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.)

Thank You!