India Heart Jouranl 470-475

Clinical Research Article

Limitations of Currently Available Thrombolytic Therapy

Parminder S Otaal1, K K Talwar
Post Graduate Institute of Medical Education and Research, Chandigarh

Acute ST-segment elevation myocardial infarction (STEMI) is a leading cause of mortality all over the world. In the 1970s, acute myocardial infarction (AMI) was demonstrated ,in nearly all cases to be the result of thrombotic occlusion of the coronary artery due to ruptured atherosclerotic plaque.1 Following this, Rentrop’s innovation ,in 1979, demonstrated that local infusion of streptokinase into the infarct related artery could promptly restore vessel patency and re-establish flow.2 Later, the efficacy of a high-dose brief duration intravenous infusion of streptokinase in achieving early patency of the infarct related vessel was demonstrated by Schroder et.al.3,4. A 26 % reduction in 30 day mortality in two landmark trials of GISSI-1 and ISIS-2 validated the use of streptokinase in treatment of acute myocardial infarction.5,6 Finally, the GUSTO -1 investigators demonstrated front loaded or accelerated alteplase or tPA to be superior to streptokinase in reducing mortality7 . Since then, several newer thrombolytic agents have been demonstrated to be effective but none of these has been shown to be superior to accelerated infusion of alteplase (tPA), still considered the gold standard for thrombolytic therapy.
Under certain circumstances, when thrombolytic therapy fails or it cannot be used, PCI remains the only alternative for restoring vessel patency. Although PCI has been shown to provide more complete and sustained reperfusion than thrombolysis, thrombolytic therapy still remains most commonly used reperfusion therapy all over the world, especially in regions where PCI is not feasible and particularly in first three hours of acute myocardial infarction when the more prompt reperfusion with thrombolytics may balance the superiority of PCI8.
The main goal of thrombolytic therapy is early and sustained vessel patency resulting in increased myocardial salvage, preservation of left ventricular function and lower mortality.9,10 Since the availability of streptokinase, many newer agents have been studied in clinical trials, some of which are no longer used in clinical practice. Presently, thrombolytics agents can be categorised as below11
A. First-generation thrombolytic agents
1. Streptokinase
2. Urokinase

Anisoylated plasminogen streptokinase activator complex( APSAC)

B. Second-generation thrombolytic agents

Tissue plasminogen activator (tPA; alteplase)
Single chain urokinase type plasminogen activator, scuPA / prourokinase

C. Third -generation thrombolytic agents

recombinant Tissue plasminogen activator rtPA (reteplase)
TNK (tencteplase)
lanoteplase
pamiteplase
staphylokinase

Currently available thrombolytic agents approved by US FDA for use in acute myocardial infarction are streptokinase, alteplase, tenecteplase and reteplase (Table 1).
Table 1. Currently Approved Thrombolytic Agents for Acute STEMI

	Streptokinase	Alteplase	Tenecteplase	Reteplase
Dose	1.5 million Units over 30-60 min	15 mg bolus; then 0.75mg/kg over 30 min; then 0.5mg/kg over 60 min (max 100 mg total dose)	0.53 mg/kg as a single bolus	Two 10 unit bolus doses given 30 min apart
Bolus administration	No	No	Yes	Yes
Half life (min)	23 min	<5 min	15-19min	13-16 min
Fibrin Specificity	No	+++	+++	++
Allergic reaction	1-4%	No	No	No
90 min patency rate (%)	~ 40-60 %	~ 80%	~ 80%	~ 80%
TIMI 3 Flow ( 90 min)	32%	55-60%	60%	55- 60%
ICH ~	0.5	0.8	Similar to alteplase	0.9
Adjunctive Heparin	No	Yes	Yes	Yes
Cost	+	+++	++	+++

STK Streptokinase, tPA alteplase, TNK tenecteplase, rPA reteplase, ICH-intracerebral haemorrhage.

Correspondence: Prof KK Talwar, Professor and Head , Department of Cardiology, Post Graduate Institute of Medical Education and Research, Chandigarh, India. Tel 0172-2755555, Fax 91-172-2744401
E-mail: kktalwar_chd@dataone.in

470

Indian Heart J. 2009; 61:470-475

Limitations of Currently Available Thrombolytic Therapy

THE IDEAL THROMBOLYTIC AGENT
An ideal thrombolytic agent is expected to restore normal epicardial and tissue level perfusion very rapidly, be easily administered as a bolus, have a prolonged half-life, slow plasma clearance and minimal bleeding complications. Further it would be highly fibrin specific with little or no systemic fibrinogen depletion. Despite the availability of newer agents, an ideal thrombolytic agent remains yet to be discovered.

Although thrombolytic therapy is an established cornerstone in the treatment of acute myocardial infarction, the use of these agents has important limitations which influence the selection of reperfusion strategies.

Limitations of Currently Available Thrombolytic Therapy

One of the most common and most serious limitations of fibrinolytic therapy is failure to achieve optimal reperfusion. The critical determinant of success of thrombolytic therapy is its very early administration. Patients treated within golden first hour from symptom onset have more than 50% reduction in mortality. Thereafter mortality advantage drops sharply and patients presenting beyond 12 hours derive little, if any, benefit from thrombolysis. However only small proportion of patients with acute myocardial infarction receive very early therapy. In GISSI-15 and ISIS-2 6 trials, only 10% patients were treated within golden first hour. Since the highest reduction in mortality is seen when reperfusion is started within 60-90 minutes of the onset of symptoms, transfer of patient to a centre with facility for primary angioplasty has not been shown to be superior to prehospital thrombolysis in reducing mortality8. As tenecteplase and reteplase can be administered as bolus, these two agents are suitable for prehospital thrombolysis. Tenecteplase is especially suited for this purpose since it is as efficacious and safe as tPA, more fibrin specific than reteplase, requires single bolus compared to two bolus doses of reteplase and is available in India. Though it is cheaper than tPA but the cost is still very high, beyond the reach of many patients. As transport time in the community in India usually exceeds 90 minutes, this agent has the potential to become a commonly used agent for prehospital thrombolysis.

Although public education, rapid triage of patients presenting with chest pain and prehospital thrombolysis may be helpful in overcoming some of these limitations but a short window period with thrombolytic therapy remains an important limitation.

Epicardial Reperfusion

Most of the initial data with thrombolytic therapy initially focused mainly on infarct related artery patency. About 60-80% of patients achieve recanalization with currently available thrombolytic therapy. Failure to restore infarct related artery patency with thrombolytic therapy is associated with higher rates of in-hospital mortality and morbidity and lack of recovery of left ventricular function compared to patients with successful thrombolysis.12,13. A retrospective analysis of six angiographic trials of different fibrinolytic regimens showed that patients who achieved normal (TIMI grade 3) flow in

IRA had a 30 day mortality pf 3.6% vs 6.6% in patients with slow (TIMI 2) flow and 9.5 % in patients with an occuluded artery (TIMI grade 0 or 1 flow) 14. As TIMI 3 flow has been shown to be superior to TIMI 2 flow in terms of reduction in infarct size as well as short and long term mortality, TIMI 3 flow should be the ultimate goal of reperfusion therapy15.The TIMI phase one trial revealed that t-PA was superior to streptokinase with twice the rate of open arteries at 90 minutes (70% vs 43%) independent of the baseline angiogram16 .Similar results were reported by a European Cooperative Study Group .17
Further accelerated dose regimen of alteplase (tPA) over 90 min produces more rapid thrombolysis than standard 3 hour infusion of tPA and this is considered a gold standard thrombolytic regimen available till date. Although the 90 minute patency rate has improved to ~ 80% with the use of tPA and third generation thrombolytics compared to ~40-60% with streptokinase, but TIMI 3 flow at 90 minutes still remains low ,even with third generation thrombolytics (tPA- 60% vs streptokinase- 30%) compared to PCI (>90%).

Microvascular Perfusion
With the recognition of significance of tissue level myocardial reperfusion in addition to normal epicardial coronary flow in salvaging jeopardized myocardium, latest data have focused attention on the importance of microvascular function and tissue perfusion. Even in patients who achieve normal (TIMI grade 3) epicardial flow in IRA after reperfusion therapy, adequate myocardial perfusion, as detected by myocardial contrast echocardiography, fails to occur in approximately 25% of patients. These patients have significantly less recovery of left ventricular function than patients with normal myocardial perfusion.18

One of the simple and readily available methods in cardiac catheterisation laboratory for tissue level perfusion is TIMI myocardial perfusion grade (TMPG). Gibson et. al19 showed that abnormal myocardial perfusion as assessed by TIMI myocardial perfusion grade (TMPG) 0/1/2 flow was associated with significantly higher (4.7%) 30 day mortality compared to TMPG 3 flow (0.7%) despite epicardial TIMI 3 flow in both. Thus

Indian Heart J. 2009; 61:470-475

471

K K Talwar

TMPG predicts mortality independent of epicardial blood flow.Other diagnostic tools to evaluate tissue and microvascular perfusion in patients with STEMI include Myocardial Contrast Echocardiography, Doppler flow wire, PET scanning, Nuclear SPECT imaging and MRI. The parameters of microvascular flow have been correlated with ST-segment resolution on 12-lead ECG. Greater degree of ST-segment resolution has been associated with higher degree of vessel patency and TIMI 3 flow20. Persistent ST segment elevation has been shown to indicate abnormalities of tissue level perfusion in spite of normal epicardial flow as well as it has been found to predict poor recovery of wall motion in the infarct area and clinical events including death20. Thus resolution of ST segment elevation on bedside 12 -lead ECG still remains the most useful and simple measure of epicardial and tissue level perfusion.
Microvascular dysfunction in acute myocardial infarction may be due to distil microembolisation, tissue inflammation and edema and arteriolar spasm. So in addition to sustained early epicardial patency, current and future fibrinolytic strategies must take into account microvascular perfusion at the cellular level.
Thus, with the currently available agents, thrombolytic regimens at the best achieve 90 minute patency rate of approximately 85% but complete reperfusion (TIMI Grade 3 flow) is restored in only 57% of cases. Even with restoration of normal epicardial coronary flow, adequate myocardial perfusion fails to occur in approximately 23% of patients. Additionally, reocculusion rates of 10-15% after successful thrombolysis further compromise the efficacy of thrombolytic therapy. So the currently available thrombolytic therapy achieves optimal reperfusion in only one fourth of the patients treated for acute myocardial infarction. This data depicts some of the important limitations of thrombolytic therapy, thus uncovering the illusion of reperfusion 21.

Reocclusion and Reinfarction

Reocclusion of the infarct-related artery after successful reperfusion remains a major limitation of thrombolysis and is associated with significant morbidity and up to a threefold increase in mortality.22 After successful thrombolysis, early thrombotic reocclusion still occurs in 5% to 10% of patients before hospital discharge and in up to 25% of patients by 3 months.23,24,25,26. Data from the Global Utilization of Streptokinase and t-PA for Occluded Arteries (GUSTO) 27, 28 trials showed that minimal lumen diameter, percent stenosis and lesion length and irregularity did not predict angiographic reocclusion at 5 to 7 days after thrombolysis. TIMI 4 study group however, identified several simply assessed angiographic variables, such as the presence of TIMI grade 2 flow, ulceration, collateral vessels and greater percent diameter stenosis at 90 min after thrombolytic therapy, to be associated with significantly higher rates of infarct-related artery reocculusion by 18 to 36 h 29. TAMI 5 investigators reported reocclusion rates of 14% for tPA and 6% for urokinase.30 Thus although various studies have identified some angiographic variables predictive of reocculusion but no such clinical factors have been identified as yet.
Despite the availability of newer agents, reocculusion rate still remains significantly high, thus limiting their use as reperfusion therapy in significant proportion of patients.

As the first generation thrombolytic agents are not fibrin specific, they convert circulating plasminogen to plasmin. As there is a constant equilibrium between circulating plasminogen and plasminogen in thrombus, there is depletion of plasminogen reducing

clot lysis and efficacy of the thrombolytic agents. This is known as Plasminogen steal. Fibrin specific agents have overcome this limitation and are also more effective than first generation agents31.
Early hazard is a well reported limitation of thrombolytic therapy with excess of deaths in first 24 hours, especially in patients treated >12 hours of symptom onset, although, this excess early mortality is offset by the 18% reduction in mortality by 35 days. The likely mechanisms responsible for early hazard include increased risk of myocardial rupture, fatal intracranial haemorrhage and possible reperfusion injury32.
Gentamycin sensitivity is a peculiar limitation for alteplase therapy as gentamycin is used in the prepration of alteplase.

3. Acute Myocardial infarction with Cardiogenic Shock

Thrombolytic therapy has decreased the incidence of cardiogenic shock in patients with STEMI. In three large series of patients with STEMI receiving thrombolytic therapy, the incidence of shock has ranged from 4.2-7.2 %.33 The GUSTO-1 trial revealed that t-PA is more efficacious than streptokinase in preventing shock. 34
In a STEMI patient developing cardiogenic shock, it is very important to rule out mechanical complications like acute mitral regurgitation or ventricular septal rupture as a cause of shock for selecting an optimal treatment strategy. The SHOCK registry is the only completed randomised trial which addresses the issue of aggressive revascularisation in patients with cardiogenic shock. In this trial 150 patients were randomised to medical therapy which included thrombolysis and 152 patients were assigned to revascularization by either angioplasty or CABG. The authors found that although there was no significant difference in primary end point of 30 day mortality between two groups ( 46.7% in invasive arm vs 57 % with medical therapy , p=0.11). At 6 months, however, a significant mortality benefit was observed in the invasive arm compared to medical therapy (50.3% vs 63.1%,p=0.002). 35
Unlike the situation in most patients with acute STEMI where thrombolytic therapy has been shown to limit infarct size, preserve left ventricular ejection fraction and decrease mortality, no apparent benefit has been observed in patients with cardiogenic shock secondary to left ventricular failure. Lower perfusion rates, higher reocclusion rates, associated mechanical complications or completed infarction may explain lack of benefit with thrombolytic therapy. As restoration of infarct artery patency is especially important in these patients, emergent mechanical revascularization is considered treatment of choice for patients with cardiogenic shock secondary to left ventricular failure and STEMI. 36

So present data indicate a limited role, if any, of thrombolytic therapy in patients with STEMI who develop cardiogenic shock secondary to left ventricular failure and invasive therapy remains treatment of choice in this subgroup of patients.

Role of thrombolysis in Late Presenters

The most common reason for treatment delay is the patient not seeking care promptly. The median delay to thrombolytic treatment in National Registry of Myocardial Infarction was 2.2 hours, although most common reason for not treating the patient with thrombolytic therapy was late presentation >6 hours after the onset of symptoms . Further the efficacy of thrombolytics is time dependent with their efficacy decreasing with delay

472

Indian Heart J. 2009; 61:437-439

Strategy of In Ambulance Thrombolysis Followed by Routine PCI in AMI

from onset of symptoms. Studies have shown that thrombolysis is most effective within the first golden hour and largely ineffective after 6 hours while primary PCI is largely effective at all points of time37.
The landmark LATE38 and EMERAS39 trials have demonstrated no mortality benefits when thrombolytics were routinely administered to patients between 12 to 24 hours after acute myocardial infarction. Use of these agents more than 12 hours after infarction increases the risk of cardiac rupture, especially in elderly. PCI has been shown to be superior to thrombolytics in such a situation. So it appears prudent to restrict late thrombolytic therapy, if any, to younger patients (<65 years) with ongoing ischemia.
Thus thrombolytics therapy has a limited role in patients presenting late after onset of symptoms, particularly the elderly.
5. Bleeding
Bleeding is the most common complication of thrombolytic therapy. Most bleeding is relatively minor and most serious events occur in patients who undergo invasive procedures. About three fourth of bleeding occurs at the vascular puncture sites40. More aggressive efforts to improve vessel patency with more potent regimens or with agents with increased fibrin specificity have resulted in high rates of intracerebral bleeding. Thus possibly a "ceiling" persists for vessel patency. The risk of intracranial haemorrhage (ICH) with alteplase is similar to that of tenecteplase but is higher than with streptokinase (0.7 % vs 0.5% resp).41 ICH results in significant mortality and universal disability in survivors. So these agents should be avoided in patients at high risk of ICH and primary PCI be preferred. The clinical variables know to predict increased risk of intracranial bleeding are: age >65 years, female sex, low body weight (< 70 Kg), hypertension at presentation and use of tPA as opposed to streptokinase42. Streptokinase should be preferred if patient with risk factors for ICH needs to be thrombolysed. One of the absolute contraindication for these agents is previous history of hemorrhagic cerebrovascular accidents.

6. Cost
Streptokinase is the most economical agent available, costing approximately Rs. 2000-3500 for a full dose of 1.5 million units. Mainly because of its cost, it remains the most commonly used agent in clinical practice in the country. Institute of Microbial Technology (IMTECH), Chandigarh has developed technology for recombinant

Streptokinase which was recently launched in the Indian market. Being a recombinant protein, it is free from any traces of streptolysin / streptodornase associated with natural streptokinase and is likely to further reduce the cost of streptokinase in the Indian market. A new clot specific streptokinase from the same institute is undergoing regulatory testing and is expected to be commercialised in the year 2011 (Personal communication – Dr Girish Sahni, IMTECH, Chandigarh). Urokinase is next commonly used agent, costing approximately Rs. 20,000 for full dose of 3 million units. It is usually used in situations where streptokinase cannot be used. At present, urokinase production is limited due to problems in the manufacturing process. tPA (alteplase) is the most expensive agent available ,costing approximately Rs. 90,000/- per full dose. Another currently available agent in India is Tenectaplase, costing approximately Rs. 30,000/- . Being fibrin specific and more economical but almost as efficacious as tPA, it is has a potential to become one of the commonly used thrombolytic agent in the Indian market.
This comparison shows that cost still remains a limiting factor for most of these agents except for streptokinase. Although tenecteplase is likely to overcome the cost limitation of tPA but as of now primary angioplasty appears to be more cost effective compared to tPA in India.
7. Re-adminstration
Streptokinase and APSAC, being foreign proteins, are antigenic and leads to formation of neutralising antibodies .Its subsequent use may not only reduce its efficacy but also increase the risk of hypersensitivity reactions. Jalihal et. al. 43 observed that titres of streptokinase neutralizing antibodies become enough to neutralise full standard dose 12 weeks after administration and maintain enough concentration to neutralize half the dose up to 34 weeks. Authors recommended not repeating the drug up to one year after exposure. However other authors found high titres of antistreptokinase antibodies persisting for upto 4 years after exposure and thus advised to avoid re-exposure within 4 years. 44 Practically, this limits re-usability of streptokinase beyond 5 days to 2 years of its administration. However other agents do not have this limitation and can be reused.
8. Contraindications to Thrombolytic Therapy
Only approximately 50-60 % of the STEMI patients are eligible for thrombolytic therapy. The rest may not be eligible due to delayed presentation, presence of contraindications or concerns of risk benefit raito.

Indian Heart J. 2009; 61:470-475

473

K K Talwar

Absolute and Relative Contraindications for Thrombolytic Therapy in Patients with Acute ST-segment Elevation Myocardial Infarction:
 Absolute Contraindications
Any prior intracranial haemorrhage
Ischemic stroke within the past 3 months (except for acute stroke within 3 hours)
Known structural cerebral vascular lesion
Known intracranial neoplasm
 Relative Contraindications
History of chronic, severe, poorly controlled hypertension
Systolic blood pressure >180mmHg or diastolic >110 mmHg
History of prior ischemic stroke > 3 months previously, dementia or known intracranial pathology not covered under absolute contraindications
Recent (within 2-4 weeks) internal bleeding
Non compressible vascular punctures
Pregnancy
Active peptic ulcer
Current use of anticoagulants; the higher the INR, the higher the risk of bleeding
For streptokinase/anistreplase; prior exposure > 5 days to < 2 years or prior allergic reaction to these agents
So thrombolytic therapy has a limited role in about half of STEMI patients and a primary percutaneous intervention is the only alternative in those patients.
Alfimeprase, desmoteplase and BB10153 are newer thrombolytic agents which are in phase III and phase II of development as of 2007 and may help to overcome some of the above discussed limitations of thrombolytic therapy.
Conclusion
Thrombolytic therapy remains the mainstay of reperfusion therapy in patients presenting with ST elevation myocardial infarction due to its universal availability and efficacy. The availability of extensive long term data on the efficacy and safety of these agents justifies the current recommendation for either thrombolysis or angioplasty in patients presenting within 3 hours of the onset of symptoms. Beyond this time interval, any delay in reperfusion progressively and more selectively decreases the benefit derived from thrombolytic therapy. Due to the inherent delay associated with primary angioplasty despite availability, prehospital thrombolysis may be a useful strategy in

reducing the time to reperfusion in patients treated within 2 hours of onset of symptoms. Due to its fibrin specificity, ease of administration as a single bolus, the efficacy equivalent to tPA and cost effectiveness, tenecteplase may soon become one of the commonly used thrombolytic agent in India. Despite these merits of thrombolytic therapy, there are some important limitations which have not yet been overcome even with the availability of newer third generation agents. Recognition of these limitations is of utmost clinical importance in appropriately selecting a suitable reperfusion therapy for an individual patient. Major intracerebral haemorrhage and bleeding complications limit more aggressive attempts at achieving rapid and sustained reperfusion. This creates an impression of ‘ceiling’ for beneficial effects of thrombolytic therapy. As the current data emphasises the significance of early and sustained epicardial and microvascular reperfusion in reducing mortality in acute myocardial infarction, further improvement can be achieved not only by discovery of newer agents /regimens but also by patient education and appropriate use of the existing strategies

References
1. Davies MJ, Woolf N, Robertson WB. Pathology of acute myocardial infarction with particular reference to occlusive coronary thrombi. Br Heart J 1976; 38: 659–64.
2. Rentrop KP, Blanke H, Karsch KR, Wiegand V, Kostering H, Oster H, Leitz K. Acute myocardial infarction: intracoronary application of nitroglycerin and streptokinase. Clin Cardiol. 1979;2:354-63.
3. Schroder R. Systemic versus intracoronary streptokinase infusion in the treatment of acute myocardial infarction. J Am Coll Cardiol.1983;1:1254-61.
4. Schroder R, Biamino G, von Leitner ER, Linderer T, Bruggemann T, Heitz J, Vohringer HF, Wegscheider K. Intravenous short-term infusion of streptokinase in acute myocardial infarction. Circulation. 1983;67:536-48.
5. Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI), Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction.. Lancet. 1986;1:397-402.
6. ISIS 2 (Second international study of Infarct survival ) Calloborative Group . Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet. 1988;2:349-60.
7. The GUSTO investigators. An international randomised trial comparing four thrombolytic stratgies for acute myocardial infarction.N Eng J Med 1993;329;673-682.

474

Indian Heart J. 2009; 61:470-475

Limitations of Currently Available Thrombolytic Therapy

8. Steg PG,Bonnefoy E,Chabaud S.Lapostolle F,Dubien PY,Cristofini P et.al Impact of time to treatment on mortality after prehospital fibrinolysis or primary angioplasty;data from the CAPTIM randomised clinical trial. Circulation; 2003;108:2851-2856 .
9. Gersh BJ, Anderson JL. Thrombolysis and myocardial salvage :results of clinical trials and the animal paradigm-paradoxic or predictable ? Circulation 1993;88:296-306
10. White H, Van de Werf FJJ . Clinical cardiology. New frontiers. Thrombolysis for acute myocardial infarction. Circulation 1998;97:1632-1646.
11. Khan IK,Gowda RM, Clinical perspectives and therapeutics of thrombolysis. Int J cardiol 2003;91:115-127.
12. Califf RM, Topol EJ,George BS, Boswick JM, Lee KL, Stump D et. al. Characteristics and outcome of patients in whom reperfusion with intravenous tissue-type plasminogen activator fails: results of the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) I trial; Circulation, Vol 77, 1090-1099
13. Morgan CD, Roberts RS, Haq A, Baigrie RS, Daly PA, Gent M et al. Coronary patency, infarct size and left ventricular function after thrombolytic therapy for acute myocardial infarction: results from the tissue plasminogen activator: Toronto (TPAT) placebo-controlled trial. TPAT Study Group ;J Am Coll Cardiol, 1991; 17:1451-1457
14. Cannon CP, Braunwald E .GUSTO ,TIMI and the case for rapids reperfusion. Acta Cardiol 1994;49:1-8
15. Gibson CM; Has my patient achieved adequate myocardial reperfusion? Circulation 2003;108;504
16. The Thrombolysis in Myocardial Infarction (TIMI) trial. Phase I findings. TIMI Study Group. N Engl J Med. 1985; 312:932-6.
17. Verstraete M, Bernard R, Bory M, Brower RW, Collen D, de Bono DP et al. Randomised trial of intravenous recombinant tissue-type plasminogen activator versus intravenous streptokinase in acute myocardial infarction. Report from the European Cooperative Study Group for Recombinant Tissue-type Plasminogen Activator. Lancet. 1985;1:842-7.
18. Ito H, Tomooka T, Sakai N, Yu H, Higashino Y, Fujii K et al: Lack of myocardial perfusion immediately after successful thrombolysis. A predictor of poor recovery of left ventricular function in anterior myocardial infarction , Circulation, Vol 85, 1699-1705
19. Gibson CM, Cannon CP, Murphy SA, Ryan KA, Mesley R, Marble SJ et al. TIMI study group, Circulation 2000; 101:125-130
20. de Lemos JA, Antman EM, Giugliano RP ,McCabe CS,Murphy SA,Van De Werf F et. al. ST –segment resolution and infarct related artery patency and flow after thrombolytic therapy. Thrombolysis In Myocardial Infarction(TIMI) 14 investigators.Am J Cardiol 2000;85:299-304.
21. Lincoff AM, Topol EJ. Illusion of reperfusion. Does anyone achieve optimal reperfusion during acute myocardial infarction? Circulation 1993; 87:1792-1805
22. Ohman EM, Califf RM, Topoi E J, and the TAMI Study Group. Consequences of reocclusion after successful reperfusion therapy in acute myocardial infarction. Circulation 1990;82:781-91.
23. Ellis SG, Topoi E J, George BS, Kereiakes DJ,Debowey D,Sigmon KN et al. Recurrent ischemia without warning: analysis of risk factors for in-hospital ischemic events following successful thrombolysis with intravenous tissue plasminogen activator. Circulation 1989;80:1159-65.
24. The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptoldnase, or both on coronary artery patency, ventricular function, and survival after acute myocardial infarction. N Engl J Med 1993;329:1615-22.

25. Meijer A, Verheugt FWA, Wetter CJPC,Lie KI,Van der pol JM,van Eenige MJ et al. Aspirin versus coumadin in the prevention of reocclusion and recurrent ischemia after successful thrombolysis: a prospective placebo-controlled angiographic study. Results of the APRICOT study. Circulation 1993;87:1524-30.
26. Gibson CM.Karha J,Murphy SA,James D,Morrow DA,Cannon CP et.al.Early and long term clinical outcomes associated with reinfarction following fibrinolytic administration in the Thrombolysis In Myocardial Infarction trials.J Am Coll Cardiol 2003;42:7-16
27. The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993;329: 673- 82.
28. Reiner JS, Lundergan CF, Boland J, for the GUSTO Investigators. Post thrombolytic angiographic features do not predict coronary reocclusion: observations from the GUSTO angiographic study ]abstract[. Circulation 1993;88 Suppl I:I-209.
29. Gibson CM, Cannon CP,Piana RN,Breall JA,Sharaf B, Flatley M et al ; THE TIMI 4 STUDY GROUP : J Am Coll Cardiol 1995;25:582-9
30. Califf RM,Topol EJ,George BS,Kereiakes DJ,Samaha JK,Anderson et al. :TAMI 5.A randomised trial of combination thrombolytic therapy and immediate cardiac catheterisation.Circulation 1989;80(suppl III);II-418.
31. Khan IK,Gowda RM, Clinical perspectives and therapeutics of thrombolysis. Int J cardiol 2003;91:115-127.
32. Fibrinolytic Trialist. 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. Fibrinolytic Therapy Trialists' (FTT) Collaborative Group. Lancet. 1994; 343:311-22.
33. Holmes DR Cardiogenic shock: a lethal complication of acute myocardial infarction. Rev Cardiovasc Med 2003; 4:131-135
34. Holmes DR, Bates ER, Kleiman NS, Sadowski Z ,Horgan JHS, Morris DC et.al. Contemporary reperfusion therapy for cardiogenic shock:the GUSTO 1 trial experience.J Am Coll Cardiol,1995;26:668-74
35. Hochman JS,Sleeper LA,Webb JG, Sanborn TA,White HD,Talley JD et.al. Early revascularisation in acute myocardial infarction complicated by cardiogenic shock.SHOCK Investigators.Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock.N Engl J Med 1999;341:625-634.
36. ER Bates and EJ Topol Limitations of thrombolytic therapy for acute myocardial infarction complicated by congestive heart failure and cardiogenic shock). J Am Coll Cardiol, 1991; 18:1077-1084.
37. Dalby M,Montelescot G.Transfer for primary angioplasty:who and how ?Heart 2002;88:570-572
38. LATE Study Group.Late Assesment of Thrombolytic Efficacy(LATE) study with alteplase 6-24 hours after onset of acute myocardial infarction.Lancet ;1993;342;759-766.
39. EMERAS Coollaborative Group.Randomised trial of late thrombolysis in patients with suspected acute myocardial infarction. Lancet,1993;342;767-772
40. Sane DC, Califf RM,Topol EJ ,Stump DC, Mark DB, Greenberg CS .Bleeding during thrombolytic therapy for acute myocardial infarction. Mechanism and management. Ann Intern Med 1989;111:1010-1022
41. Verstraete M.Third generation thrombolytic agents.A J Cardiol 2000;109:52-8
42. Simoons ML,Maggioni AP,Knatterud ,Leimberger JD,Schroder R,Braunwald E et al. Individual risk assessment for intracranial hemerrhage during thrombolytic therapy Lancet 1993:342:1523-8.
43. Jalihal S, Morris GK.Antistreptokinase titres after intravenous streptokinase.Lancet 1990;335:184-185
44. Elliot JM,Cross DB, Cederholm-Williams SA, White HD.Neutralising antibodies to streptokinase four years after intravenous thrombolytic therapy.Am J Cardiol,1993;71:640-645

Indian Heart J. 2009; 61:470-475

475