The DANAMI-2 Trial
A Comparison of Coronary Angioplasty with Fibrinolytic
Therapy in Acute Myocardial Infarction
Henning Rud Andersen et al for the DANAMI-2 investigators
N Engl J Med 2003; 349: 733-42
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
N Engl J Med 2003; 349: 733-42
DANAMI-2: Primary Results
P<0.001
P=0.05
P=0.002
16%
30 Day Death / MI / Stroke (%)
Non-Transfer Sites
Transfer Sites
Combined
16%
16%
14.2%
13.7%
12.3%
12%
12%
8.0%
8%
4%
N=107
8.5%
8%
8%
4%
4%
N=63
0%
12%
N=80
N=48
0%
Lytic
Primary PCI
6.7%
N=27
N=15
0%
Lytic
Primary PCI
Lytic
Primary PCI
N Engl J Med 2003; 349: 733-42
DANAMI-2: Results
Death
Recurrent MI
Stroke
P=0.35
P<0.001
P=0.15
10%
8%
8%
8%
6.3%
7.8%
6.6%
6%
6%
4%
4%
6%
4%
1.6%
2%
2%
2.0%
2%
1.1%
0%
0%
Lytic
Primary PCI
0%
Lytic
Primary PCI
Lytic
Primary PCI
N Engl J Med 2003; 349: 733-42
DANAMI-2: Risk of Recurrent MI Largely Drives
Results of the Composite Endpoint
The DANAMI 2 Investigators state that:
“Although the rates of death, clinical reinfarction, and
stroke were all reduced with angioplasty, the better overall
outcome after angioplasty was driven primarily by the
reduction in the rate of reinfarction. Our finding of a higher
30-day mortality rate among patients with reinfarction
accords with recent results by Gibson et al. and indicates
that clinical reinfarction in our trial was a severe event.”
Recurrent MI During Index Hospitalization is
Associated with Higher Mortality at 2 Years
Kaplan-Meier survival estimates, by early reinfarction
1
No early reinfarction
10.1%, n=19,265
Early reinfarction
19.6%, n=836
0.75
Log-rank p<0.0001
0.5
0
0.5
1
Years
1.5
2
Gibson CM et al, J Am Coll Cardiol 2003;42:7–16.
Similar to DANAMI 2, A Lower Rate of Recurrent MI Following
PCI Drives the Benefit Observed in Many of the Recent Primary
PCI vs Fibrinolytic Trials
CAPTIM
DANAMI-2
C-PORT
PCAT
840
1,572
451
2,725
n
PCI
t-PA*
PCI
t-PA
PCI
t-PA
PCI
Lytic
Death
4.6%
3.7%
6.6%
7.6%
6.2%
7.1%
6.2%
8.2%
ReMI
1.7%
3.7%
1.6%
6.3%
5.3%
10.6%
4.8%
9.8%
Stroke
0%
1.0%
1.1%
2.0%
2.2%
4.0%
0.7%
1.9%
*Pre-hospital administration.
P<0.05: ReMI;death (PCAT only); stroke (PCAT only).
Grines C, et al. Am Heart J. 2003;145:47-57.
CM Gibson 2003
If Recurrent MI Drives The Results of DANAMI 2 and Other
Recent Trials, Can We Reduce The Risk of Recurrent MI
Following Fibrinolytic Administration?
• Yes.
• Performance of early rescue PCI (early PCI of a closed
artery), adjunctive PCI (early PCI of an open artery) , and
delayed PCI are collectively associated with a reduction in
recurrent MI after fibrinolytic administration.
Gibson CM et al, J Am Coll Cardiol 2003;42:7–16.
Risk of Early Recurrent MI Following Thrombolysis in 20,101
Patients
% Recurrent MI
5
4.5
4
P< 0.001
3
1.6
2
1
0
No PCI
PCI
Gibson CM et al, J Am Coll Cardiol 2003;42:7–16.
Is Performance of Rescue / Adjunctive / Delayed PCI After Fibrinolytic
Administration Associated With Improved Mortality at 2 Years?
• Yes.
• Performance of early rescue PCI (early PCI of a closed
artery), adjunctive PCI (early PCI of an open artery) , and
delayed PCI are collectively associated with a reduction in
mortality.
Gibson CM et al, J Am Coll Cardiol 2003;42:7–16.
2 Year Survival Following Rescue PCI
1
Survival
0.9
Rescue PCI
Log rank p=0.03
0.8
No Rescue PCI
0.7
Survival was Improved in patients with 90 minute
TIMI Grade 0/1 Flow who underwent rescue PCI
0.6
0.5
0
0.5
1
Years
1.5
2
Gibson et al, Circulation 2002, 105:1909-1913
2 Year Survival Associated with Adjunctive PCI in Patients with
an Open Artery Following Thrombolytic Administration
1
Immediate Adjunctive PCI
Delayed PCI
No PCI
0.9
p=0.11; after adjusting for stent use p=0.07 for adjunctive PCI
0.8
Survival tended to be improved in patients with an open artery at 90
minutes who underwent immediate adjunctive or delayed PCI
0.7
0
0.5
1
Years
1.5
2
Gibson et al, Circulation 2002, 105:1909-1913
Performance of Early PCI After Fibrinolysis is Associated with
Improved Survival at 2 Years in 20,101 Patients
1
PCI
Survival
0.9
No PCI
Log rank p<0.0001
0.8
0.7
0
0.5
1
Years
1.5
2
Gibson CM et al, J Am Coll Cardiol 2003;42:7–16.
Are The Benefits of PCI After Fibrinolysis True for Both Low Risk and
High Risk Patients?
• Yes.
• Similar relative risk reductions in survival following PCI
have been observed among low, intermediate and high risk
patients.
Gibson CM et al, J Am Coll Cardiol 2003;42:7–16.
Mortality to 2 Years by In-Hospital PCI, Stratified by TIMI Risk
Score in 20,101 Patients
Mortality (%)
30%
p<0.001
p<0.001
p<0.001
27.3%
20%
15.0%
10.3%
10%
6.2%
3.7%
1.7%
0%
PCI
No PCI
PCI
PCI
No PCI
No PCI
Low Risk
Intermediate Risk
High Risk
TRS 0-2
TRS 3-4
TRS >5
Gibson CM et al, J Am Coll Cardiol 2003;42:7–16.
Are the There Recent Randomized Trials to Support PCI
Following Fibrinolytic Administration?
• Yes.
• In August of 2003, the SIAM 3 and ALKK study were
published contemporaneously with the DANAMI 2 Trial.
CM Gibson 2003
SIAM III Trial
Randomized trial of thrombolysis (rPA) with transfer for early PCI (within 6 hours; n=82) or thrombolysis
with delayed angiography at 2 weeks (n=81) in patients with acute MI presenting at community hospitals
Death/reMI/ischemic
events/TLR at 6 months
p=0.001
EF at 6 months
p=0.018
61.5%
60%
60%
56.4%
50.6%
40%
40%
25.6%
20%
20%
0%
0%
rPA + Early PCI
rPA + Delayed PCI
rPA + Early PCI
rPA + Delayed PCI
J Am Coll Cardiol 2003;42:634-41
ALKK Trial
Randomized trial of angioplasty (n=149) or medical therapy (n=151) in stable patients 8-42 days post
acute MI
Event-free* Survival
at 1 Year
p=0.06
100%
100%
90%
Survival at Long-term
(mean 56 months)
follow-up
p=0.02
96%
89%
82%
80%
80%
60%
60%
40%
40%
20%
20%
0%
0%
PTCA
Medical Therapy
PTCA
* Survival free of reinfarction, ischemia-driven (re)
PTCA, CABG, or rehospitalization for severe angina
Medical Therapy
Circulation. 2003;108:1324-1328
If PCI After Fibrinolysis is Associated with Benefit, was PCI
Frequently Performed After Fibrinolysis in DANAMI 2?
No.
As stated by the authors:
“The frequency of rescue angioplasty was low.”
Rescue angioplasty was performed infrequently (15 cases,
1.9% of patients)
If PCI After Fibrinolysis is Associated with Benefit, Could the Results in the
Fibrinolytic Arm Have Been Improved in DANAMI 2?
Observational and randomized trial data from other trials
presented above suggest that outcomes may have been
improved if PCI had been performed more frequently after
fibrinolysis, but this cannot be ascertained from the data at
hand in DANAMI 2.
CM Gibson 2003
Are Prolonged Door to Balloon Times Associated With Higher
Mortality?
• Yes.
• Door to balloon delays beyond 90 minutes are associated
with a rise in mortality.
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
>180
Door-to-Balloon Time (minutes)
JAMA 2000; 283:2941-7.
Primary PCI for STEMI
Time to Reperfusion and 30-Day Mortality
CADILLAC
Zwolle
6
12
n=2,002
Mortality (%)
5
P=0.04 ( 3h v  3h)
4
3
10
n=1,791
1994-2001
8
P<0.001
5.6
6
2.3
9.6
2.2
2
4
3.1
2.5
1
0.9
2
0
0
<3
3-6
Time to Reperfusion (h)
>6
<2
2-4
4-6
Time to Reperfusion (h)
Brodie BR, et al. J Am Coll Cardiol. 2003;41(suppl A):368A. De Luca G, et al. J Am Coll Cardiol. 2003;41(suppl A):368A.
>6
Was the Door to Balloon Delay in Performing PCI 3 Hours in
DANAMI 2?
• No.
• It was actually much quicker at 90 to 110 minutes.
• Are door to balloon times among transfer patients this
quick in the United States?
• No.
• Currently, the median delay in the US is 185 minutes, only
4.8% of arteries are opened in under 90 minutes as
suggested by the ACC/AHA guidelines.
CM Gibson 2003
DANAMI vs US AMI:
Are We As Quick in the US?
225
Median Time (min)
200
185
175
150
125
100
110
90
75
50
25
0
DANAMI
On-Site Primary PCI
DANAMI
Transfer Primary PCI
US AMI
Transfer Primary PCI
Pinto D, et al. Cardiovascular Reviews and Report. 2003;24:267-276.
Is There A Time Dependence of the Potential Advantage of PCI
Over Fibrinolysis?
• Yes.
• Delays in door to balloon times of over 60 minutes beyond
that of a center’s door to needle time may nullify the
benefits of primary PCI.
Benefits of PCI vs Lysis: The Importance of Timing
Kent DM et al Eff Clin Pract 4: 214, 2001
Are There Potential Benefits of Even Quicker Fibrinolytic
Administration Such as Pre Hospital Fibrinolytic Therapy?
• Yes.
• A recent meta analysis of 6 trials suggests a relative risk
reduction in mortality of 16%
• The CAPTIM trial suggests that pre hospital therapy
administered to those patients with a short duration of
symptoms (< 2 hours) may be associated with improved
clinical outcomes over primary PCI.
Results of Randomized Trials of
Pre-hospital Thrombolysis on Hospital Mortality
All Trials
Study
No. of
Patients
Quality
Score
OR (95% CI)
MITI, 1993
360
0.91
0.69 (0.30-1.57)
EMIP, 1993
5469
0.85
0.86 (0.72-1.03)
GREAT, 1991
311
0.78
0.56 (0.25-1.23)
Roth et al, 1990
116
0.65
0.80 (0.17-3.77)
78
0.63
0.46 (0.04-5.31)
100
0.48
0.74 (0.14-3.56)
Schofer et al, 1990
Castaigne et al, 1989
Overall
6434
Favors
Pre-hospital
Thrombolysis
Favors
In-hospital
Thrombolysis
0.83 (0.70-0.98)
Morrison LE, et al. JAMA. 2000;283:2686-2691.
CAPTIM 1-Year Results
Sx  2 h
Sx  2 h
7.5
10.0
Death
Death
P=0.057
Death
P=0.47
5.7
7.5
5.0
Percent
5.9
5.0
3.7
2.5
2.2
2.5
0.0
0.0
Pre-hospital Lysis
Primary PCI
Pre-hospital Lysis
Primary PCI
Touboul P. Presented at: The 18th International Symposium on Thrombolysis and Interventional Therapy in Acute Myocardial Infarction George Washington University Symposium; November 16, 2002; Chicago, Ill.
CAPTIM 1-Year Results
Sx  2 h
Sx  2 h
7.5
7.5
Shock Randomization to DC
P=0.032
Death
Shock Randomization to Adm
P=0.0007
5.3
5.0
Percent
5.0
3.6
2.5
2.5
1.3
0.0
0.0
0.0
Pre-hospital Lysis
Primary PCI
Pre-hospital Lysis
Primary PCI
Touboul P. Presented at: The 18th International Symposium on Thrombolysis and Interventional Therapy in Acute Myocardial Infarction George Washington University Symposium; November 16, 2002; Chicago, Ill.
Is Restoration of Epicardial Blood Flow Before PCI Associated
with Improved Clinical Outcomes in STEMI?
• Yes
Facilitated PCI in STEMI: Pre-PCI Angiographic Findings and Mortality
1.0
0.5%
2.8%
96
4.4%
94
TIMI 3 (n=375)
TIMI 2 (n=295)
TIMI 0/1 (1,657)
92
Log-rank P
for trend
P=0.009
Survival
98
90
0.9
0.8
TFG 2
TFG 3
TFG 0/1
3- way log-rank
P=0.0013
0.7
0
1
2
3
4
5
6
0
Months
0.5
1.0
1.5
2.0
1.0
Stone GW, et al. Circulation. 2001;104:636-641.


In both primary PCI and adjunctive/
rescue PCI, TIMI flow grade before PCI
is associated with long-term mortality
In adjunctive/rescue PCI, TIMI myocardial
perfusion before PCI is associated with
long-term mortality
Survival
Survival (%)
100
0.9
0.8
Log-rank
P=0.03
TMPG 2/3
TMPG 0/1
0.7
0
0.5
1.0
1.5
2.0
Gibson CM, et al. Circulation. 2002;105:1909-1913.
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.
PACT Substudy: Time to Reperfusion and LV Function in MI
Probability of Regional LV Dysfunction (Abnormal Chords) Increases as Time to
Achieve Reperfusion Increases
0.95
Time Delay
(min)
30
Probability
0.90
0.85
60
0.80
0.75
90
0.70
120
0.65
0.60
2
4
6
Time (h)
Lundergan CF, et al. Am J Heart. 2002;144:456-462.
8
10
0
1
2
Odds Ratio
3
4
Door-to-Thrombolysis in Myocardial Infarction (TIMI) Time and Mortality
8
P<0.05
6.7
7
After linear logistic regression,
only age, gender, and door-toTIMI grade 3 time (OR 1.27/
15 min) were independently
correlated with in-hospital
mortality
Mortality (%)
6
5
4
Similar to the OR of
1.6/ 25 min in GUSTO IIb trial
(Berger PB et al, Circulation
1999;100:14-20)
3
2
1.8
1
0
n=394
n=105
1h
>1h
Juliard J-M, et al. Am J Cardiol. 2003;91:1401-1405.
Can Glycoprotein IIbIIIa Inhibition Be Administered Safely
Following Fibrinolysis in the Cath Lab?
• Yes.
• Non-randomized trial data suggests that this is not only
safe but tends to be associated with reduced mortality.
GP IIb/IIIa Inhibitor Use With Early PCI After Full-Dose Fibrinolytic Therapy: Clinical
Outcomes and Bleeding Complications
Mortality (%)
CHF (%)
Re-infarction (%)
Re-PCI (%)
CABG (%)
ICH (%)
Severe Bleeding (%)
Moderate Bleeding (%)
Mod-Severe Bleeding (%)
GP IIb/IIIa
Inhibitor
(n=1,032)
4.6
6.8
1.8
2.1
1.6
0.4
2.2
7.1
10.2
No GP IIb/IIIa
Inhibitor
(n=2,386)
6.6
6.5
1.5
3.3
2.8
0.9
1.7
6.5
8.1
Odds Ratio*
95% CI
0.71
1.23
1.07
1.27
0.64
0.60
1.64
1.47
1.64
0.49-1.01
0.87-1.74
0.56-2.03
0.75-2.16
0.36-1.15
0.19-1.90
0.93-2.88
1.07-2.02
1.24-2.16
P=0.06
Odds Ratio represents odds of the event for patients receiving GP IIb/IIIa inhibitors. Bleeding reported by GUSTO scale categories.
Adapted with permission from Roe MT, et al. Safety of adjunctive glycoprotein IIb/IIIa blockade during rescue/early percutaneous
coronary intervention following full-dose fibrinolytic therapy for acute myocardial infarction. Poster presented at the American College of
Cardiology 52nd Annual Scientific Session; March 30-April 2, 2003; Chicago, Il.
CM Gibson 2003
GP 2b3a Inhibition After Full Dose Lysis
Assess risk of ICH:
High Risk: elderly female, low body weight,
elevated blood pressure, elevated Cr, inferior MI
Low Risk: young male, large, normotensive, normal
Cr, anterior MI
Assess Fibrinogen Depletion:
Stat fibrinogen on pt. arrival, ? above 100
TNK does not deplete fibrinogen, drug of choice for
combination with PCI
tPA drops near 100 for 18-24 hrs
rPA often dips below 100 for 18-24 hrs
CM Gibson 2003
Conclusions
• Time is muscle irrespective of the reperfusion strategy (drug or
device)
• Benefits of PCI over fibrinolytic therapy are explained at least in
part by a reduction in recurrent MI among patients treated with PCI
• In the modern era of interventional cardiology (stents,
thienopyridines, GP 2b3a inhibition), the performance of PCI after
fibrinolytic administration may reduce the risk of recurrent MI and
may be associated with reduced long term mortality compared to
fibrinolysis alone
CM Gibson 2003
Conclusions
• Safety and efficacy of full dose fibrinolytic monotherapy is well
characterized while half dose fibrinolytic monotherapy is not well
characterized
• Half dose fibrinolysis with simultaneous full dose GP 2b3a
inhibition (“combination therapy”) is equal in clinical efficacy to
fibrinolytic monotherapy but is associated with more major bleeding
(GUSTO V, ASSENT 3)
• This is in contrast to full dose fibrinolytic monotherapy followed by
full dose GP2b3a inhibition in the cardiac catheterization laboratory
(hours later) which in non-randomized data tends to be associated
with lower mortality (4.6% vs 6.6%, p=0.06) yet with a slight rise in
moderate (7.1% vs 6.5%) and severe (2.2% vs 1.7%) bleeding
CM Gibson 2003
Conclusions
• Future prospective randomized trials will assess the
efficacy of a variety of fibrinolytic and other pharmacologic
agents before PCI and the concept of “facilitated PCI”
CM Gibson 2003
Designs of Upcoming Facilitated PCI Trials
ASSENT 4
TNK
Heparin/ASA
ADVANCE
TNK +
Integrilin
Integrilin
TITAN
Integrilin in
ER
Integrilin in cath lab
FINESSE
r-PA
r-PA + abciximab in ER vs
CCL
CM Gibson 2003
Selection of the Optimal Reperfusion Options for the STEMI Patient: 2003
Full Dose
Fibrinolytic
Monotherapy
•Door to balloon (D-B)
> 90 min
•Lack of access to
skilled PCI center
•(D-B) – (D-N) > 1 h
•< 1 h from symptom
onset
Invasive Strategy
• Cardiogenic shock (age < 75)
• Bleeding risk
• Diagnosis in doubt
(pericarditis/aneurysm)
• Door to balloon < 90 min
• Skilled PCI center available, defined
by:
– Operator experience > 75 cases/yr
– Team experience > 36 primary PCI/yr
• Age > 75
CM Gibson 2003
• Symptoms > 2-3 h