REPERFUSION THERAPY FOR

ACUTE MYOCARDIAL
INFARCTION
Jason S. Go, MD, FACC
Interventional Cardiology and Peripheral Vascular Intervention
Altru Health System
 DISCLOSURES
None
 CORONARY ARTERY DISEASE
Major cause of morbidity and mortality in developed countries
2010 Heart disease and Stroke statistics
17.6 mil with CHD
8.5 mil with hx of MI
10.2 mil with angina
1/2 of all middle-age men and 1/3 of middle-age women will develop CHD
Responsible for 1/3 of all deaths among individuals > 35 years old
 CORONARY SYNDROMES
CAD with Stable angina
Unstable angina
Non-ST elevation MI (NSTEMI)
ST-elevation MI (STEMI)
 ST SEGMENT ELEVATION
MYOCARDIAL INFARCTION
Presentation in up to 33% of ACS cases
Diagnosis based on typical ST changes
Usually represent an acute thrombotic occlusion of an epicardial coronary
artery
Requires prompt recognition, triage, and reperfusion
 WHY REPERFUSION?
Addresses primary problem of acute STEMI
Improves outcomes
 REPERFUSION STRATEGIES
Pharmacologic Reperfusion
Fibrinolytic Therapy
Mechanical Reperfusion
Primary Percutaneous Coronary Intervention (Primary PCI)
FIBRINOLYTIC THERAPY
 FIBRINOLYTIC THERAPY
Plaque rupture and thrombus formation remain the primary cause of acute
vessel occlusion that leads to STEMI
Fibrinolytic therapy was a major advance in the treatment of acute STEMI
since >90% of STEMI is due to plaque rupture and subsequent thrombus
formation
Remains a viable option for reperfusion therapy due to the limited availability
of Primary PCI therapy.
 FIBRINOLYTIC AGENTS
Streptokinase
Alteplase (tPA)
Reteplase (rPA)
Tenecteplase (TNK-tPA)
 FIBRINOLYTIC AGENTS
Streptokinase
single chain polypeptide derived from beta-hemolytic streptococcus
binds to plasminogen, forming a complex that becomes an active enzyme that
cleaves peptide bonds on other plasminogen molecules
leading to plasmin activation
High doses are necessary to neutralize the plasma levels of antistreptococcal
antibodies.
1.5 million units over 60 minutes. All patients receiving streptokinase therapy for
acute MI should also receive aspirin (325 mg/day).
 FIBRINOLYTIC AGENTS
Streptokinase
Streptokinase is antigenic
Major allergic reactions are rare, with anaphylaxis occurring in less than 0.5
percent of cases. Less severe symptoms such as shivering, pyrexia, or rash may
appear in up to 10 percent.
The biologic efficacy of streptokinase is not reduced by an allergic reaction.
Hypotension may occur during streptokinase infusion and usually responds to
fluids, dopamine, or cessation or slowing of the infusion.
Bleeding is the most common complication with minor bleeding at puncture sites
occurring in 3 to 4 percent of patients.
Major bleeding is much less common, and the risk of stroke is less than 1 percent
in all patients and 1.6 percent in patients above the age of 70.
 FIBRINOLYTIC AGENTS
GISSI-I (n=11,712)
18

16

14

12
Mortality %

10

0
Overall Mortality < 1hr from symptom onset 1-3 hrs from symptom onset 3-6 hrs from symptom onset
No Treatment Streptokinase
 FIBRINOLYTIC AGENTS
ISIS-2 (n=>17,000)
14

12

10
Mortality %

0
ASA only Streptokinase only ASA + Streptokinase
Treatment Placebo
 FIBRINOLYTIC AGENTS
ALTEPLASE (recombinant tissue-type plasminogen activator, tPA)
naturally occurring enzyme (serine protease)
In contrast to streptokinase, it is fibrin-specific
fibrin-bound tPA has increased affinity for plasminogen and enhances its
activation.
Non-fibrin-bound tPA does not extensively activate plasminogen.
Short half-life (three to four minutes).
Not associated with allergic or hypotensive effects
Intravenous heparin required as concomitant therapy to maintain vessel
patency and to prevent reocclusion
 FIBRINOLYTIC AGENTS
GUSTO-I (n = >41,000)
8
7.5
7
6.5
Mortality %

6
5.5
5
4.5
4
3.5
3
Streptokinase + SQ UFH Streptokinase + IV UFH tPA + IV UFH Streptokinase + tPA
Thrombolytic Regimen
 FIBRINOLYTIC AGENTS
Benefit of accelerated tPA in acute MI
 FIBRINOLYTIC AGENTS
GUSTO-I (n = >41,000)
9

7
Mortality %

3
Streptokinase + SQ UFH tPA + IV UFH
Death + Non Fatal CVA (Net Clinical Benefit)
 FIBRINOLYTIC AGENTS
RETEPLASE (recombinant plasminogen activator, rPA)
a nonglycosylated deletion mutant of wild-type recombinant tissue-type
plasminogen activator (tPA).
Reteplase is less fibrin selective and has a longer half-life than alteplase.
Similar outcomes with Reteplase and Alteplase
 FIBRINOLYTIC AGENTS
GUSTO-III (n = 15,059)
12

10

8
Mortality %

0
Mortality Stroke Death + non fatal stroke 1 yr Mortality
Reteplase Alteplase
 FIBRINOLYTIC AGENTS
TNK-tPA (Tenecteplase)
Genetically engineered, multiple point mutant of recombinant tissue-type
plasminogen activator (tPA)
Longer plasma half-life allowing for a single intravenous bolus injection.
14 times more fibrin specific
80-fold higher resistance to inhibition by plasminogen activator inhibitor 1 (PAI-1)
than standard tPA
When compared to tPA
Similar efficacy
Modestly less bleeding risk
Easier administration
 FIBRINOLYTIC AGENTS
ASSENT-2 (n = 16,949)
35

30

25

20

15

10

0
Mortality Stroke ICH Non-Cerebral bleeding Transfusion
TNK tPA
 TIMI FLOW AND SURVIVAL
30 day mortality in the GUSTO-I trial
10
9
8
7
Mortality %

6
5
4
3
2
1
0
TIMI 0,1 TIMI 2 TIMI 3
TIMI 0,1 TIMI 2 TIMI 3
PRIMARY PCI
 PRIMARY PCI
Reperfusion method of choice for acute STEMI
Achieves a high rate of TIMI 3 flow (>90%)
Decreased risk of bleeding and stroke
Improved outcomes
 PRIMARY PCI
Primary PCI trials
Primary PCI with balloon angioplasty (PTCA) vs Fibrinolytic therapy
Primary PCI with stents vs Fibrinolytic therapy
Primary PCI with stents vs balloon angioplasty
 PRIMARY PCI
Primary PCI with balloon angioplasty vs Fibrinolytic therapy
Lower 30 day mortality (4.4 vs 6.5%)
Lower death + non-fatal reinfarction (7.2 vs 11.9%)
Lower stroke rate (0.7 vs 2.0%)
Limited value
Most contemporary PCI use stents
Older trials did not use contemporary fibrinolytic regimens
 PRIMARY PCI
Primary PCI with stents vs balloon angioplasty alone
CADILLAC and Stent PAMI trials
 PRIMARY PCI
CADILLAC (n = 2082)
45

40

35

30

25
%

20

15

10

0
Combined MACE Target Vessel Revascularization Angiographc Restenosis Reocclusion of IRA
PTCA groups Stent groups
 PRIMARY PCI
Stent PAMI (n = 900)
40

35

30

25

20
%

15

10

0
MACE Angina @ 6 months Target Vessel Revascularization Restenosis
PTCA Stent
 PRIMARY PCI
Primary PCI with stents vs fibrinolysis
Balloon angioplasty is better than fibrinolysis
PCI with stents is better than balloon angioplasty
Therefore: PCI with stents is better than Fibrinolysis
 PRIMARY PCI
Trials of PPCI + stent vs Fibrinolytic Rx
60

50

40

30
%

20

10

0
DANAMI-2* PRAGUE-2 AIR PAMI** STAT* STOPAMI-1*
Stent Fibrinolytics
CHOICE OF REPERFUSION THERAPY IN STEMI
 CHOICE OF REPERFUSION
THERAPY IN STEMI
General Concepts
Door to Needle time (D2N)
Door to Balloon time (D2B)
PCI related delay = D2B D2N
Prompt restoration of NORMAL blood flow in the infarct-related artery is
essential to myocardial salvage and mortality reduction in patients with
STEMI
Gains from reperfusion are greatest in the first few hours of symptom onset
and rapidly decline afterwards
 FACTORS AFFECTING CHOICE OF
REPERFUSION THERAPY
Time to thrombolysis and 35-day mortality
 FACTORS AFFECTING CHOICE OF
REPERFUSION THERAPY
PCI related delay
Difference between the door-to-balloon time and the door-to-needle time.
Overestimates the reperfusion delay for PCI since PCI reperfusion is immediate
while fibrinolytic therapy generally does not reestablish perfusion for about 30
minutes.
Does not reflect quality of reperfusion
Patient related factors
Non-patient related factors
 FACTORS AFFECTING CHOICE OF
REPERFUSION THERAPY
Absolute Risk Reduction in 4-6 week MORTALITY rates with Primary PCI as a
function of PCI-related time delay
 FACTORS AFFECTING CHOICE OF
REPERFUSION THERAPY
Absolute Risk Reduction in 4-6 week MACE (death, MI, CVA) rates with
Primary PCI as a function of PCI-related time delay
 FACTORS AFFECTING CHOICE OF
REPERFUSION THERAPY
Patient related factors
Age
Duration of symptoms
Location of MI
Risk status
Contraindications to Fibrinolytics
 FACTORS AFFECTING CHOICE OF
REPERFUSION THERAPY
Time at which PCI loses superiority in survival over fibrinolysis varies
depending upon patient risk

Pre-Hospital AGE < 65 years Age > 65 years

Delay (min) Anterior MI Non-Anterior Anterior MI Non-Anterior
MI MI
0-120 min 39 min 56 min 109 min 154 min
> 120 min 50 min 103 min 142 min 183 min
 FACTORS AFFECTING CHOICE OF
REPERFUSION THERAPY
ABSOLUTE Contraindications to Fibrinolytic Therapy
History of ICH
Ischemic CVA within 3 months (except acute CVA < 3hrs)
Intracranial AVM or CA
Aortic Dissection
Active Bleeding (except menstrual bleeding)
Head Trauma within 3 months
 FACTORS AFFECTING CHOICE OF
REPERFUSION THERAPY
RELATIVE Contraindications to Fibrinolytic Therapy
HTN >180/110
Ischemic CVA > 3 months ago
Dementia
Other intracranial disease
Traumatic or Prolonged CPR > 10 minutes
Major surgery in the last 3 weeks
Internal bleeding in the last 2-4 weeks or active peptic ulcer
Non-compressible vascular punctures
Pregnancy
Current anticoagulant therapy
Prior exposure to streptokinase*
 FACTORS AFFECTING CHOICE OF
REPERFUSION THERAPY
Non-patient related factors
Day and time of presentation
Weather
Local / Regional expertise
SUMMARY AND CONCLUSIONS
 SUMMARY
Fibrinolytic PROS and CONS
PROS
Ease of administration
Availability in most hospitals and EDs
Very good efficacy in the first 3 hours (particularly in the 1st hour) of symptom onset
CONS
Less effective than PCI (~40-50% TIMI 3 flow rate vs > 90% for PCI)
Risk of bleeding and disabling stroke/ICH
Markedly less effective after 3 and 6 hours
 SUMMARY
Primary PCI PROS and CONS
PROS
Very effective for reperfusion (over 90% TIMI 3 flow restoration)
Excellent long term outcomes
Efficacy is established over a broader time duration (up to 18 hours+)
Safety less bleeding and stroke
CONS
Limited availability of Primary PCI capable centers
Potential variability in outcomes with operator expertise
May not be feasible in all instances (weather, concurrent STEMIs, etc)
Other complications unique to PCI
 CONCLUSIONS
Primary PCI is the preferred reperfusion therapy for acute STEMI
Superior Efficacy (over 90% restoration of TIMI 3 flow)
Superior Safety (less stroke / bleeding)
Superior Long term outcomes (less reinfaction / restenosis)
Less impacted by patient related factors (symptom onset, etc)
Better outcomes for high risk patients
Fibrinolytic therapy should be given
If the PCI related delay is > 90 minutes
Presentation < 1 hr from symptom onset
Logistic issues (simultaneous STEMI)
THANK YOU
Time for questions?