1. Thrombolytic Therapy in AMI Overview
Dr.Vinod Sharma
National Heart Institute
New Delhi

2. STEMI represents the critical phase of Acute Coronary Syndrome
ST Elevation MI

3. 1. Time is Myocardium 2. Infarct Size is Outcome
100 D 80 60
Mortality Reduction (%) C 40 20 B A
Extent of
Myocardial Salvage 4 8 12 16 20 24
Time From Symptom Onset to Reperfusion Therapy, h
Critical Time-dependent Period
Goal: Myocardial Salvage
Time-independent Period
Goal: Open Infarct-Related Artery
Gersh BJ, et al. JAMA. 2005;293:979.

4. Wave front phenomenon of myocardial infarction propagation
(Reimer et al: Circulation 1977)
Area of necrosis compared with area of risk when artery was occluded:
At 40 minutes : 45% of myocardium irreversibly
injured.
55% of myocardium at risk was salvageable.
At 3 hours : 33% salvageable
At 6 hours : 16% salvageable
Benefit of reperfusion is time dependent from the first moment of occlusion
Denktal et al: JACC: 2011: 4: 599

5. Reduction in Long Term Mortality
We expect that this strategy will result in 15 and maybe even 20 extra lives saved per 1000 treated.
This estimate is Based on available evidence, showing that a one-hour of reduction in treatment delay
Reduces 1-yerar mortality by 14% and an observational study documenting that in our county
One-year mortality is 11% among STEMI patients treated by PCI.
Therefore, the beneficial effect of earlier reperfusion thereapy may be of the
Same magnitude as the beneficial effect obtained when we introduced aspirin instead of placebo,
Fibrinolysis instead of placebor or primary PCI instead of fibrinolysis.
Every 30-minute delay from onset of symptoms to reperfusion. 1 year mortality is increased by 8%
De Luca et al, Circulation 2004 5

6. Reperfusion is the key to save myocardium and life….
Aim is to open the blocked I.R.A. and Re -establish the coronary blood flow
Rapid
Early
Complete
Sustained

7. Reperfusion Strategy in Acute STEMI
Thrombolysis
Primary Angioplasty
Pharmaco-invasive strategy

9. Thrombolytic Therapy in STEMI
Streptokinase
1933 William Smith Tillett
1958 Sol Sherry
Changed the focus from “palliation” to “cure” in AMI

10. Consequences of activation of fibrin-bound or circulating plasminogen
Consequences of activation of fibrin-bound or circulating plasminogen. Plasminogen activators with little or no affinity for fibrin do not distinguish between fibrin-bound and circulating plasminogen. Activation of circulating plasminogen results in systemic plasminemia and subsequent degradation of fibrinogen and other clotting factors

11. Generational classification of the thrombolytic agents

14. STEMI Care in India & the Real World: Challenges Ahead
In a registry involving 50 cities, only 58.5% of patients with STEMI were thrombolysed mostly with Streptokinase and a minority received percutaneous coronary intervention (PCI).

16. Meta-analysis: No difference in mortality when all alteplase (including accelerated and non-accelerated alteplase regimens) compared with Streptokinase

17. Reteplase
A single chain, nonglycosylated peptide fibrin specific recombinant plasminogen activator derived from t-PA
It is preferentially active fibrin bound plasminogen rather than fluid phase plasminogen indicating fibrin selectivity.
___________________________________________________
Bolus administration of Reteplase results in rapid reperfusion requiring significantly shorter time to reperfusion compared to Alteplase, Streptokinase & Urokinase.

18. (1995) International Joint Efficacy Comparison of Thrombolytics
(1995) International Joint Efficacy Comparison of Thrombolytics. Randomised, double-blind comparison of reteplase double bolus administration with streptokinase in acute myocardial infarction (INJECT): trial to investigate equivalence. Lancet 346:

19. INJECT Trial
Reteplase double dose (10 U + 10 U n = 2695) was compared with standard dose of STK (1.5 million over 60 months)
Reteplase was as effective as STK in reducing mortality risk [Mortality at 35 days – 9% Vs 9.5% (STK) (Reteplase)]

20. TIMI 3 flow rate at 90 minutes
RAPID 1 Compared the three regimens of Reteplase with Alteplase infusion

21. TIMI 3 flow rate at 90 minutes
RAPID 2 Compared the efficacy of double dose Reteplase with Alteplase Infusion

23. Tenecteplase in Acute MI
TIMI – 10A Trial (1997)
Dose dependent increase in TIMI-3 flow rates in the
5-50 mg dose ranges (P = 0.032).
TIMI – 10B Patency Trial
n = 886, yrs old, bolus Inj. of TNKase achieved TIMI-3 flow rate of 55% (30 mg),
63% (40 mg)
66% (50 mg) bolus

24. Tenecteplase in Acute MI (contd)
ASSENT – 1 (1999) Safety Trial
n = 3235
Stroke rate at 30 days 1.5% & ICH
Serious bleeding (1.4% TNKase group Vs 7% Alteplase)

25. ASSENT-2 Survival Study
Tenecteplase in AMI
ASSENT-2 Survival Study
No difference between TNKase & Alteplase in mortality (6.18% Vs 6.15%) & Stroke rate including ICH (0.93% Vs 0.94%).
Tendency for ICH to be decreased by TNKase among high risk population of females > 75 years old with weight < 75 Kg (1.14% Vs 3.02%).
Mortality significantly lower in TNKase group when treatment given more than 4 hours after onset of symptoms (7.0% Vs 9.2%).

26. Efficacy & Safety of Tenecteplase in Indian patients with STEMI
I Sathyamurthy, KN Srinivasan et al, IHJ 2008

27. ELAXIM INDIAN REGISTRY
Adverse events reported
Indian Registry
ASSENT-2
Any bleeding (excluding ICH*)
4.62%
21.76%
ICH (without GpIIb/IIIa inhibitors)
0.48%
0.93%
Stroke (Non-ICH)
0.24%
1.78%
Myocardial re-infarction
3.33%
4.10%
Ventricular arrhythmias
5.71%
20.5%
Mortality (All cause)
3.48%
6.18%
* ICH = Intracranial hemorrhage

28. Favorable Pharmacokinetics; briHighest Reperfusion rates;
Ease of Use;
Favorable Pharmacokinetics; briHighest Reperfusion rates;
Agent most used in Clinical Trials
Table 3. Properties of approved fibrinolytic agents
Mehta, Textbook of
STEMI Interventions 28

29. Pre-Hospital Thrombolysis

32. French USIC 2000 survey: real world
No reperfusion
Pre-hosp TT
Hosp TT
Primary PCI
Patients
386
(30%)
155 (12%)
322 (25%)
425 (33%)
Age (year) 71 60 61
Time to admission (h)
2.8
2.4
2.2
2.1
1 year death
14.7%
3.2%
9.0%
7.9%
USIC. Circulation 2004;110:

33. Benefits of Early Administration of Thrombolytics
USIC. Circulation 2004;110: 33

34. Clinical Studies with TNKase in STEMI
Trial (Year)
Patients
Comparison
Main findings
ASSENT-4 (2006)
1,667
F-PCIc vs P-PCIb
death/ischemia/bleeding in the F-PCI group
WEST (2006)
304
TNKase vs F-PCIc vs P-PCI
TNKase and F-PCI comparable to P-PCI
GRACIA-2 (2007)
212
TNKased vs P-PCI
reperfusion with TNKase Similar ventricular damage
bP-PCI : Primary angioplasty
cF-PCI : Primary angioplasty, facilitated by TNKase
dTNKase followed by routine angioplasty within 3-12 hours (pharmaco-invasive approach)

36. STREAM SUBSTUDY – ABORTED STEMI MORE COMMON WITH STRATEGY OF EARLY FIBRINOLYSIS
ABORTED MI
Time Since Symptoms to Start of Reperfusion
Pharmaco-Invasive group
N = 99 (11.1%)
100 minutes
Primary PCI Group
N = 59 (6.9%)
P < 0.01
178 minutes

37. ABORTED MYOCARDIAL INFARCTION
ST Segment Resolution > 50% (90 minutes post TNK & 30 minutes post PCI)
Minimal Biomarker Rise (CK-MB < 2 times the ULN, T/I < 5 times the UNL)
Those who develops new pathological Q waves are excluded.

38. Comparison of 30-Day Outcomes by Treatment Strategy in STREAM Substudy
ABORTED MI
(n = 158)
No ABORTED MI (n = 1,596)
P Value
Primary Composite Endpoint Pharmacoinvasive
Primary PCI
5.1%
10.2%
12.0%
12.9%
0.38
0.545
Cardiogenic shock
Pharmacoinvasive
3.4%
4.4%
4.6%
0.26
1.00
CHF
1.0%
6.6%
7.3%
0.23
0.423
Overall 7%
12.5%
0.042

39. STREAM SUBSTUDY: ABORTION OF STEMI
ONE YEAR FOLLOW UP
All Cause Mortality
Aborted MI Vs Non-aborted MI
3.1% Vs 4.5%
(P = .818)

40. STREAM TRIAL Coronary Flow Data
> 70% of patients receiving early fibrinolysis had TIMI flow grade 2 or 3, compared with 20% of those arriving for primary PCI.
Larger clinical benefit at longer term follow up.

41. Limitations of Thrombolysis

42. Absolute contraindications
Contraindications and cautions for fibrinolytic use in ST-segment elevation myocardial infarction (STEMI)
Absolute contraindications
Any prior intracranial hemorrhage
Known structural cerebral vascular lesion (e.g. arteriovenous malformation)
Known malignant intracranial neoplasm (primary or metastatic)
Ischemic stroke within 3 months except acute ischemic stroke within 3 hours
Suspected aortic dissection
Active bleeding or bleeding diathesis (excluding menses)
Significant closed head or facial trauma within 3 months

43. Relative contraindications
Contraindications and cautions for fibrinolytic use in ST-segment elevation myocardial infarction (STEMI) (contd)
Relative contraindications
History of chronic severe poorly controlled hypertension
Severe uncontrolled hypertension on presentation (SBP > 180 mm Hg or DBP > 110 mm Hg)
History of prior ischemic stroke > 3 months, dementia, or known intracranial pathology not covered in contraindications.
Traumatic or prolonged (> 10 min) CPR or major surgery (< 3 wk)
Recent (within 2 – 4 wk) internal bleeding
Noncompressible vascular punctures
For streptokinase, anistreplase: prior exposure (> 5 days ago) or prior allergic reaction to these agents.
Pregnancy
Active peptic ulcer
Current use of anticoagulants: The higher the INR, the higher the risk of bleeding.

44. Limitations of Thrombolytic therapy in STEMI
Efficacy of thrombolysis declines rapidly with the increase in the time to treatment interval.

45. Thrombolysis in Myocardial Infarction (TIMI) – 1 Trial
Patient treated with STK showed a decrease in coronary artery patency (TIMI flow 2003) from 44% in 41 patients treated before 4 hours to 24% in 78 patients treated after 4 hours.
No difference was found in coronary patency in patient treated with tPA within (n = 41) or after 4 hours (n = 72).
Circulation 1987: 76: 147

46. Effect of Lytic Agent and Symptom Time on TIMI Grade 2 to 3 Flow at 90 minutes
Substance & Flow
0 – 180 Minutes
181 – 360 Minutes P
APSAC
Patients, n
TIMI 2 or 3, n (%)
TIMI 3, n (%)
156
114 (75.1)
95 (59.5) 46
38 (60.9)
16 (34.8)
0.09
0.004
STREPTOKINASE
133
85 (63.9)
49 (36.8) 76
39 (51.3)
21 (27.6)
0.1
UROKINASE 69
48 (69.5)
43 (62.5) 48
29 (60.5)
20 (41.7)
0.03

47. Effect of Lytic Agent and Symptom Time on TIMI Grade 2 to 3 Flow at 90 minutes (Contd…)
Substance & Flow
0 – 180 Minutes
181 – 360 Minutes P
STANDARD RECOMBINANT tPA
Patients, n
TIMI 2 or 3, n (%)
TIMI 3, n (%) 72
46 (63.9)
35 (48.6) 49
38 (77.5)
32 (63.5)
0.15
0.09
FRONT-LOADED RECOMBITANT tPA
190
165 (84.8)
138 (72.5) 86
75 (84.8)
66 (76.3) NS
RETAPLASE
118
90 (76.2)
75 (63.6) 68
52 (76.4)
43 (63.2)
APSAC indicates anisoylated plasminogen-streptokinase activator complex
ALKK STUDY GROUP – ZEYMER et al. AHJ 1999

48. Importance of time to reperfusion in patients undergoing fibrinolysis
Importance of time to reperfusion in patients undergoing fibrinolysis. For every 30-minute delay, there is a progressive increase in the in-hospital mortality rate

49. Why Thrombolysis cannot Salvage myocardium when used late after symptom onset?
Even if timely applied, blood flow in the infarct related artery is restored in only 85% of patient & only half of them regain a normal coronary blood flow (GUSTO )
GUSTO-1 Trial – the 30 day Mortality
< 2 hours – 5.5%
> 4 hours – 9%

50. Recurrent MI rates in recent fibrinolytic trials which utilized a conjunctive antithrombin strategy.
Figure 2. Recurrent MI rates in recent fibrinolytic trials which utilized a conjunctive antithrombin strategy. The sample size frequency of cointervention with urgent and non-urgent PCI and the type of antithrombin therapy used are shown, and the trials with their sample sizes are presented in ascending order of their re-MI rates. ASSENT 3 indicates ASsessments of the Safety and Efficacy of a New Thrombolytic regimen; CAPTIM, Comparison of Angioplasty and Prehospital Thrombolysis In acute Myocardial Infarction; C-PORT, Cardiovascular Patients Outcomes Research Team; DANAMI-2, DANish trial in Acute Myocardial Infarction; ENTIRE, ENoxaparin as adjunctive antithrombin Therapy for ST-elevation myocardial Infarction REsults; GUSTO V, Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries; HERO-2, Hirulog Early Reperfusion/Occlusion 2; TNK + Enox, Tenecteplase plus enoxaparin; rPA + Hep, reteplase plus heparin; tPA + Hep, tissue plasminogen activator plus heparin; and SK + Bival, streptokinase plus bivalirudin.
Paul W. Armstrong et al. Circulation. 2003;107:

51. Limitations of Thrombolytic Therapy Stroke
Fibrinolytic Therapy Trialist Collaborators (FIT)
- Thrombolysis is associated with an increase in stroke rate compared to control group (1.2% vs 0.8%)
GUSTO-1 Study
STK 1.19%
STK+ tPA 1.64%
STREAM Trial

52. Strokes and Nonintracranial Bleeding Events within 30 days

53. Limitations of Thrombolytic Therapy
AGE
Short & long term mortality increases with age
GUSTO-1 – 30 days Mortality
- < 65 yrs – 3%
- 65 – 74 yrs - 9.5%
- 75 – 85 yrs %
- > 85 yrs %
Increase in stroke, cardiogenic shock, bleeding & reinfarction
Accelerated t-PA was associated with fewer combined death or disabling stroke in all but older patients

54. PTCA vs. Fibrinolysis: Short Term Clinical Outcomes (23 RCTs)
Frequency (%)
P<0.0001
P=0.0002
P=0.0003
P<0.0001
P=0.032
P=0.0004
P<0.0001
Hem.
Stroke
Death
Death, no SHOCK data
ReMI
Rec. Isch
Stroke
Major Bleed
Death MI CVA
Keeley E. et al., Lancet 2003; 361:13-20. 54

55. Primary PCI in STEMI

56. Is there still a Role for Fibrinolysis in era of primary percutaneous Intervention?

57. Selection of Reperfusion Strategy in STEMI
Time since the onset of symptoms
Risk of Mortality from STEMI
Availability of skilled PCI Laboratory
Time required for Transport
Any contraindication to thrombolysis including bleeding, ICH
Patient preference
ACC/AHA STEMI Guidelines 2013

58. The degree of reversibility and extent of myocardial necrosis were both time dependent
Reimer 1979

59. Fibrinolytics are needed because primary PCI cannot be delivered to all patients with STEMI within evidence based time frames needed for full effectiveness.

60. Superiority of 1° PCI Over Lysis Lost After a DB − DN Delay of 114 Minutes
Fibrinolysis Better
0.8
1.25
1.5
0.5
1.0
2.0
Odds of Death
PCI Better
120 60 75 90
105
135
150
165
180
114
PCI Related Delay (DB − DN) (min)
Pinto DS, et al. Circulation. 2006;114: 60

61. Survival benefit with PPCI in STEMI is attenuated if DB time is delayed by > 1 hour beyond the DN time for thrombolytic therapy.
Longer DB-DN times would be associated with high mortality rates and reduced survival advantage.
In addition to PPCI delays, patient risk factors viz. would significantly modulate the relative survival advantage of PPCI over fibrinolysis.

62. 95.8% of patients treated after 90 minutes
Door to balloon
Door to door

63. S2D time is an average of 300 minutes
Lancet 2008; 371: 1435–42 63

64. Despite the clinical superiority of PAMI, thrombolytic therapy is the default treatment in many countries due to the practical limitations of PAMI

65. Fibrinolysis Vs PPCI – “Real World Applicability”
Country Fibrinolysis PPCI
Canada & 66% – 11%
Western Europe
UK % 11 – 21%
Germany 36 – 42% 10 – 25%
France 32 – 45% 13 – 18%
Israel & 35 – 45% 11 – 17%
Scandinavia
Australia & – 53% 8.7 – 17.4%
New Zealand
Eur J Clin Pharmacol 2009

66. Timely reperfusion is the more important than the choice of reperfusion
The timeliness of treatment with either PPCI or thrombolysis as per ACC 2007 guidelines is a strong predictor of overall mortality .
However, no association is observed with choice of reperfusion therapy.
Untimely PPCI has worse prognosis than timely fibrinolysis and untimely fibrinolysis has poor prognosis than timely PPCI.
JAMA 2010, 303 (21):

67. On-site FT better than delayed PCI
PCI-related delays are extensive among patients transferred for transfer for PCI (X-PCI) and are associated with poorer outcomes.
No differential excess in mortality was seen with X-PCI compared with on-site fibrinolysis (O-FT) even with long PCI-related delays, but as XDB door-to-needle time times increase, the mortality advantage for X-PCI over O-FT declines
Circulation. 2011;124:

68. “In the golden hour, when symptom duration is within 1 to 2 hours, prompt FT may provide clinical benefit compared with primary PCI & should be considered as a potentially preferable option”.
“Beyond this critical time window, the available data suggest that symptoms duration need not guide the choice of reperfusion therapy, provided that the Fibrinolytic drug considered for use is fibrin specific”.
Peter Bogaty: Circulation 2009

70. Reperfusion at a Non-PCI capable Hospital
Indications for Fibrinolytic therapy when there is a > 120 min delay from FMC to Primary PCI

71. Reperfusion strategy in STEMI Where are we at the dawn of 2016?
Thrombolysis Thrombolysis or Primary Angioplasty Thrombolysis And Early Angioplasty Pharmaco-invasive stragey

72. THANK YOU