Thrombolytic Therapy

C. Wongvipaporn Division of Cardiology in Medical Department of Khonkaen University

Scope of Topic
Definition Coagulating pathway Pathophysiology of Thrombus Classification of Thrombolytic drugs Mechanism of Thrombolytic drugs Indication General contraindication Monitoring

Definition and History

Definition I
Thrombolytic therapy
Thrombolytic drugs: are proteins that activate a plasma proenzyme, plasminogen, to the active enzyme plasmin. Plasmin then solubilizes fibrin and degrades a number of other plasma proteins, most notably fibrogen. Fibrinolytic drugs

Definition II
Thrombolytic (clot-dissolving): eg Streptokinase, TPA. Breaks up clot by splitting fibrin Anticoagulant (Clot preventing): prevents formation of fibrin, prevents spreading of clot & formation of new clot Antiplatelet (clot preventing): prevents platelets sticking together prevents spreading of clot & formation of new clot.

Coagulating pathway

Pathophysiology of Thrombus

Myocardial infarction: Thrombosis superimposed upon atherosclerosis

Thrombus

Normal artery

Artery with lipid rich plaque

Totally occluded coronary artery

Pathophysiology

Thrombus
An acute coronary syndrome that usually results from a sudden reduction in coronary blood flow by thrombosis superimposed on atherosclerosis

Scanning electron micrograph of a thrombus

ESC/ACC, 2000
Pathophysiology

Classification of Thrombolytic drugs

Currently available thrombolytic agents

Third-generation thrombolytics tenecteplase (TNK-tPA) Second-generation thrombolytics recombinant tissue plasminogen activator (t-PA or rt-PA), reteplase (rPA) First-generation thrombolytics streptokinase, urokinase, anistreplase

Mechanism of Thrombolytic drugs

General action
Converts plasminogen to plasmin Degrades fibrin in clots. Alteplase, reteplase, and urokinase directly activate plasminogen. Anistreplase and streptokinase bind with plasminogen to form activator complexes, which then convert plasminogen to plasmin.

The ideal thrombolytic agent

Rapid acting High efficacy in terms of both 60-90 minute vessel patency and TIMI grade 3 flow Low incidence of adverse reactions, particularly bleeding and stroke Low reocclusion rate Easily administered (bolus vs infusion) Simple, patient-tailored dosage regimen Good long term effects on clinical outcome Cost-effective

Key characteristics of newer thrombolytics compared to alteplase

Characteristic Immunogenicity Plasminogen activation Fibrin specificity Plasma half-life Dose PAI-1 resistance Genetic alteration to native t-PA Alteplase (t-PA or rt-PA) No Direct ++ 4-6 min 15 mg bolus plus 90 min infusion up to 85 mg No No (recombinant version) Reteplase (rPA) No Direct + 18 min 10+10MU double bolus 30 min apart ? Yes Tenecteplase (TNK-tPA) No Direct +++ 20 min 0.5 mg/kg single bolus Yes Yes

Based on Ross AM, Clin Cardiol 1999

Drug

Loading Dose

Maintenance Dose 1.5 million IU (45 mL NaCl) 50 mg over 30 min** and 35 mg over next hr*** (100 mL sterile H2O)

Duration Of Infusion 1 hr

Concurrent Heparin No

Streptokinase

No

tPA (Alteplase)

15 mg

90 min

Yes

Given by 10 + 10 U double bolus, rPA (Reteplase) 10 U bolus over 2 min, wait 30 min and repeat 10 U over 2 min. 30-50 mg by single bolus body weight (see package insert for precise dosing)

34 min

Yes

TNK (Tenecteplase)

5-10 sec

Yes

Interfacing Heparin And Thrombolytic Agents

Drug First Step Second Step Infuse thrombolytic agent in prescribed fashion Third Step Last Step Restart heparin Infusion with or without a loading Stop dose when APTT or thrombolytic thrombin time returns to agent infusion less than twice normal (usually after 3-4 hours)

SK, UK

Stop heparin Infusion

tPA

If it is elected to discontinue heparin during tPA Infusion for PE, follow directions for the other thrombolytic agents given above.

Indication

Indication of Thrombolytic Rx
Acute management of coronary thrombosis (MI)
Symptoms <12 h and ST-segment elevation or left bundle-branch block on ECG (1A) Symptoms 12 to 24 h who have ST-segment elevation or left bundle-branch block (2B)

Massive pulmonary emboli Deep vein thrombosis Arterial thromboembolism Acute ischemic stroke

Time-to-treatment is critical to outcomes

Optimal timeline response, transportation and treatment of STEMI patients

PATIENT EMS HOSPITAL TIME

Symptoms to 911 call

Dispatch

EMS to patient

EMS to hosp

Fibrinolysis (door-to-needle)

1 h, 15 min

5 min

1 min

9 min

30 min

30 min
Door-to-balloon

90 min

2 h, 15 min

ACC/AHA Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction Executive Summary. Can J Cardiol 2004;20:977-1025.

Thrombolytic trials show consistent benefit

Trial GUSTO I GUSTO III ASSENT-2 InTIME-2 GUSTO V ASSENT-3 HERO-2 ASSENT-3 Experimental treatment Front-loaded alteplase rPA TNK-tPA Lanoteplase rPA + abciximab Half-dose TNK-tPA + abciximab Streptokinase + bivalirudin TNK-tPA + enoxaparin Control treatment Streptokinase Front-loaded alteplase Front-loaded alteplase Front-loaded alteplase rPA TNK-tPA Steptokinase + UFH TNK-tPA + UFH Exp. better Ctrl. better Exp. better Ctrl. better Exp. better Ctrl. better Death Myocardial Intracranial reinfarction haemorrhage

Adapted from: Boersma et al Lancet 2003

#1 Reason MDs cite tPA Ineligibility: Limited treatment window

Since launch, tPAs 0-3 hour treatment window has limited its uptake.
Unlike standard hospitals, Stroke Centers provide rapid triage and accurate assessment to achieve their goal of providing Activase to all eligible patients.

Patient Arrives (<1hr)

Initial ER Eval

CT Scan

More Evaluation

Door-toNeedle
60-90 min

Lytic Decision
Opportunity to give tPA because within 0-3 hr

Stroke Center

30-40 min

10-20 min

10-20 min

Standard Hospital

50-80 min

30-40 min

40-60 min

120-180 min

Cant give IV tPA because > 3 hrs

Source: Genentech Stroke Assessment Market Research, 02/2003 07/2003

Thrombolytic Therapy In Ischemic Stroke

Dosing tPA (Alteplase) In Acute Ischemic Stroke Inclusion Criteria
Duration of symptoms and findings less than 3 hours CT scan of head shows no intracranial bleeding Blood pressure not higher than 185/100 mm Hg (BP must be kept below 185/110 mm Hg during and after therapy)

tPA (Alteplase) Dose 0.9 mg/kg IV over one hour (no concurrent heparin or aspirin) Note: Patients must be carefully selected and treated within 3 hours. Other thrombolytic agents cannot be substituted for tPA. Please refer to the reference given below before using tPA in ischemic stroke. Clinical debate: should thrombolytic therapy be the first-line treatment of acute ischemic stroke? New England Journal Of Medicine 1997; 337:1309-13

Stroke - Management
Thrombolytic Agents
Streptokinase
VEGGIE trial

rPA
NINDS trial
randomized 624 patients to treatment within three hours of symptom onset with either placebo or intravenous alteplase (0.9 mg/kg up to 90 mg; 10 percent as a bolus, then a 60 minute infusion) Treatment with alteplase led to complete or near complete recovery at three months. Severe systemic hemorrhage occurred in less than 1 percent of patients.

Thrombolytic drugs in Stroke

Drugs Streptokinase Alteplase Loading Dose 1.5 mU iv in 1 hr 0.09 mg/kg (10% of the 0.9 mg/kg dose) as an I.V. bolus over 1 minute 0.81 mg/kg (90% of the 0.9 mg/kg dose) as a continuous infusion over 60 minutes. IV Infusion Dosage/Duration

Heparin should not be started for 24 hours or more after starting alteplase for stroke. Dont use aspirin or heparin during 24 hr of thrombolytic Rx

Thrombolytic in PVD
Peripheral Intra-arterial Infusion SK: 20,000 IU bolus followed by 2,000 IU/min for 60 min. UK: 6,000 IU/min for 1-2 hrs. (Both SK and UK should be given with concurrent systemic heparin.) Peripheral venous infusion SK: 250,000 units to start, then 100,000 units/hour for 2472 hours depending on location. Clotted IV Catheter Clearance with UK Inject UK 5,000 IU in 1 mL into catheter. For central venous catheter inject 5,000 IU/mL in volume equal to volume of the catheter. Allow 30-60 min for thrombolysis. Clotted AV Cannula Clearance with SK Inject SK 250,000 in 2 mL in each end of cannula. Clamp ends and allow 30-60 min for thrombolysis.

Thrombolytic drugs in PAD

IV Infusion Dosage/Duration 100,000 IU/hr for 2472 hr

Drugs Streptokinase Alteplase

Loading Dose 250,000 IU/30 min.

0.02-0.1 mg/kg/hour for up to 36 hours Advisory Panel to the Society for Cardiovascular and Interventional Radiology on Thrombolytic Therapy recommendation: < or =2 mg/hour and subtherapeutic heparin (aPTT <1.5 times baseline)

Thrombolytic drugs in Prosthetic valve

Drugs Streptokinase Loading Dose 250,000 IU over 30 min IV Infusion Dosage/Duration 100,000 IU/hr for 24 hr

Alteplase

100 mg given over a period of 25 h

After successful thrombolytic, heparin must be start.

European Heart Journal Supplements (2001) 3 (Supplement Q), Q22Q26

Thrombolytic in Massive PE
Thrombolytic therapy is indicated in patients with massive PE, as shown by shock and/or hypotension. The use of thrombolytic therapy in patients with submassive PE (RV hypokinesia) is controversial. Thrombolytic therapy is not indicated in patients without right ventricular overload.
Task Force Report, Eur Heart J 2000;21:1301

Thrombolytic drugs in PE
Drugs Streptokinase Loading Dose 250,000 IU/30 min. IV Infusion Dosage/Duration 100,000 IU/hr for 24 hr (72 hrs if concurrent DVT is suspected).

Alteplase

I.V.: 100 mg over 2 hours.

After successful thrombolytic, heparin must be start.

General contraindication

Contraindications
Aortic dissection Hypersensitivity. Cross-sensitivity with anistreplase and streptokinase may occur. Active internal bleeding History of cerebrovascular accident, Recent CNS trauma or surgery, neoplasm, or arteriovenous malformation. Severe uncontrolled hypertension and known bleeding tendencies. Pregnancy

Precautions
Recent (within 10 days) major surgery, trauma, GI or GU bleeding. Severe hepatic or renal disease. Subacute bacterial endocarditis or acute pericarditis. Use cautiously in geriatric patients. Safety not established in pregnancy, lactation, or children.

Drugs Interaction
Concurrent use with aspirin, NSAIDs, warfarin, heparins, abciximab, ticlopidine, or dipyridamole may increase the risk of bleeding, although these agents are frequently used together or in sequence. Risk of bleeding may also be increased by concurrent use with cefamandole, cefotetan, cefoperazone, plicamycin, and valproic acid.

Monitoring

Monitoring
Efficacy
AMI
Anginal free, arrhythmia, ST segment resolution, enzyme, imaging

PE
BP, Oxygination

PAD
Pain free, color, pulse, imaging

Prosthetic valve
HF, Click Echocardiography

Stroke
Neuro deficite

Side effect
Bleeding
Internal: GI, CNS, others External: puncture sites

Hypersensitive reaction

The hyperfibrinolytic effect disappears within a few hours after discontinuation, but a prolonged thrombin time may persist for up to 24 hours due to the decrease in plasma levels of fibrinogen and an increase in the amount of circulating fibrin(ogen) degradation products (FDP).

Anistreplase and streptokinase may be less effective if administered between 5 days and 6 mo of a streptococcal infection.