1. MANAGEMENT OF ACUTE MYOCARDIAL
INFARCTION AND THE RATIONALE FOR EARLY
REPERFUSION
“TIME IS MUSCLE!”
Strategies for reducing time
to treatment
Strategy: •Public education to shorten
the delay in summoning help
Re-establish myocardial
Aims: reperfusion before •Implementation of
• Prevent death irreversible damage emergency department
• Limit the extent of occurs: thrombolysis protocols
myocardial damage • mechanically (PCI) •Use of rapid diagnostic
• Minimise patient´s • pharmacologically techniques to confirm AMI
discomfort and (induction of •Implementation of pre-
distress thrombolysis by hospital thrombolysis by
thrombolytic agent) trained emergency personnel
Van de Werf et al. Eur Heart J 2003; 24: 28–66.

2. Primary PCI for AMI
AMI Treatment Objectives
General Objectives:
1) Stabilize patient
2) Open artery to TIMI-3 flow
3) Reduce cardiac work
4) Prevent recurrent
thrombosis
Reduce Recurrent Triggering
Specific Objectives - Bed Rest
Restore Epicardial Flow - BP Control
Promote Vasodilation -  - Blocker
- Nitrate
- Calcium channel blocker Treat and Prevent
Complications of Acute
Open Artery Ischemic or Necrotic
- Fibrinolysis Myocardium
- Primary PCI -  - Blocker
Prevent Thrombosis - Anti-arrhythymic
- Anti-Platelet Agents - GP IIb/IIIa Inhibitor
- Anti-Thrombin Agent
Adapted from Califf RM. In: Braunwald E., ed. Atlas of Heart Diseases. 1996:Ch. 1, with
permission

3. Drop of rt-PA breaking down the surface of thrombus.
Scanning electron microscopic photograph by Dr. h.c Lennart Nilsson

4. For every 30-minute delay from onset of symptoms to
primary PCI, there is an 8 percent increase in the
relative risk of 1-year mortality
Importance of time to reperfusion in patients undergoing primary percutaneous coronary
intervention (PCI) for ST segment elevation myocardial infarction (STEMI). This plot is based
on the pooled data from 1791 patients undergoing primary PCI for STEMI. After adjusting for
baseline risk, there is a curvilinear relationship between the time elapsed from the onset of
symptoms to balloon inflation and the rate of mortality at 1 year. For every 30-minute delay
from onset of symptoms to primary PCI, there is an 8 percent increase in the relative risk of
1-year mortality.
(From De Luca G, Suryapranata H, Ottervanger JP, et al: Time-delay to treatment and mortality in primary angioplasty
for acute myocardial infarction: Every minute counts. Circulation 109:1223, 2004

5. Time Dependency?

6. Generally caused by a Results from stabilization of a
platelet aggregate at site of
Pathophysiology of STEMI1
completely occlusive
thrombus in a coronary artery plaque rupture by fibrin mesh
Platelet
RBC
Fibrin mesh
GPIIb/IIIa
RBC=red blood cell
• The common link between UA/NSTEMI and STEMI is that thrombus formation occurs
secondary to the rupture or fissuring of an atherosclerotic plaque in the coronary arteries
• This leads to thrombotic occlusion of the coronary artery with interruption of blood flow,
resulting in myocardial ischemia and/or necrosis (death of myocardial cells)
• Patients with ACS are at high risk of subsequent life-threatening atherothrombotic events such
as MI, stroke or vascular death
1. Adapted from Antman EM. In: Califf RM, ed. Atlas of Heart Diseases, VIII. Philadelphia,
PA: Current Medicine, 1996.

7. GOALS IN REPERFUSION IN AMI
 RAPID
 COMPLETE - TIMI III - EPICARDIAL ARTERY
 INTEGRITY OF MICROCIRCULATION MYOCARDIAL PERFUSION
TIMI GRADE - III
 SUSTAINED

8. 12
M 10 9.3%
o
r 8 p = 0.003 vs TIMI 0/1
t
a 6.1 %
6 p < 0.0001 vs TIMI 0/1
l P < 0.0001 vs TIMI 2
i
4 3.7 %
t
y
2
%
0

9. TITAN Other Angiographic Efficacy Endpoint:
TIMI Myocardial Perfusion (TMP) Grades
8 TMP Grade 3 TMP Grade 2 TMP Grade 1 TMP Grade 0
7 Normal ground glass Stain present
Dye strongly persistent No or minimal blush
appearance of blush Blush persists
6 Dye mildly persistent at end of washout
on next injection
at end of washout Gone by next injection 6.2%
5
p = 0.05 5.1%
4
3
4.4%
2
2.0%
1 n = 46 n = 79 n = 434
n = 203
0
© TIMI 2005. Duplication prohibited by law
Gibson et al, Circulation 2000

10. Assessing Reperfusion Options for Patients
with STEMI1
STEP 1: Assess time and risk (time from symptom onset, risk of STEMI, risk of
thrombolysis, time for transport to PCI lab)
STEP 2: Determine whether fibrinolysis or invasive strategy is preferred*
Fibrinolysis preferred if: Invasive strategy preferred if:
• Early presentation (<3 hours) • Skilled PCI lab with surgical backup
• Invasive strategy not an option available
• Delay to invasive strategy • High risk (i.e. cardiogenic shock)
• Contraindications to fibrinolysis
• Late presentation (>3 hours)
• Diagnosis of STEMI is in doubt
*If presentation is <3 hours from onset and there is no delay to an invasive
strategy, there is no preference for either strategy
1. Antman EM et al. Circulation 2004; 110: 588–636.

11. Because the benefits of fibrinolytic therapy are directly related to the time from
symptom onset, treatment benefit is maximized by the earliest possible
application of therapy1
Contraindications and cautions for fibrinolysis in patients with STEMI include:1
1. Any prior intracranial hemmorrhage (ICH)
2. A known structural cerebral vascular lesion or malignant intracranial
neoplasm
3. Ischemic stroke within 3 months EXCEPT acute ischemic stroke within 3
hours
4. Suspected aortic dissection
5. Active or recent bleeding or bleeding diathesis
6. Systolic blood pressure (SBP) >180 mm Hg or diastolic blood pressure
(DBP) >110 mm Hg
7. Current use of anticoagulants
8. Traumatic or prolonged cardiopulmonary resuscitation (CPR) or major
surgery
Reference
1. Antman EM et al. Circulation 2004; 110: 588–636.

12. Common thrombolytics regimens for
STEMI1
Initial treatment Co-therapy Contraindications
Streptokinase (SK) 1.5 million U in 100 mL None or iv Prior SK or
D5W or NS over 3060 min heparin x 2448 hrs anistreplase
Alteplase (tPA) 15 mg iv bolus, then iv heparin x 2448 hrs
0.75 mg/kg over 30 min,
then 0.5 mg/kg iv over 60 min
Total dose not over 100 mg
Reteplase (r-PA) 10 U + 10 U iv bolus given iv heparin x 2448 hrs
30 min apart
Tenecteplase Single iv bolus iv heparin x 2448 hrs
(TNK-tPA) 30 mg if <60 kg
35 mg if 60 kg to <70 kg
40 mg if 70 kg to <80 kg
45 mg if 80 kg to <90 kg
50 mg if ≥90 kg
Note: ASA should be given to all patients without contraindications
1. Van de Werf F et al. Eur Heart J 2003; 24: 2866.

13. Prothrombotic effects of fibrinolytic therapy.
Coronary thrombus is composed of a platelet
core with fibrin-thrombin admixture
(“white” and “red” clot)

14. CONTRAINDICATIONS TO FIBRINOLYTIC
THERAPY
Absolute contraindications
 Hemorrhagic stroke or stroke of unknown origin at anytime
 Ischemic stroke in preceding 6 months
 Central nervous system trauma or neoplasms
 Recent major trauma/surgery/head injury (within
preceding 3 weeks)
 Gastrointestinal bleeding within the last month
 Known bleeding disorder
 Aortic dissection
 Non-compressible punctures (e.g. liver biopsy, lumbar
puncture)

15. Primary PCI versus fibrinolysis for MI
Meta analysis of 23 trials
15 14
10
Percentage
8
7 7
5
5
3
2
1
0
Death Re MI Total Stroke Total
fibrinolysis prim PCI
P<0.0001
Keeley EC. Lancet 2003;361:13-20

16. PAMI VS THROMB.META ANALYSIS

17. Contemporary Mortality Differences Between
Primary PCI and Thrombolysis in STEMI
5,295 Belgian STEMI patients stratified by TIMI risk profile.
Primary PCI Thrombolysis
In-Hospital Mortality (n = 4,574) (n = 721) P Value
High Risk 23.7% 30.6% 0.03
Intermediate Risk 2.9% 3.1% 0.30
Low Risk 0.3% 0.4% 0.60
The mortality benefit of primary PCI over early thrombolysis was
offset if the door-to-balloon time exceeded 60 min.
Conclusion: Primary PCI in patients with STEMI reduces in-hospital mortality
compared with initial thrombolysis, but the benefit is restricted to high-risk
patients.
Claeys MJ, et al. Arch Intern Med.
2011;171:544-549.

18. IMPACT OF TIME-TO-TREATMENT AND 30 DAY
MORTALITY : PCI VS. THROMBOLYSIS
Thrombolysis PCI
12
30-35-DAY MORTALITY (%)
10
8
6
4
2
0 1 2 8
3 4 5 6 7
TIME FROM ONSET OF PAIN TO THERAPY IN HOURS
The figure shows the increase in mortality over time in relation to the start of
reperfusion therapy with pharmacological vs. mechanical means, compiling data from a
meta-analysis of thrombolysis trials and the NRMI-2 results for mechanical reperfusion.
Cannon et al. J Thromb Thrombol 1994; 1: 27–34.
Cannon et al. JAMA 2000; 283: 2941–2947. Huber et al. Eur Heart J 2005; 26: 1063–1074.

19. CONTRAINDICATIONS TO FIBRINOLYTIC
THERAPY
Relative contraindications
 Transient ischaemic attack in preceding 6 months
 Oral anticoagulant therapy
 Pregnancy or within 1 week post-partum
 Refractory hypertension (systolic blood pressure > 180
mm Hg and/or diastolic blood pressure > 110 mm Hg)
 Advanced liver disease
 Infective endocarditis
 Active peptic ulcer
 Refractory resuscitation

20. Strategies for improving
pharmacological reperfusion
• Despite the success of thrombolysis in clinical
practice, various strategies have been investigated in order to
improve the effectiveness of pharmacological reperfusion.
• The following sections consider the experience to date with
strategies such as:
1. Improved fibrinolytic agents offering increased
convenience and safety
2. Improved antithrombotic co-therapies
3. Improved antiplatelet co-therapies.

21. Strategies for improving pharmacological
reperfusion
Improved
antiplatelet
co-therapy
i.v. glycoprotein IIb/IIIa
inhibitors
Clopidogrel
Improved Improved
fibrinolytic antithrombotic
Agents co-therapy
convenience Direct thrombin
inhibitors
(tenecteplase, retepla)
(hirudin, bivalirudin)
Low mol.
Risk of major bleeds
weight heparins
(tenecteplase)
(enoxaparin)

22. Enoxaparin improves infarct-related artery patency at 90
minutes Enoxaparin improves infarct-
TIMI 2 related artery patency at 90
100 minutes
TIMI 3
In the HART II study, 90
% of patients
80
27.2 minutes after starting
60 27.5 therapy, patency rates (TIMI
40 flow grade 2/3) were 80.1%
20 52.9 and 75.1% in the enoxaparin
47.6
0 and UFH
groups, respectively.
Enoxaparin Overall, enoxaparin
Unfractionated heparin appeared to be at least as
effective as UFH as an
TIMI flow at 90 minutes
adjunct to
thrombolysis, with a trend
toward higher recanalization
rates and less reocclusion at
5 to 7 days.
Therefore, such a regimen was evaluated in ASSENT-3, the first large-scale trial to compare the two
antithrombotics in combination with fibrinolysis.
The ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3
randomised trial in acute myocardial infarction. Lancet 2001; 358: 605–13.
Ross et al, Circulation 2001

23. TRANSFER – AMI
STUDY DESIGN - I
• 52 sites in canad with no pci capability
• randomised, nonblinded
• within 12 hours of chest pain
• Higher risk killip class ii or iii
• BP < 100 AND HR > 100,RV inf.
• Shock, cabg exclude
N. Eng. J. Med. 2009, 360, 2705

24. TRANSFER – AMI
STUDY DESIGN - I
AMI Stent 1059 Patients
TR. TO PCI CENTER IMM.
Standard treatment Early pci within 6 hours
(522) + Stent
TNK, CLOP. ± GP II b / III a Blockers
ASP, HEP.
Angio meantime
32.5 HRS (89 %)
PCI – 67 %
N. Eng. J. Med. 2009, 360, 2705

25. CLINICAL ENDPOINTS
– TRANSFER - AMI
End Point Standard Routine Early Relative Risk with
Treatment PCI (N=536) Routine Early PCI
(N=522) (95 % CI) P Value
Efficacy end points at 30
days – no (%)
Primary end point 90 (17.2) 59 (11.0) 0.64 (0.47-0.87) 0.004
Death 18 (3.4) 24 (4.5) 1.30 (0.71-2.36) 0.39
Reinfarction 30 (5.7) 18 (3.4) 0.57 (0.33-1.04) 0.06
Death or reinfarction 47 (9.0) 38 (7.1) 0.79 (0.52-1.19) 0.25
Recurrent ischemia 11 (2.1) 1 (0.2) 0.09 (0.01-0.68) 0.003
Death, reinfarction, or 58 (11.1) 39 (7.3) 0.65 (0.44-0.96) 0.03
recurrent ischemia
New or worsening 29 (5.6) 16 (3.0) 0.54 (0.30-0.98) 0.04
congestive heart failure
Cardiogenic shock 16 (3.1) 24 (4.5) 1.46 (0.79-2.72) 0.23
N. Eng. J. Med. 2009, 360, 2705

26. 1.0 0.12 TRANSFER-AMI
Standard treatment
Cumulative Incidence of Death or Reinfarction
0.10
0.8 0.08
0.06 Routine early PCI
0.6 0.04
0.02
0.4 0.00
0 1 2 3 4 5
6
P=0.36
0.2
0.0
0 1 2 3 4 5 6
Months from Randomization
No. at risk
Standard treatment 522 473 465 462 462 460 458
Routine early PCI 537 497 487 487 484 483 481
N. Eng. J. Med.
Kaplan-Meir Curves for Death or Reinfarction and for Reinfarction Only at 6 Months 2009, 360, 2705

27. 1.0 0.20 TRANSFER-AMI
Cumulative Incidence of Primary End Point
Standard treatment
0.15
0.8
0.10 Routine early PCI
0.6
0.05
0.4 0.00
0 1 2 3 4 5
6
0.2 P=0.04
0.0
0 5 10 15 20 25 30
Days from Randomization
No. at riskc
Standard treatment 522 442 434 434 433 433 432
Routine early PCI 537 488 486 483 481 480 478
Primary End Points at 30 Days N. Eng. J. Med.
Composite of Death, reinfarction, worsening heart failure or cardiogenic shock 2009, 360, 2705

28. Primary Endpoint: 30-Day Death, re-
MI, CHF, Severe Recurrent Ischemia, Shock
18 16.6
16
14
OR=0.537 (0.368, 0.783); p=0.0013
% of Patients
12
10.6
10
8
6
4 Standard (n=496)
2 Pharmacoinvasive (n=508)
0
0 5 10 15 20 25 30
Days from Randomization
n=496 422 415 415 414 414 412
n=508 468 466 463 461 460 457

29. TRANSFER-AMI Summary
• Compared with ‘Standard Treatment’, a ‘Pharmacoinvasive
Strategy’ of routine early PCI within 6 hrs after thrombolysis is
associated with a 6% absolute (46% relative) reduction in the
composite of death, reinfarction, recurrent ischemia, heart
failure and shock
• The pharmacoinvasive strategy is not associated with any
increase in transfusions, severe bleeding or intracranial
hemorrhage despite high use of GP IIb/IIIa inhibitors during PCI
• In contrast to older trials, routine early PCI after thrombolysis
using stents and contemporary pharmacotherapy is safe and
effective
– Benefit seen despite high cath/PCI rates in Standard Treatment
group (including ~40% rescue PCI)
N. Eng. J. Med. 2009, 360, 2705

30. 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 with transfer without transfer
100 mg
(n=567) (n=223)
(n=782)
Death / MI / Stroke at 30 Days
Stopped early by safety and efficacy committee

31. DANAMI-2: transfer for primary PCI
vs on-site Alteplase (n=1572)
P=0.0003
15.0% Primary angioplasty 13.7%
Thrombolysis
P=0.35
10.0%
7.8% P<0.001 8.0%
6.6% 6.3% p=0.002
5.0%
1.6% 2.0%
1.1%
0.0%
Death Re-MI Stroke Any event
Anderson 2003;349:733

32. PRAGUE-2 study design
• Randomised 850 patients with acute ST-elevation
myocardial infarction (STEMI) presenting within 12 h of
symptom onset to the nearest community hospital.
• Thrombolysis group, n=421
or
• Immediate transport for primary percutaneous coronary
intervention (PCI group, n=429).

33. Prague-2: Transfer for PCI vs
on-site thrombolysis in acute MI (n=850)
Mortality at 30 days
20%
Transfer for PCI
15.3%
15% Streptokinase
10.0%
10%
6.8% 7.3% 7.4%
6.0%
5%
p=0.12 p=0.02
0%
All patients Rx <3hrs of Rx >3hrs of
symptoms symptoms
Symptoms to balloon 277 min
Symptom to lysis 195 min
Planned 1200 patients Widimsky, Eur Heart J 2003;24:94

34. Transfer for primary PCI vs on-site lytic
Quantitative review of 5 trials*
*LIMI, Prague I & II, Air PAMI, DANAMI-2
Primary PCI (n=1466) 15.0%
15.0%
Thrombolysis (n=1443)
10.0% 8.9% P<0.0001
8.2%
7.0% 6.7%
5.0%
P=0.057 P<0.0001
1.8% 2.2%
1.1%
0.0%
Death Re-MI Stroke Any event
Keeley, Lancet 2003;361:13

35. REACT TRIAL DESIGN
STEMI – Within 6 hours of chest pain
427 with failed thrombolysis
RPCI 144 Rethrombolysis Routine
Within 12 hours 142 Treatment
For symptoms 141
Heparin

36. REACT Trial (Rescue PCI)
Event Free Survival
100 R-PCI 81.5 % (95 % CI 74.0%-87.0%)
Conservative 67.5 % (95 % CI 58.9 %-74.6%)
80
Event Free Survival
60 Repeated thrombolysis 64.1 % (95 % CI 55.5 %-71.5 %)
40
20 P=0.004
0
0 40 80 120 160 200 240 280 320 360 400
Days after Randomization
JACC 2009, 54, 118

37. REACT Trial
Longer-Term Mortality
100 R-PCI 80.6 % (95 % CI 60.2%-91.2%)
80
Event Free Survival
60
Repeated thrombolysis 76.0% (95 % CI 67.4%-82.6%)
40 Conservative 72.2% (95 % CI 60.6%-80.9%)
20 P=0.026
0
0 1 2 3 4 5 6 7
Years from Randomization
Numbers at risk
R-PCI 144 132 131 119 84 40 14 0
Repeated thrombolysis 142 119 117 104 66 35 8 0
Conservative 141 118 112 100 72 33 8 0
JACC 2009, 54, 118

38. REACT Trial (Rescue PCI) 1-Year Revascularization HRs
Repeated thrombolysis HR=1.05
vs Conservative 95% 0.68 to 1.62
R-PCI vs HR=1.05
Repeated thrombolysis 95% 0.32 to 0.86
HR=0.50
R-PCI vs Conservative 95% 0.30 to 0.83
0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2.0
Favors Comparative Group Favors Reference Group
Hazard Ratio
Absolute revascularization : Repeat thrombolysis n=41;
Conservative n=4(20); R-PCI n=25
JACC 2009, 54, 118

39. RESCUE PCI – Death
Odds Ratio, random model
Bilateral CI, 95 % for trials, 95 % for MA
Treatment Better Control Better
Conservative vs rescue balloon PTCA Invasive Cons.
5/74 6/75
LIMI
1/16 4/12
Belinkie
RESCUE 4/78 7/73
Total 0.53 p=0.18 10/160 17/168
Conservative vs rescue stent PCI
REACT 7/141 15/144
MERLIN 15/153 17/154
Total
0.68 p=0.19 22/294 32/298
Total 32/462 49/458
0.63 p=0.055
Relative Risk 0 0.5 1 1.5 2 2.5 3 events / size
Metanalysis Collect et al, JACC

40. RESCUE PCI – Death or Reinfarction
Odds Ratio, random model
Bilateral CI, 95 % for trials, 95 % for MA
Treatment Better Control Better
Conservative vs rescue balloon PTCA Invasive Cons.
10/74 12/75
LIMI
2/16 4/12
Belinkie
RESCUE 4/78 7/73
Total 0.62 p=0.18 16/168 23/160
Conservative vs rescue stent PCI
REACT 8/141 22/144
MERLIN 26/153 32/154
Total
0.60 p=0.033 34/294 54/298
Total 50/462 77/458
0.60 p=0.012
Relative Risk 0 0.5 1 1.5 2 2.5 3 events / size
Metanalysis Collect et al, JACC 2006, 48, 136

41. Major components of time delay between onset of infarction and
restoration of flow in the infarct-related artery.

42. The previous figure shows infarction and restoration of flow in the infarct-
related artery. Plotted sequentially from left to right are the time for patients
to recognize symptoms and seek medical attention, transportation to the
hospital, in-hospital decision-making and implementation of reperfusion
strategy, and time for restoration of flow once the reperfusion strategy has
been initiated. The time to initiate fibrinolytic therapy is the “ door-to-needle”
(D-N) time; this is followed by the period of time required for pharmacological
restoration of flow. More time is required to move the patient to the
catheterization laboratory for a percutaneous coronary interventional (PCI)
procedure, referred to as the “ door-to-balloon” (D-B) time, but restoration of
flow in the epicardial infarct-related artery occurs promptly after PCI. At the
bottom are shown a variety of methods for speeding the time to reperfusion
along with the goals for the time intervals for the various components of the
time delay. (Adapted from Cannon CP, Antman EM, Walls R, Braunwald E: Time
as adjunctive agent to thrombolytic therapy. J Thromb Thrombolysis 1:27,
1994.)

43. Thank You!