Time Is Myocardium and the Wavefront of Necrosis

1
Time Is Myocardium and the Wavefront of Necrosis
CM Gibson 2002
2
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

3
DANAMI-2 Study Design
High-risk ST elevation MI patients (gt4 mm
elevation), Sx lt 12 hrs 5 PCI centers (n443) and
22 referring hospitals (n1,129), transfer in lt 3
hrs
Primary PCI without transfer (n223)
Primary PCI with transfer (n567)
Lytic therapy Front-loaded tPA 100 mg (n782)
Death / MI / Stroke at 30 Days
Stopped early by safety and efficacy committee
4
DANAMI-2 Centers
5
DANAMI-2 Primary Results
Non-Transfer Sites
Combined
Transfer Sites
P0.048
P0.0003
P0.002
RRR 40
RRR 45
RRR 45
Death / MI / Stroke ()
Lytic
Primary PCI
Lytic
Primary PCI
Lytic
Primary PCI
6
Trials Comparing Primary PTCA With Fibrinolytic
Therapy GUSTO-IIb Cohort
Composite Outcome ()
P0.033
PNS
GUSTO-IIb Angioplasty Substudy Investigators. N
Engl J Med. 19973361621-1628.
7
DANAMI-2 Results
Stroke
Death
Recurrent MI
P0.15
Plt0.0001
P0.35
Lytic
Lytic
Primary PCI
Primary PCI
Lytic
Primary PCI
8
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
9
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
10
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
11
Thrombus Remains Following Thrombolysis
Van Belle et al. Circulation. 19989726-33.
12
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 (P0.01).

Ohman et al. Circulation. 199082781-791.
13
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
14
2 Year Survival Following Rescue PCI
Rescue PCI
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 p0.006
No PCI
Survival
Years
CM Gibson, AHA 2001
15
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
16
Rate of Rescue / Adjunctive PCI Use in DANAMI 2
Compared with Other Recent Trials
Recurrent MI
tPA Hep
rPA Hep
TNK Abx
TNK Hep
TNK Enox
rPA Abx
TNK Enox
11.9
9.1
5.6
8.6
2.5
14.4
Urgent PCI
44.4
Non-Urgent PCI
17.4
19.4
16.5
CM Gibson 2002
Urgent non-urgent combined
17
ENTIRE TIMI 23 30 Day Death/MI
11.3
P0.01
4.9
FULL Dose TNK
HALF Dose TNK Abx
P0.002
15.9
P0.005
159
324
Pts
6.5
5.5
4.4
MI
P0.003
Death
N 82 160 77 164
18
ENTIRE TIMI 23 Recurrent MI In Patients NOT
Undergoing PCI (N259)
FULL Dose TNK
HALF Dose TNK Abx
180
79
Pts
38
77
41
103
N
19
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
  door-to-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 lt 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
20
DANAMI 2 Door to Balloon Times
Community Hospital Thrombolysis (n782)
PCI, non-transported patients (n223)
PCI, transported patients (n567)
21
Cannon CP et al, JAMA 2000
22
NRMI-2 Primary PCI Door-to-Balloon time vs.
Mortality
N27,080 P lt 0.00001
Door-to-Balloon Time (minutes)
23
Door to Balloon Times Among Patients Transferred
in NRMI 4
Data to Cath Lab Arrival 50th 137 Min. 25th
87 Min. 75th 220 Min.
Door to Data 50th 8 Min. 25th 4 Min. 75th 16
Min.
Cath Lab to Balloon 50th 39 Min. 25th 29
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 lt 90 Min. 4.8
Sample Size 1,292 Time Period October 2000
September 2001
NRMI 4 Transfer-In Annual Data Report 2002
Gibson CM, 2002
24
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
25
NRMI 2-3 Primary PCI vs. Thrombolysis
1996-2000N62,000 Patients
In-hospital Mortality

• Volume Hosp Tlysis Prim PCI P value
• lt 16 /yr 25 5.9 6.2 NS
• 17-48/yr 50 5.9 4.5 lt0.001
• gt48/yr 25 5.4 3.4 lt0.001
• Non-fatal stroke 1.1 0.4 lt0.001

Magid et al. JAMA 2000
26
NRMI-2 Primary PCI Institutional Volume vs.
Mortality
N27,080 P lt 0.00001
Institutional Monthly Volume of Primary
Angioplasty Cases
27
Primary PCI Door-to-Balloon time vs. Mortality
Stratified by Institutional Volume
lt1 / month N4,740 P 0.0008
1-3 / month N14,078 P lt 0.0001
gt3 / month N14,078 P lt 0.0001
Door-to-Balloon Time (minutes)
28
Hospital Volume of Primary PTCA vs. Mortality
0.87
0.83
0.72
P value for trend lt 0.001
N Pt 2,825 5,245 9,303
19,162 Hosp 113
112 113
112
Canto. NEJM 2000
29
Randomized Trial Results Versus Community-Setting
Results NRMI-2 Cohort
n2,958, lytic eligible, no shock at presentation
Percent
PNS
PNS
Tiefenbrunn AJ, et al. J Am Coll Cardiol.
1998311240-1245.
30
Trials Comparing Primary PTCA With Fibrinolytic
Therapy MITI Cohort
Thrombolytic therapy
Primary angioplasty
P0.80
Time After Discharge (years)
Every NR, et al. N Engl J Med. 19963351253-1260.
31
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
32
Relative Speed and Magnitude of Patency
Lytic 2b3a 94 by 60 min.
Pre Hospital Lytic 2b3a
Lytic
2 hour Door to Balloon
? ED arrival
? Drug administration
? Pre Hospital Drug administration
Time (minutes)
Adapted from Gibson CM. Am Interm Med.
1999130841-847.
33
Fibrinolytic Therapy Pre-PCI
PRAGUE
PACT
Patients transferred for PCI
TIMI 2/3 flow pre PCI
TIMI 2/3 flow pre PCI
SK
Placebo
tPA
Placebo
Adapted from Ross AM, et al. J Am Coll Cardiol.
1999341954-1962.
Adapted from Widimsky P, et al. J Eur Heart J.
200021823-831.
34
Convalescent LV Function by Patency Group Global
Ejection Fraction
P0.004
Convalescent LVEF
Adapted from Ross AM, et al. J Am Coll Cardiol.
1999341954-1962.
35
Relationship of TIMI 3 Flow Before PCI to 6 Month
Survival
Stone et al. Circ 2001 104 636-641
36
Preliminary Designs of Upcoming Facilitated PCI
Trials
ASSENT 4 TNK Heparin / ASA
ADVANCE TNK Integrilin Integrilin
TIGER TNK TNK Integrilin
TITAN Integrilin in ER Integrilin in Cath Lab
FINESSE rPA rPA abciximab in ER vs CCL

CM Gibson 2002
37
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
38
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
39
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
40
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