abciximab in
ER vs CCL
CM Gibson 2002
DANAMI 2 Conclusions
• Among patients transferred for primary PCI with a median
door to balloon time of 114 minutes, the incidence of the
composite endpoint of death, recurrent MI, and stroke is
reduced compared with the administration of tPA and
heparin when used in conjunction with a rescue /
adjunctive PCI rate of 2.5%.
CM Gibson 2002
DANAMI 2 Conclusions
• The median US door to balloon time for transfer patients
is 198 minutes, and is not as rapid as in DANAMI 2 (114
minutes)
• The composite endpoint was driven primarily by a lower
rate of recurrent MI among PCI patients
• Current strategies that employ higher rates of rescue and
adjunctive PCI after fibrinolysis and higher rates of
enoxaparin use have been associated with lower rates of
recurrent MI than that reported in DANAMI 2
CM Gibson 2002
DANAMI 2 Conclusions
• As an endpoint, recurrent MI may more often be detected
among patients treated with fibrinolysis who undergo
delayed or late PCI because post PCI CK release may not
be detected during primary PCI
• DANAMI 2 trial was performed in a dedicated network of
centers. Larger hospital / and operator volumes are
associated with improved outcomes and the ability to
implement this strategy in smaller volume hospital systems
with less experienced operators is not yet tested
• To this end, US community hospital registry experience
suggests no benefit of primary PCI over fibrinolysis
CM Gibson 2002
DANAMI 2 Conclusions
• DANAMI 2 did not assess the effectiveness
of “facilitated PCI” in which pharmacologic
and mechanical strategies are combined.
• Upcoming trials will test the effectiveness of
“facilitated PCI”
CM Gibson 2002