MANAGEMENT OF ACUTE MYOCARDIAL INFARCTION AND THE RATIONALE FOR EARLY
REPERFUSION
Aims:• Prevent death • Limit the extent of
myocardial damage• Minimise patient´s
discomfort and distress
“TIME IS MUSCLE!”
Strategy:Re-establish myocardial
reperfusion before irreversible damage occurs:• mechanically (PCI)• pharmacologically
(induction of thrombolysis by thrombolytic agent)
Van de Werf et al. Eur Heart J 2003; 24: 28–66.
Strategies for reducing time to treatment• Public education to shorten
the delay in summoning help
• Implementation of emergency department thrombolysis protocols
• Use of rapid diagnostic techniques to confirm AMI
• Implementation of pre-hospital thrombolysis by trained emergency personnel
AMI Treatment ObjectivesGeneral Objectives:1) Stabilize patient
3) Reduce cardiac work2) Open artery to TIMI-3 flow
4) Prevent recurrent thrombosis
- - Blocker- Anti-arrhythymic
Treat and Prevent Complications of AcuteIschemic or NecroticMyocardium
- Bed Rest- BP Control
Reduce Recurrent Triggering
- - Blocker
Specific Objectives
Promote Vasodilation- Nitrate- Calcium channel blocker
Restore Epicardial Flow
Open Artery- Fibrinolysis- Primary PCI Prevent Thrombosis- Anti-Platelet Agents- Anti-Thrombin Agent
- GP IIb/IIIa Inhibitor
Adapted from Califf RM. In: Braunwald E., ed. Atlas of Heart Diseases. 1996:Ch. 1, with permission
Primary PCI for AMI
Drop of rt-PA breaking down the surface of thrombus.
Scanning electron microscopic photograph by Dr. h.c Lennart Nilsson
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
Time Dependency?
Pathophysiology of STEMI1
1. Adapted from Antman EM. In: Califf RM, ed. Atlas of Heart Diseases, VIII. Philadelphia, PA: Current Medicine, 1996.
Results from stabilization of a platelet aggregate at site of
plaque rupture by fibrin mesh
Platelet
RBC
Fibrin mesh
GPIIb/IIIa
Generally caused by a completely occlusive
thrombus in a coronary artery
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
GOALS IN REPERFUSION IN AMI
RAPID
COMPLETE - TIMI III - EPICARDIAL ARTERY
INTEGRITY OF MICROCIRCULATION MYOCARDIAL PERFUSION TIMI GRADE - III
SUSTAINED
Series10
2
4
6
8
10
12
Mortality%
p = 0.003 vs TIMI 0/1
p < 0.0001 vs TIMI 0/1P < 0.0001 vs TIMI 2
9.3%
6.1 %
3.7 %
0
1
2
3
4
5
6
7
8
6.2%6.2%
4.4%4.4%
2.0%2.0%n = 203n = 203 n = 46n = 46 n = 434n = 434
TMP Grade 3 TMP Grade 3
p = 0.05p = 0.05
Mor
talit
y (%
)M
orta
lity
(%)
n = 79n = 79
5.1%5.1%
Gibson et al, Circulation 2000Gibson et al, Circulation 2000
Normal ground glassappearance of blushDye mildly persistent
at end of washout
Normal ground glassappearance of blushDye mildly persistent
at end of washout
Dye strongly persistentat end of washout
Gone by next injection
Dye strongly persistentat end of washout
Gone by next injection
Stain presentBlush persists
on next injection
Stain presentBlush persists
on next injection
No or minimal blushNo or minimal blush
TMP Grade 2 TMP Grade 2 TMP Grade 1 TMP Grade 1 TMP Grade 0 TMP Grade 0
TITAN Other Angiographic Efficacy Endpoint: TIMI Myocardial Perfusion (TMP) Grades
© TIMI 2005. Duplication prohibited by law
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)• Invasive strategy not an option• Delay to invasive strategy
• Skilled PCI lab with surgical backup available
• High risk (i.e. cardiogenic shock)• Contraindications to fibrinolysis• Late presentation (>3 hours)• Diagnosis of STEMI is in doubt
1. Antman EM et al. Circulation 2004; 110: 588–636.
*If presentation is <3 hours from onset and there is no delay to an invasive strategy, there is no preference for either strategy
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
neoplasm3. Ischemic stroke within 3 months EXCEPT acute ischemic stroke within 3
hours4. Suspected aortic dissection5. 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 anticoagulants8. Traumatic or prolonged cardiopulmonary resuscitation (CPR) or major
surgery
Reference
1. Antman EM et al. Circulation 2004; 110: 588–636.
Common thrombolytics regimens for STEMI1
Initial treatment Co-therapy Contraindications
Streptokinase (SK) 1.5 million U in 100 mL None or iv Prior SK orD5W or NS over 3060 min heparin x 2448 hrs anistreplase
Alteplase (tPA)15 mg iv bolus, then iv heparin x 2448 hrs0.75 mg/kg over 30 min,then 0.5 mg/kg iv over 60 minTotal dose not over 100 mg
Reteplase (r-PA) 10 U + 10 U iv bolus given iv heparin x 2448 hrs30 min apart
Tenecteplase Single iv bolus iv heparin x 2448 hrs(TNK-tPA) 30 mg if <60 kg
35 mg if 60 kg to <70 kg40 mg if 70 kg to <80 kg45 mg if 80 kg to <90 kg50 mg if ≥90 kg
1. Van de Werf F et al. Eur Heart J 2003; 24: 2866.
Note: ASA should be given to all patients without contraindications
Prothrombotic effects of fibrinolytic therapy.Coronary thrombus is composed of a platelet
core with fibrin-thrombin admixture (“white” and “red” clot)
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)
Death Re MI Total Stroke Total0
5
10
15
7 7
2
14
5
3
1
8
fibrinolysis prim PCI
Perc
enta
gePrimary PCI versus fibrinolysis for MI
Meta analysis of 23 trials
Keeley EC. Lancet 2003;361:13-20
P<0.0001
PAMI VS THROMB.META ANALYSIS
Contemporary Mortality Differences Between Primary PCI and Thrombolysis in STEMI
Conclusion: Primary PCI in patients with STEMI reduces in-hospital mortality compared with initial thrombolysis, but the benefit is restricted to high-risk patients.
5,295 Belgian STEMI patients stratified by TIMI risk profile.
Claeys MJ, et al. Arch Intern Med.2011;171:544-549.
In-Hospital MortalityPrimary PCI
(n = 4,574)Thrombolysis
(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.
IMPACT OF TIME-TO-TREATMENT AND 30 DAY MORTALITY : PCI VS. THROMBOLYSIS
30-3
5-D
AY M
OR
TALI
TY (%
)
Thrombolysis PCI
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.
TIME FROM ONSET OF PAIN TO THERAPY IN HOURS
0
6
12
2
4
2 4 6 8
10
8
1 3 5 7
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.
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
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-therapies3. Improved antiplatelet co-therapies.
Strategies for improving pharmacological reperfusion
Improved antiplatelet co-therapy
i.v. glycoprotein IIb/IIIa inhibitors
Clopidogrel
Improved antithrombotic
co-therapyDirect thrombin
inhibitors (hirudin, bivalirudin)
Low mol. weight heparins
(enoxaparin)
Improved fibrinolytic
Agentsconvenience
(tenecteplase, retepla)
Risk of major bleeds
(tenecteplase)
Enoxaparin improves infarct-related artery patency at 90 minutes
EnoxaparinUnfractionated
heparin
020406080
100
52.947.6
27.227.5
TIMI 2TIMI 3
% o
f pati
ents
Ross et al, Circulation 2001
TIMI flow at 90 minutes
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.
Enoxaparin improves infarct-related artery patency at 90 minutesIn the HART II study, 90 minutes after starting therapy, patency rates (TIMI flow grade 2/3) were 80.1% and 75.1% in the enoxaparin and UFH groups, respectively. Overall, enoxaparin appeared to be at least as effective as UFH as an adjunct to thrombolysis, with a trend toward higher recanalization rates and less reocclusion at 5 to 7 days.
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
TRANSFER – AMI STUDY DESIGN - I
AMI Stent 1059 Patients TR. TO PCI CENTER IMM.
Standard treatment(522)
TNK, CLOP.ASP, HEP.
Early pci within 6 hours+ Stent± GP II b / III a Blockers
Angio meantime 32.5 HRS (89 %)
PCI – 67 %
N. Eng. J. Med. 2009, 360, 2705
CLINICAL ENDPOINTS – TRANSFER - AMI
End Point Standard Treatment
(N=522)
Routine Early PCI (N=536)
Relative Risk with Routine Early PCI
(95 % CI) P ValueEfficacy 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 recurrent ischemia
58 (11.1) 39 (7.3) 0.65 (0.44-0.96) 0.03
New or worsening congestive heart failure
29 (5.6) 16 (3.0) 0.54 (0.30-0.98) 0.04
Cardiogenic shock 16 (3.1) 24 (4.5) 1.46 (0.79-2.72) 0.23
N. Eng. J. Med. 2009, 360, 2705
Kaplan-Meir Curves for Death or Reinfarction and for Reinfarction Only at 6 Months
Months from Randomization
1.0
0.8
0.6
0.4
0.2
0.00 1 2 3 4 5 6
P=0.36
0.12
0.10
0.08
0.06
0.04
0.02
0.00
Cum
ulati
ve In
cide
nce
of D
eath
or R
einf
arcti
on
0 1 2 3 4 5 6
Standard treatment
No. at riskStandard treatment 522 473 465 462 462 460 458Routine early PCI 537 497 487 487 484 483 481
Routine early PCI
TRANSFER-AMI
N. Eng. J. Med. 2009, 360, 2705
Primary End Points at 30 DaysComposite of Death, reinfarction, worsening heart failure or cardiogenic shock
Days from Randomization
1.0
0.8
0.6
0.4
0.2
0.00 5 10 15 20 25 30
P=0.04
0.20
0.15
0.10
0.05
0.00
Cum
ulati
ve In
cide
nce
of P
rimar
y En
d Po
int
0 1 2 3 4 5 6
Standard treatment
No. at riskcStandard treatment 522 442 434 434 433 433 432Routine early PCI 537 488 486 483 481 480 478
Routine early PCI
TRANSFER-AMI
N. Eng. J. Med. 2009, 360, 2705
0
2
4
6
8
10
12
14
16
18
0 5 10 15 20 25 30
10.6
16.6
Days from Randomization
% o
f Pati
ents
Standard (n=496)Pharmacoinvasive (n=508)
n=496n=508
422468
415466
415463
414461
414460
412457
Primary Endpoint: 30-Day Death, re-MI, CHF, Severe Recurrent Ischemia, Shock
OR=0.537 (0.368, 0.783); p=0.0013
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
High-risk ST elevation MI patients (>4 mm elevation), Sx < 12 hrs5 PCI centers (n=443) and 22 referring hospitals (n=1,129), transfer in < 3 hrs
High-risk ST elevation MI patients (>4 mm elevation), Sx < 12 hrs5 PCI centers (n=443) and 22 referring hospitals (n=1,129), transfer in < 3 hrs
Lytic therapyFront-loaded tPA
100 mg
(n=782)
Lytic therapyFront-loaded tPA
100 mg
(n=782)
Death / MI / Stroke at 30 DaysDeath / MI / Stroke at 30 Days
DANAMI-2: Study Design
Primary PCIwith transfer
(n=567)
Primary PCIwith transfer
(n=567)
Primary PCIwithout transfer
(n=223)
Primary PCIwithout transfer
(n=223)
Stopped early by safety and efficacy committeeStopped early by safety and efficacy committee
DANAMI-2: transfer for primary PCIvs on-site Alteplase (n=1572)
DANAMI-2: transfer for primary PCIvs on-site Alteplase (n=1572)
Anderson 2003;349:733
p=0.0026.6%
1.6% 1.1%
8.0%
6.3%
2.0%
13.7%
0.0%
5.0%
10.0%
15.0%
Death Re-MI Stroke Any event
Primary angioplastyThrombolysis
P=0.35
P=0.0003
7.8% P<0.001
• 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=421or
• Immediate transport for primary percutaneous coronary intervention (PCI group, n=429).
PRAGUE-2 study design
Prague-2: Transfer for PCI vson-site thrombolysis in acute MI (n=850)
Widimsky, Eur Heart J 2003;24:94
Mortality at 30 days
Symptoms to balloon 277 minSymptom to lysis 195 minPlanned 1200 patients
6.8% 7.3%6.0%
10.0%7.4%
15.3%
0%
5%
10%
15%
20%
All patients Rx <3hrs ofsymptoms
Rx >3hrs ofsymptoms
Transfer for PCI
Streptokinase
p=0.12 p=0.02
7.0%7.0%
1.8%1.8%1.1%1.1%
8.2%8.2%8.9%8.9%
6.7%6.7%
2.2%2.2%
15.0%15.0%
0.0%0.0%
5.0%5.0%
10.0%10.0%
15.0%15.0%
DeathDeath Re-MIRe-MI StrokeStroke Any eventAny event
Primary PCI (n=1466)Primary PCI (n=1466)
Thrombolysis (n=1443)Thrombolysis (n=1443)
Transfer for primary PCI vs on-site lyticQuantitative review of 5 trials*
Transfer for primary PCI vs on-site lyticQuantitative review of 5 trials*
Keeley, Lancet 2003;361:13
*LIMI, Prague I & II, Air PAMI, DANAMI-2
P=0.057 P<0.0001
P<0.0001
REACT TRIAL DESIGN
STEMI – Within 6 hours of chest pain
427 with failed thrombolysis
RPCI 144Within 12 hours
For symptoms
Rethrombolysis142
Routine Treatment
141Heparin
100
80
60
40
20
0
Even
t Fre
e Su
rviv
al
Days after Randomization0 40 80 120 160 200 240 280 320 360 400
REACT Trial (Rescue PCI) Event Free Survival
JACC 2009, 54, 118
R-PCI 81.5 % (95 % CI 74.0%-87.0%)
Conservative 67.5 % (95 % CI 58.9 %-74.6%)
Repeated thrombolysis 64.1 % (95 % CI 55.5 %-71.5 %)
P=0.004
100
80
60
40
20
0
Even
t Fre
e Su
rviv
al
Years from Randomization0 1 2 3 4 5 6 7
REACT Trial Longer-Term Mortality
JACC 2009, 54, 118
R-PCI 80.6 % (95 % CI 60.2%-91.2%)
Conservative 72.2% (95 % CI 60.6%-80.9%)
Repeated thrombolysis 76.0% (95 % CI 67.4%-82.6%)
P=0.026
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
Absolute revascularization : Repeat thrombolysis n=41; Conservative n=4(20); R-PCI n=25
JACC 2009, 54, 118
Repeated thrombolysisvs Conservative
R-PCI vsRepeated thrombolysis
R-PCI vs Conservative
REACT Trial (Rescue PCI) 1-Year Revascularization HRs
Favors Comparative Group
0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2.0
Hazard Ratio
Favors Reference Group
HR=1.0595% 0.68 to 1.62
HR=1.0595% 0.32 to 0.86
HR=0.5095% 0.30 to 0.83
RESCUE PCI – Death
Metanalysis Collect et al, JACC 2006, 48, 136
Conservative vs rescue balloon PTCA
LIMI
Belinkie
RESCUE
Total
Conservative vs rescue stent PCI
REACT
MERLIN
Total
Total
Relative Risk
5/74
1/16
4/78
10/160
7/141
15/153
22/294
32/462
Odds Ratio, random modelBilateral CI, 95 % for trials, 95 % for MA
Invasive Cons.
0 0.5 1 1.5 2 2.5 3
Treatment Better Control Better
6/75
4/12
7/73
17/168
15/144
17/154
32/298
49/458
0.53 p=0.18
0.68 p=0.19
0.63 p=0.055
events / size
RESCUE PCI – Death or Reinfarction
Metanalysis Collect et al, JACC 2006, 48, 136
Conservative vs rescue balloon PTCA
LIMI
Belinkie
RESCUE
Total
Conservative vs rescue stent PCI
REACT
MERLIN
Total
Total
Relative Risk
10/74
2/16
4/78
16/168
8/141
26/153
34/294
50/462
Odds Ratio, random modelBilateral CI, 95 % for trials, 95 % for MA
Invasive Cons.
0 0.5 1 1.5 2 2.5 3
Treatment Better Control Better
12/75
4/12
7/73
23/160
22/144
32/154
54/298
77/458
0.62 p=0.18
0.60 p=0.033
0.60 p=0.012
events / size
Major components of time delay between onset of infarction and restoration of flow in the infarct-related artery.
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.)
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