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Thrombolysis

Cardiovascular diseases are most common causes of mortality and morbidity among all diseases in the country. They a re also a leading causes for premature deaths and loss of working hours in the country. The most important management strategy in the patients with myocardial infarction is prompt restoration of perfusion in the intact area. Hence, it is obvious to achieve early restoration of complete infarct artery perfusion. Apart from different management plans, early and safer use of thrombolytic implementation is very essential. French investigators had performed coronary angioscopy between one and 30 days of post-MI in a 56 (Average age 55).

• One third plaques (36%) were ulcerated

• More than three-fourth plaques were yellow (higher incidences of recurring blockages)

Eligibility

The proportion of patients presenting with AMI are eligible for thrombolytic therapy has varied in reports because of eligibility criteria. Eligibility is based on the admission ECG and time window criteria or on a discharge diagnosis of myocardial infarction Patients with ineligibility for thrombolysis therapy should be considered for percutaneous.

• Chest pain consistent with angina

• ECG Changes: (1) ST 1 mm, 2 contiguous limb leads (2) ST 2mm. 2 contiguous precordial leads

• New left bundle branch block

• Absence of contraindications

Timing

The timing of the onset of ischemic symptom is the most important factor to determine occlusion and necrosis of infarct related aner? All clinical trials agree unquestionably for earl5 thrombolytic interventions. As implied benefits from treatment, one hour earlier in GUSTO-I, five lives saved per 1000 patients. It is mandatory that whichever the thrombolytic regimen is used, it is imperative to have early treatment. Treatment delays reduce all the benefits for eligible patients.

Treatment delay is possible in following group of patients:

1. Lack of public awareness

2. Elderly female

3. Diabetic patient

4 Hypertensive patient

5. Previous infarctions

6. Previous bypass surgery

Age

Advanced age has been associated with more mortality and morbidity in acute myocardial infarction. Regardless of thrombolytic therapy, the elderly patient population is associated with more mortality and intracerebral hemorrhage after thrombolytic therapy.

With all concerns related to age, physicians are more reluctant to use thrombolytic therapy in patients > 75 5'ears of age. According to American College Of  Cardiology American Heart Association's guidelines physicians should be judicious in the selection selection of older patients for thrombolysis and suggested that treatment of patients > 75 years old is not established by the available evidence.

FTT overview showed that mortality was significantly lower in patients 65 to 74 years old who had received thrombolytic therapy than in control patients(16.1% Vs 13.5%: p<--0 00001}, and there was a nonsignificant trend towards a reduction in mortality in patients:> 75 years old(25.3% Vs 24.3%).

• Higher frequency of anginal equivalents

• More nondiagnostic ECGs

• Later presentation

• Higher incidences of co-morbid disease

• Relative contraindications

In the terms, of cost effectiveness the cider population with AMI. arc likely to obtain greater benefit from thrombolytic therapy as the average number of life years life years added by treatment with accelerated alteplase is greater than younger patients. (See table)

The greater cardiac benefit of alteplase in the elderly maintains the advantage of this therapy up to the age of 85 years. For the patients >85 years of age, the best regimen in GUSTO-1 was streptokinase plus subcutaneous heparin.

Infarct Site

Benefits of the thrombolytic therapy usually related with ST-segment elevation rather than the site of the infarct. Patients with anterior or inferior infarct should receive thrombolytic therapy. In the FTT overview, patients with inferior ST-segment elevation who were randomized within 12 hours of symptom onset had a mortality reduction of 13%.

Beneficial Group of Patients

• Acute inferior wall myocardial infarction

• Acute inferior wall myocardial infarction with previous history of AMI 

• Acute inferior wall MI with anterior ST-segment depression 

• Acute inferior and right ventricular myocardial infarction

• Acute inferior myocardial infarction complicating with second- or third- degree heart block

• AMI with occlusive thrombus in circumflex artery

• True posterior wall myocardial infarction

• AMI complicating with bundle branch block

Contraindications

As thrombolytic therapy has become more widely used and the results of the all major clinical trials have confirmed its efficacy and safety. Hence, all the contraindications have widened in some instances and narrowed in other instances.

Factors Affecting Contraindications for the Thrombolytic Therapy in AMI

• Size of the infarct

• The hemodynamic status

• History' of previous infarction

• Time elapsed since symptom onset

• Patient's age

• Availability of Other Reperfusion Therapy Options

Contraindications for the Thrombolytic Therapy in AMI

Factors That Should Not Be Considered Contraindications

• Menstruation

• Nontraumatic cardiopulmonary resuscitation

• Diabetes

Controversial aspects of thrombolytic therapy in AMI-

• ST-Segment Depression:

Patients without ST-segment elevation are currently not given thrombolytic therapy. A possible explanation is pro, coagulant effect of fibrinolytic agents, which may cause progression of nonobstructive mural thrombus to complete occlusion. Theoretically, thrombolytic therapy could worsen a coronary artery stenosis by causing intraplaque hemorrhage, and a lysis of a subocclusive thrombus cause distal embolism and infarction./ Certain other clinical trials show contradictory results, therefore, it is imperative to define role of thrombolytic therapy in ischemic chest pain and deep ST-segment depression.

• Cardiogenic Shock:

In patients with cardiogenic shock, thrombolysis may be less effective. In GISSI-I and FTT clinical trials, mortality with thrombolysis was observed high. In cardiogenic shock, angioplasty is considered main therapeutic manifestation over thrombolytic therapy. In the circumstances, where angioplasty is unavailable, thrombolysis with non-fibrin specific agent streptokinase, should be given.

• Prior Coronary Artery Bypass Graft Surgery

Prior CABG is an independent predictor of a higher 30-day mortality rate

Reasons for the poor outcome in CABG patients:

1. Higher prevalence of multivessel disease

2. Impaired ventricular function

3. Lower 90-minute coronary artery patency rate after thrombolysis

4. Larger thrombi

Even with potent anti-thrombotic agents may not be able to improve significant clinical outcome.

• Pre-hospital treatment:

Pre-hospital administration of thrombolytic therapy has been proved the greatest value in scatterlv populated communities with the transport delays to the hospital >1 hour. It is imperative to have well trained staff' and defibrillators.

• Late Treatment

The window period of 12 hour time for the administration of thrombolytic therapy is now widely accepted.

• Reduces infarct size

• Improves scar formation & healing

• Decreases infarct expansion

• Decreases non-infarct zone remodeling

• Decreases left ventricular volumes

• Reduces mural thrombus formation

• Lower incidences of arrhythmias

• Provision of collateral blood flow to another infarct zones

As patients from the LATE and ASSET studies were not subdivided by ECG criteria, the benefit in patients presenting between 13 and 18 hours with ST-segment elevation or bundle-branch block could be of the order of 10 lives saved per 1000 patients treated.

Choice of Fibrinolytic Agent

It is desirable to have ideal thrombolytic agent to obtain optima_! benefits from therapeutic management plan.

Characteristics of an "Ideal' Thrombolytic Agent

• Rapid reperfusion(15-30min)
• Close to 100 % efficacy to gain reperfusion
• Can be administered through a rapid intravenous bolus
• Lower incidences of intracranial hemorrhage
• Lower incidences of systemic bleeding and other complications
• Very specific for recent thrombi
• Lower incidences of reocclusion
• Long-term sustained patency
• No antigenicity
• Acceptable cost
• No negative interaction with adjunctive treatment
 

Newer Fibrinolytic/thrombolytic Agents

Newer fibrinolytic agents are being developed to improve the efficacy of clot lysis and or ease of administration Novel plasminogen activators have been purified from natural sources with one or more of the following properties:

• Prolongation of half life

• Allowing bolus administration

• Enhanced fibrin specificity

• Resistance to natural inhibitors

Thromboxane Synthase Inhibitor

Thromboxane Receptor Blockers: Daltroban Vapiprost Fetroban (BMS 180291-1 )

Combined Thromboxane Synthase: Ridogrel (Potent)

Inhibitors and Receptor Blockers: Picotamide (Weaker)

Blockers Of The Platelet Glycoprotein

lib/ilia Receptors:

a. Monoclonal antibodies against GPilb/IIIa receptors 7E3Fab, Abciximab

b. Synthetic inhibitors of GPIIb/IIIa receptors: Eptifibatide (Intergrelin), Fradafiban (BlBU 10 XX), Lamifiban (RO 44-9883), Tirofiban(MK383), (SC-5468A)

Specific Thrombin Inhibitors:

Hirudin

Hirulog

Argatroban

Napsagatran

Inogatran

Efegatran

DuP714

Other Direct Antithrombins

Thrombolytic Drugs: Streptokinase, Acylated plasminogen-streptokinase complex, bat t-PA, Prourokinase, Uroki-nase

Tissue-type plasminogen activator (t-PA)

Mutants of t-PA: Reteplase

TNK-tPA

Monteplase (E6010)

Recombinant Chimeric Plasminogen

Activators

Desmodus Salivary Plasminogen Activator ZN 152387 recombinant DSPA product

Staphylokinase

Recombinant Staphylokinase (STAR)

Pharmaco-Clinical Properties of Newly Established Fibrinolytic Agents

Streptokinase

Streptokinase is a nonenzyme protein produced by several strains of hemolytic streptococci. It consists of a single polypeptide chain of 414 amino acids with a molecular weight of about 50,0000. It activates plasminogen to plasmin indirectly by following mechanisms:

• Formation of an equimolar complex with plasminogen

• Catalyzes the activation of plasminogen to plasmin

• Plasminogen-streptokinase molecules are converted to plasminogen-streptokinase complexes.

Almost all individuals have measurable circulating streptokinase-neutralizing antibodies, which may be because of previous infections with fi hemolytic

streptococci Hence, during thrombolytic therapy, sufficient streptokinase must be infused to neutralize these antibodies.

Anisoylated Plasminogen-streptokinase Complex (APSAC, Anistreplase)

APSAC was produced with the aim of controlling the enzymatic activity of plasminogen-streptokinase complex by a specific reversible chemical protection of its catalytic center. Anistreplase is an equimolar noncovalent complex between human Lys-plasminogen and streptokinase. It has a catalytic center located in the carboxy-terminal region of the molecule, while the Lysine-binding sites are found within the amino-terminal region of plasminogen. Thus reversible acylation of the catalytic center would thus not affect the weak fibrin-binding capacity of Lys-plasminogen in the complex.

Plasminogen Activator 

• Prourokinase, Urokinase                                         • Streptokinase

• Tissue-type Plasminogen Activator                          • Acylated plasminogen-streptokinase complex

• Mutants of I-PA                                                      • Staphylokinase

Reteplase                                                                   • bat t-PA

TNK-tPA

A plasma half-life of 70 minutes was found for anistreplase, compared with 25 minutes for the plasminogen-streptokinase complex formed in vivo after administration of streptokinase. Patients with high streptokinase antibodies do not respond to Anistreplase, and Anistreplase causes a marked increase in streptokinase antibody titer within 2 to 3 weeks, which persists for months.

This is a single-chain nonglycosylated deletion variant of rt-PA consisting only of the K2 and the protease domains of human t-PA Production of reteplase in E. Coli leads to formation of inactive protein aggregates (inclusion bodies). It is believed that fibrin binding is mediated through both the finger domain and the lysine binding site in the K2 domain of t-PA. Reteplase and t-PA are inhibited by PAI-I to a similar degree, but affinity of reteplase for binding to endothelial cells and monocytes reduced, probably as a consequence of deletion of the finger and epidermal growth factor domains in reteplase, which seem to be involved in the interaction with endothelial cell receptors.'

TNK-TPA

TNK-TPA is a genetically engineered triple-combination mutant of native tissue plasminogen activator with amino acid substitutions at the following sites:

• Replacement of threonine by an asparagine

• Above replacement is added by a glycosylation site to the position 103

• An asparagine is replaced by a glutamine; hence removes a glycosylation site from site 117

• Four amino acids, lysine, histidine, arginine, are replaced by four alanines at sites 296299.

This substitution result in a reduced plasma clearance, increased fibrin specificity, and resistance to plasminogen activator inhibitor-l. A comparison of bolus dose of TNK-TPA with accelerated 90 rain. infusion of native rt-PA demonstrated a similar plasma concentration profile for the two regimes. Based on the pharmacokinetic analysis, it appeared that a 30mg bolus dose of TNK-TPA could provide a similar plasma exposure to 100 mg of accelerated infusion of t-PA. TNK-TPA gave an encouraging initial indications that it will be angiographically efficacious(TIMI-10A). In initial phase I study, there were 4 deaths of the 113 patients (mortality=3.5%). No patients experienced a stroke and there were no cases of intracranial hemorrhages in the study. The Phase II safety trial is a randomized, open label trial, which will be conducted world wide. This safety trial will have two dose arms(30 mg and 50 mg TNK-TPA) and no t-PA arm. A total of 3000 patients will be enrolled, 1500 patients per arm. the primary end point for this trial is safety, with intracerebral hemorrhage, death, total stroke, recurrent myocardial infarction, cardiogenic shock, anaphylaxis, pulmonary edema, revascularization, and serious/life threatening bleeding complications being the prespecified end points. Based on the patency and safety data from the Phase II trials, Phase HI will be designed to compared TNK-TPA to an accelerated(90-min) infusion of Activase. The primary end point of a Phase III trial will likely be "net clinical benefit," defined as mortality plus nonfatal stroke.

Lanoteplase

Lanoteplase (or n-PA) is a deletion mutant of alteplase in which one amino acid is substituted in position 117. In the In TIME-i trial, a single 120-IU/kg bolus of

anasteplase produced 1'I%,II grade 3 flow, in 57 1o of patients compared with 40 4,0 in patients treated with alteplase, there were fewer adverse events with lanoteplase. Lanoteplase will be compared with alteplase in a large mortality trial (TIME-2), and the results should be available in early 2006.

Saruplase

Saruplase, or prourokinase, is a naturally occurring glycoprotein that is rapidly converted into Urokinase by plasmin but appears to have some intrinsic plasminogen activating potential. Compare to streptokinase, recombinant Saruplase is appeared with earlier reperfusion, higher patency rates, and slightly less fibrinogen breakdown. In the SESAM study, similar TIMI grade 2 and 3 flows were observed with Saruplase and a 3-our infusion of alteplase. In the COMPASS equivalence trial, 30-day mortality rates were observed lower with Saruplase than with streptokinase, but also increased rate of intracranial hemorrhage.

Staphylokinase

Staphylokinase, a 136 amino acid protein produced by certain strains of Staphylococcus aureus, has a unique mechanism of fibrin selectivity. It has been found as potent as alteplase, and more fibrin specific n It induces antibody formation and resistance to repeated administration. Its immunogenicity can be reduced by site directed mutagenesis. Recombinant Staphylokinase (STAR) was very impressive for venous clot lysis in animal studies with comparable results than that of streptokinase. lt is more potent than streptokinase towards platelet rich clots and it is potentially less immunogenic.

Recycling of staphylokinase to fibrin bound plasminogen, after neutralization of the complex. 9,411 result in more efficient generation of active complex.

Recombinant Chimeric Plasminogen Activators

Recombinant Chimeric plasminogen activators have been constructed primarily using different regions of t-PA and scu-PA. One important variant is K1K2Pu. Preliminary trial suggests that two bolus injections of 10 mg K1K2Pu may produce fibrin specific coronary thrombolysis.

Desmodus Salivary Plasminogen Activator

The saliva of vamp ire bats contains variety of factors that presumably satisfy two essential properties; (l) Maintain prolonged bleeding time (2)Blood fluidity. Different molecular forms have been purified from Desmodus Salivary plasminogen activator (DSPS).

DSPA ₁ (Mr 43) High molecular form, 85% homology to human t-PA

DSPA ₂ (Mr 39)

DSPA Lacks finger-like structure

DSPA Lacks finger and epidermal growth factor structure

Clopidogrel Bisulfate

Clopidogrel Bisulfate is new antiplatelet agent of thienopyridines class, which acts by direct inhibition of adenosine diphosphate (ADP) by binding to its receptor and subsequent ADP-mediated activation of the glycoprotein GP IIb/IIIA complex?

Thrombolysis

Recommendations:

Class I 

1. ST elevation (Greater than 0.1 mV in two or more continuous leads at any time during the observation period

2. Time to the therapy 12 hour or less since the onset of symptoms

3. Age less than 75 years

4. Bundle branch block (With AMI) 

Class IIa  

1. ST elevation, age 75 years or older 

Class IIb 

1. ST elevation, time to therapy (as above) greater than 12 to 24 hour

2. Blood pressure on presentation greater than 180 mmHg systolic and/or greater than 110 mmHg diastolic with high risk of MI

3. ST segment elevation, time to therapy greater than 24 hour. ischemic pain resolved

4. ST-segment depression only