FIBRINOLYTIC THERAPY

1. FIBRINOLYTIC THERAPY:
PHYSICIAN’S POINT
DR. SANDEEP BANSAL
DM (Cardiology), DNB (Cardiology), MNAMS,
FESC, FSCAI,FAPSIC
PROFESSOR AND HEAD OF DEPARTMENT
Department of Cardiology
Vardhman Mahavir Medical College & Safdarjung Hospital ,
New Delhi

2. RECAP

3. A History of Streptokinase Use in Acute Myocardial
Infarction Nikhil Sikri Amit Bardia Tex Heart Inst J 2007;34:318-27)
In 1958, Sherry and others started using streptokinase in
patients with Acute Myocardial Infarction and changed the
focus of treatment from palliation to “cure.”

4. GISSI-1: Streptokinase 18% reduction in
mortality at 21 d.

5. In ISIS-2, 35-day survival benefits obtained with combination
streptokinase and aspirin (55 fewer deaths per 1,000) persisted through
ten years of follow-up (42 fewer deaths per 1,000). In GISSI-I, an
absolute benefit of 19 lives saved/1,000 patients treated through ten
years was evident.
Ten-year survival in GISSI-1 and ISIS-2 .

6. Brief Review of Thrombolytic Trials
GISSI-1:
Streptokinase 18% reduction in mortality at 21 d
GUSTO-1:
tPA gives 15% reduction in 30-day mortality compared to Streptokinase
Inject trial :
Reteplase equivalent to streptokinase
GUSTO-3:
Reteplase had no benefit over tPA but is easier to use (double bolus).tPA
better than reteplase beyond 4 hours.
ASSENT 2:
TNKase is similar to tPA but with less non-cerebral bleeding and better
mortality with symptoms>4 hrs: Single bolus, fibrin selective, resistance to
PAI-1
*Overall risk of ICH is 0.7%; Strokes occurred in 1.4%

7. WHICH THROMBOLYTIC – GUSTO I
Califf R et al. Circulation 1996;94:1233-1238
14%
RRR
6.3%
Alteplase
7.2%
Streptokinase
V/S
30 Day
Mortality
9.1%
Alteplase
10.1%
Streptokinase
1 year
Mortality
Across all the subgroup of patients Alteplase was either superior or was better than STK

8. INJECT study main results
35 days
Mortality
Total Stroke
From which hemorrhagic
Total Stroke
≤ 75 yrs
> 75 yrs
6 Months Mortality
Streptokinase
(n = 3004)
9,53%
1%
0,37%
0,8%
2,5%
12,05%
Reteplase
(n = 3006)
9,02%
1,23%
0,77%
1,1%
2,6%
11,02%
p
NS
NS
NS
NS
NS
Equivalence Proven
Lancet 1995 ; 346 : 329 -336

9. The mortality rate at 30 days was 7.47
percent for reteplase and 7.24 percent for
alteplase (adjusted P =0.54)
GUSTO III study: Reteplase versus Alteplase
in reducing 30 day mortality

10. Single-bolus tenecteplase compared with front-loaded
alteplase in acute myocardial infarction: the ASSENT-2
double-blind randomised trial Lancet 1999; 354: 716–22

11. Summary of evidence
Thrombolytic in STEMI Parameter Study
Alteplase > Streptokinase 30 day mortality GUSTO-I
Alteplase > Streptokinase  90 minute patency
 Left ventricular function
GUSTO Angiographic study
Tenecteplase = Alteplase 90 min patency rate & 30
day mortality
TIMI 10 B & ASSENT 2
Tenecteplase > Alteplase Significant fewer bleeds ASSENT 2
Reteplase = Streptokinase 35 day mortality INJECT
Reteplase < Alteplase
&Tenecteplase (beyond 4
hours of symptom onset)
30 day mortality GUSTO-III & ASSENT 2

12. PHYSICIAN’S POINT-1
WHY THROMBOLYSE WHEN ANGIOPLASTY IS
THE BEST TREATMENT

13. 30 Day Mortality with Reperfusion Therapy
in AMI
Meta-Analysis Comparison
13
11.5%
9.6%
6.5%
4.4%
0%
5%
10%
15%
Placebo Lytic Lytic PTCA
11 PTCA-lytic trials
(n=2,606) - PCAT
9 placebo controlled
lytic trials (n=58,800)
FTT:
17%; p<0.0001
34%; p=0.02
Death, %

14. US Hospitals with Angioplasty Services
Only 39% of U.S. Hospitals Have Primary
Angioplasty Services- 2013

16. A comparison of AMI scenario in India
vs developed countries

17. CREATE REGISTRY

18. AMBULANCE PHT, PHT, PPCI OR IHT
CAPTIM- thrombolysis within 2 h of symptom onset showed a strong
trend towards lower 30 day mortality than those who had
undergone PPCI.
PRAGUE- within 3 h of symptom onset, mortality rates were almost
identical

20. NORDISTEMI
•Primary PCI is the preferred treatment of STEMI
•However, in many areas of the world, primary PCI cannot be
performed within the recommended time limits (<90-120 min)
•In these remote areas, thrombolysis is still the treatment of choice
•Optimal treatment after thrombolysis for STEMI in rural areas
remains unclear
Acute STEMI < 6 hours
Expected time delay to PCI > 90 min
≤ 75 years
Aspirin 300 mg, Tenecteplase (TNK)
Enoxaparin 30 mg iv + 1mg/kg sc, Clopidogrel
300mg
Immediate transfer
for angiography/PCI
Ischemia-guided treatment
in local hospitals with transfer
for rescue PCI if needed

21. Reperfusion therapy for STEMI: is there still a role
for thrombolysis in the era of primary percutaneous
coronary intervention?
• In 19 012 matched STEMI patients from the National Registry of
Myocardial Infarction database, the delay to PCI wherein the
mortality advantage for X-PCI was nullified compared with O-FT
was approximately 120 min. Extensive delays were found to
attenuate the mortality benefit of X-PCI [number needed to treat
(NNT) 23 for PCI-related delay >60 min; NNT 44 for PCI-related
delay 60-90 min; and NNT 250 for PCI-related delay >90 min].

22. For STEMI patients with symptom duration ≤ 6 hours, we suggest
administration of fibrinolytics either
• tenecteplase (Grade1A),
•reteplase (Grade1B),
•alteplase (Grade1C) or
•streptokinase (Grade 2B) alongside contemporary adjunctive medical
therapy for PI approach.

23. •DANAMI 2- indicate that the three quarters of patients receiving
fibrinolysis alone with TIMI risk scores < 5 fared equally well to those
undergoing primary PCI.
•Dose of tenecteplase = 50% in patients ≥ 75 years –improved safety
profile.
•A low cost fibrinolytic agent e.g. streptokinase and aspirin- well
established and far superior to no reperfusion therapy at all.
• This the “minimum standard of care” well aligned with the still-
current admonition from the 2004 ACC/AHA STEMI guidelines i.e. that
“the appropriate and timely use of some form of reperfusion therapy is
likely more important than the choice of therapy”.

24. WHAT IS THE IMPORTANCE OF TIMI RISK SCORE<5

25. Selection of a strategy for reperfusion
Primary PCI—defined as an emergent percutaneous catheter
intervention in the setting of STEMI, without previous fibrinolytic
treatment—is the preferred reperfusion strategy in patients with
STEMI, provided it can be performed expeditiously (i.e. within
guideline-mandated times), by an experienced team, and regardless of
whether the patient presents to a PCI-capable hospital

27. PHYSICIAN’S POINT-2
SO WHAT DO WE KNOW ABOUT THROMBOLYSIS

28. Benefit of thrombolytic therapy:
FTT Collaborative Group meta-analysis
Fibrinolytic Therapy Triallists’ (FTT) Collaborative Group: Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview
of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Lancet 1994; 343:311-322

29. Thrombolytics for AMI
Benefits
• Widespread availablity
• 12-17% survival benefit
• Preserves LVEF
Limitations
• 20% of vessels remain occluded
• 45% have TIMI flow< 3
• Median time to reperfusion is 45 minutes
• No reliable marker of reperfusion
• Recurrent ischemia occurs in 15-30%
• Intracranial bleeds occur in 0.5-1.5%

31. Fibrinolytic Agents
First Generation
• SK: streptokinase
• u-PA: urokinase
• (APSAC: anistreplase)
Second Generation
• rtPA: alteplase
• rPA: reteplase
rscu-PA: prourokinase
saruplase
A-74187
on the market
in development
Third Generation
• TNK-tPA: tenecteplase
nPA: lanoteplase
E6010: monteplase
YM866: pamiteplase
DSPAa1: vampire bat tPA
• K2tu-PA: amediplase
• PEG-Sak: pegylated variants of
staphylokinase e.g. SY161-P5 SY19-P5

32. Characteristics of the Ideal Fibrinolytic Agent
• Long half-life/single-bolus administration
• High fibrin specificity/decreased bleeding and ICH
• Rapid and consistent achievement of TIMI grade 3
flow
• No effect on blood pressure
• No antigenicity
• No re-occlusion
• Great resistance to PAI-1
• Low cost
• Compatible with other intravenous agents

34. PHYSICIAN’S POINT-2
COSTEFFECTIVENESS OF TENECTEPLASE AS
THROMBOLYTIC

35. FEATURE STK
TNK/TP
A DIFF. IMPLICATION
< 75 years 1 more life saved per 100
> 75 years 2 more lives saved per 100
Anterior Wall MI ~2 more lives saved per 100
>2 Units blood
transfused 6.00% 1.66% 4.34%4 patients saved per 100
Cardiogenic Shock 6% 3.90% 2.40%2 patients saved per 100
Allergic Reactions 6% 1.60% 4.20%4 patients saved per 100
Ventricular Tachycardia 6.50% 5.60% 0.90%1 patients saved per 100
Ventricular Fibrillation 6.90% 6.30% 0.60%1 patient saved per 100
Asystole 6.40% 5.30% 1.10%1 patient saved per 100
Sustained Hypotension 12.50%10.10% 2.40%2 patients saved per 100
COST EFFECTIVENESS OF TREATMENT

36. FEATURE STK
TNK/
TPA
DIF
F. REMARKS
Atrial Fibrillation or
Flutter 9.80%
8.60
%
1.2
0%1 patient saved per 100
Thrombolysis Failure
rate
38%-
56.8%
14%-
28%
Acute Mitral
Regurgitation 2.60%
0.60
%
2.0
0%2 patients saved per 100
Ventricular Septum
defect 0.40%
0.30
%
0.1
0%
Anaphylaxis 0.60%
0.10
%
0.5
0%1 patient saved per 200 treated
Congestive heart failure 16.80%
15.2
0%
1.6
0%Nearly 2 patients treated saved per 100
AV Block 8.70%
7.30
%
1.4
0%3 patients saved per 200 treated
Avg. no. of days of
hospitalisation 8-14 days
4-10
days
COST EFFECTIVENESS OF TREATMENT

37. COST EFFECTIVENESS OF TREATMENT
• 1 MORE LIFE SAVED PER 100 PATIENTS TREATED
PROMPTED AGENCIES IN US TO ACCEPT tPA AS
STANDARD MODE OF THERAPY.
• WE HAVE NOW AN AGENT THAT IS
– AS EFFICACIOUS,
– SAFER,
– EASIER TO ADMINISTER
– HAS COST DIFFERENCE THAT IS LESS
– BENEFITS IN PHARMACOINVASIVE

38. THANK YOU