REPERFUSION THERAPY FOR ACUTE 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 disease and 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 among individuals > 35 years old CORONARY SYNDROMES

• CAD with Stable 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 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

• • (tPA) • (rPA) • (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 (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

10

8

Mortality % Mortality 6

4

2

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

8

6 Mortality % Mortality 4

2

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 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 6 5.5

5 Mortality % Mortality 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

8

7

6

Mortality % Mortality 5

4

3 Streptokinase + SQ UFH tPA + IV UFH + 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

6

Mortality % Mortality 4

2

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

5

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 6 5

4 Mortality % Mortality 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 (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

5

0 Combined MACE Target Vessel Angiographc Restenosis Reocclusion of IRA PTCA groups Stent groups PRIMARY PCI

Stent PAMI (n = 900) 40

35

30

25

% 20

15

10

5

0 MACE Angina @ 6 months Target Vessel Revascularization Restenosis PTCA Stent PRIMARY PCI

• Primary PCI with stents vs • 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 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 in the last 3 weeks • Internal bleeding in the last 2-4 weeks or active peptic ulcer • Non-compressible vascular punctures • Pregnancy • Current 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?