ThrombolyticThrombolytic TherapyTherapy

C. WongvipapornC. WongvipapornDivision of Cardiology in Medical Division of Cardiology in Medical

Department of Department of KhonkaenKhonkaen UniversityUniversity

Scope of TopicScope of Topic

DefinitionDefinitionCoagulating pathwayCoagulating pathwayPathophysiologyPathophysiology of Thrombusof ThrombusClassification of Classification of ThrombolyticThrombolytic drugsdrugsMechanism of Mechanism of ThrombolyticThrombolytic drugsdrugsIndication Indication General contraindicationGeneral contraindicationMonitoringMonitoring

Definition and HistoryDefinition and History

Definition IDefinition I

ThrombolyticThrombolytic therapytherapyThrombolyticThrombolytic drugsdrugs: : areare proteinsproteins thatthat activateactivatea a plasmaplasma proenzymeproenzyme,, plasminogenplasminogen,, toto thetheactiveactive enzymeenzyme plasminplasmin.. PlasminPlasmin thenthensolubilizessolubilizes fibrinfibrin andand degradesdegrades a a numbernumber ofofotherother plasmaplasma proteinsproteins,, mostmost notablynotably fibrogenfibrogen..FibrinolyticFibrinolytic drugsdrugs

Definition IIDefinition II

ThrombolyticThrombolytic (clot(clot--dissolving):dissolving): egegStreptokinase, TPA. Breaks up clot by Streptokinase, TPA. Breaks up clot by splitting fibrinsplitting fibrinAnticoagulant (Clot preventing):Anticoagulant (Clot preventing): prevents prevents formation of fibrin, prevents spreading of formation of fibrin, prevents spreading of clot & formation of new clot clot & formation of new clot AntiplateletAntiplatelet (clot preventing):(clot preventing): prevents prevents platelets sticking together prevents platelets sticking together prevents spreading of clot & formation of new clot. spreading of clot & formation of new clot.

Coagulating pathwayCoagulating pathway

PathophysiologyPathophysiology of of ThrombusThrombus

Myocardial infarction: Thrombosis Myocardial infarction: Thrombosis superimposed upon atherosclerosissuperimposed upon atherosclerosis

Normal artery Artery with lipid rich plaque

Totally occluded coronary artery

Thrombus

Pathophysiology

ThrombusThrombusAn acute coronary An acute coronary syndrome that syndrome that usually results from usually results from a sudden reduction a sudden reduction in coronary blood in coronary blood flow by thrombosis flow by thrombosis superimposed on superimposed on atherosclerosisatherosclerosisScanning electron Scanning electron

micrograph of a micrograph of a thrombusthrombus

ESC/ACC, 2000Pathophysiology

Classification of Classification of ThrombolyticThrombolytic drugsdrugs

Currently available thrombolytic agentsCurrently available thrombolytic agents

Third-generation thrombolyticstenecteplase (TNK-tPA)

Second-generation thrombolyticsrecombinant tissue plasminogen activator (t-PA or rt-PA), reteplase (rPA)

First-generation thrombolyticsstreptokinase, urokinase, anistreplase

Mechanism of Mechanism of ThrombolyticThrombolyticdrugsdrugs

General actionGeneral action

Converts Converts plasminogenplasminogen to to plasminplasminDegrades fibrin in clotsDegrades fibrin in clots. . AlteplaseAlteplase, , reteplasereteplase, and , and urokinaseurokinasedirectly activate directly activate plasminogenplasminogen. . AnistreplaseAnistreplase and streptokinase bind with and streptokinase bind with plasminogenplasminogen to form activator complexes, to form activator complexes, which then convert which then convert plasminogenplasminogen to to plasminplasmin. .

The ideal The ideal thrombolyticthrombolytic agentagent

•• Rapid actingRapid acting•• High efficacy in terms of both 60High efficacy in terms of both 60--90 minute 90 minute

vessel vessel patencypatency and TIMI grade 3 flowand TIMI grade 3 flow•• Low incidence of adverse reactions, Low incidence of adverse reactions,

particularly bleeding and strokeparticularly bleeding and stroke•• Low Low reocclusionreocclusion raterate•• Easily administered (bolus Easily administered (bolus vsvs infusion)infusion)•• Simple, patientSimple, patient--tailored dosage regimentailored dosage regimen•• Good long term effects on clinical outcomeGood long term effects on clinical outcome•• CostCost--effectiveeffective

Key characteristics of newer thrombolyticscompared to alteplase

Key characteristics of newer thrombolyticscompared to alteplase

Based on Ross AM, Clin Cardiol 1999

YesYesNo (recombinant version)

Genetic alteration to native t-PA

Yes?NoPAI-1 resistance

±0.5 mg/kg single bolus

10+10MU double bolus 30 min apart

15 mg bolus plus 90 min infusion up to 85 mg

Dose

20 min18 min4-6 minPlasma half-life

++++++Fibrin specificity

DirectDirectDirectPlasminogen activation

NoNoNoImmunogenicity

Tenecteplase(TNK-tPA)

Reteplase(rPA)

Alteplase(t-PA or rt-PA)

Characteristic

Drug Loading Dose Maintenance Dose

Duration Of Infusion

Concurrent Heparin

Streptokinase No 1.5 million IU (45 mL NaCl) 1 hr No

tPA (Alteplase) 15 mg

50 mg over 30 min** and 35 mg over next hr*** (100 mL sterile

H2O)

90 min Yes

rPA (Reteplase)Given by 10 + 10 U double bolus, 10 U bolus over 2 min, wait 30 min and repeat 10 U over 2 min.

34 min Yes

TNK (Tenecteplase)

30-50 mg by single bolus body weight(see package insert for precisedosing)

5-10 sec Yes

Interfacing Heparin And Interfacing Heparin And ThrombolyticThrombolytic Agents Agents

Drug First Step Second Step Third Step Last Step

SK,UK

StopheparinInfusion

Infusethrombolytic

agent inprescribed

fashion

Stopthrombolytic

agent infusion

Restart heparin Infusionwith or without a loading

dose when APTT orthrombin time returns toless than twice normal(usually after 3-4 hours)

tPAIf it is elected to discontinue heparin during tPA Infusion for PE, followdirections for the other thrombolytic agents given above.

IndicationIndication

Indication of Indication of ThrombolyticThrombolytic RxRx

Acute management of coronary thrombosis Acute management of coronary thrombosis ((MIMI))Symptoms <12 h and STSymptoms <12 h and ST--segment elevation or left segment elevation or left bundlebundle--branch block on ECG (1A)branch block on ECG (1A)Symptoms 12 to 24 h who have STSymptoms 12 to 24 h who have ST--segment segment elevation or left bundleelevation or left bundle--branch block (2B)branch block (2B)

Massive pulmonary emboli Massive pulmonary emboli Deep vein thrombosisDeep vein thrombosisArterial Arterial thromboembolismthromboembolismAcute ischemic strokeAcute ischemic stroke

TimeTime--toto--treatment is critical to outcomestreatment is critical to outcomes

Optimal timeline – response, transportation and treatment of STEMI patients

ACC/AHA Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction – Executive Summary. Can J Cardiol2004;20:977-1025.

5 min 1 min 9 min 30 min

PATIENT EMS HOSPITAL TIME

Fibrinolysis(door-to-needle)

≤ 30 min1 h, 15 min

Symptoms to 911 call

Dispatch EMS EMSto patient to hosp

2 h, 15 minDoor-to-balloon

≤ 90 min

Thrombolytic trials show consistent benefitThrombolytic trials show consistent benefit

Adapted from: Boersma et al Lancet 2003

Ctrl. better

Exp. better

Myocardial reinfarction

Ctrl. better

ASSENT-3HERO-2

Ctrl. better

Exp. better

Exp. better

ASSENT-3GUSTO VInTIME-2ASSENT-2GUSTO IIIGUSTO I

Intracranial haemorrhage

Death

TNK-tPA + UFHSteptokinase + UFHTNK-tPArPAFront-loaded alteplaseFront-loaded alteplaseFront-loaded alteplaseStreptokinase

Control treatment

TNK-tPA + enoxaparinStreptokinase + bivalirudinHalf-dose TNK-tPA + abciximabrPA + abciximabLanoteplaseTNK-tPArPAFront-loaded alteplase

Experimental treatmentTrial

#1 Reason MDs cite tPA Ineligibility:#1 Reason MDs cite tPA Ineligibility:““Limited treatment windowLimited treatment window””

Since launch, tPA’s 0-3 hour treatment window has limited its uptake.

Initial ER Eval

CT Scan

Lytic Decision

MoreEvaluation

Stroke Center

Standard Hospital

60-90 min

120-180min

30-40min

10-20min

10-20min

50-80min

30-40min

40-60min

Door-to-Needle

Opportunity to give tPA

because within 0-3 hr

Patient Arrives (<1hr)

Can’t give IV tPA because

> 3 hrs

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

Unlike standard hospitals, Stroke Centers provide rapid triage and accurate assessment to achieve their goal of providing Activase to all eligible patients.

ThrombolyticThrombolytic Therapy In Therapy In Ischemic StrokeIschemic Stroke

Dosing Dosing tPAtPA ((AlteplaseAlteplase) In Acute Ischemic Stroke) In Acute Ischemic StrokeInclusion CriteriaInclusion Criteria

Duration of symptoms and findings less than 3 hours Duration of symptoms and findings less than 3 hours CT scan of head shows no intracranial bleeding CT scan of head shows no intracranial bleeding Blood pressure not higher than 185/100 mm Hg (BP must be kept beBlood pressure not higher than 185/100 mm Hg (BP must be kept below low 185/110 mm Hg during and after therapy) 185/110 mm Hg during and after therapy)

tPAtPA ((AlteplaseAlteplase) Dose) Dose0.9 mg/kg IV over one hour (no concurrent heparin or aspirin) 0.9 mg/kg IV over one hour (no concurrent heparin or aspirin)

Note: Patients must be carefully selected and treated within 3 hNote: Patients must be carefully selected and treated within 3 hours. ours. Other Other thrombolyticthrombolytic agents cannot be substituted for agents cannot be substituted for tPAtPA. Please . Please refer to the reference given below before using refer to the reference given below before using tPAtPA in ischemic in ischemic stroke.stroke.

Clinical debate: should Clinical debate: should thrombolyticthrombolytic therapy be the firsttherapy be the first--line line treatment of acute ischemic stroke? New England Journal Of treatment of acute ischemic stroke? New England Journal Of Medicine 1997; 337:1309Medicine 1997; 337:1309--1313

Stroke Stroke -- ManagementManagement

Thrombolytic AgentsThrombolytic AgentsStreptokinaseStreptokinase

VEGGIE trialVEGGIE trial

rPArPANINDS trialNINDS trial

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

Drugs Loading Dose IV Infusion Dosage/Duration

Streptokinase 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.

Alteplase

Heparin should not be started for 24 hours or more after starting alteplase for stroke.

Don’t use aspirin or heparin during 24 hr of thrombolytic Rx

ThrombolyticThrombolytic drugs in Strokedrugs in Stroke

ThrombolyticThrombolytic in PVDin PVDPeripheral IntraPeripheral Intra--arterial Infusionarterial Infusion

SK: 20,000 IU bolus followed by 2,000 IU/min for 60 min.SK: 20,000 IU bolus followed by 2,000 IU/min for 60 min.UK: 6,000 IU/min for 1UK: 6,000 IU/min for 1--2 hrs. 2 hrs. (Both SK and UK should be (Both SK and UK should be

given with concurrent systemic heparin.)given with concurrent systemic heparin.)Peripheral venous infusionPeripheral venous infusion

SK: 250,000 units to start, then 100,000 units/hour for 24SK: 250,000 units to start, then 100,000 units/hour for 24--72 hours depending on location.72 hours depending on location.Clotted IV Catheter Clearance with UKClotted IV Catheter Clearance with UK

Inject UK 5,000 IU in 1 Inject UK 5,000 IU in 1 mLmL into catheter. For central into catheter. For central venous catheter inject 5,000 IU/venous catheter inject 5,000 IU/mLmL in volume equal to in volume equal to volume of the catheter. Allow 30volume of the catheter. Allow 30--60 min for 60 min for thrombolysisthrombolysis. . Clotted AV Clotted AV CannulaCannula Clearance with SKClearance with SK

Inject SK 250,000 in 2 Inject SK 250,000 in 2 mLmL in each end of in each end of cannulacannula. Clamp . Clamp ends and allow 30ends and allow 30--60 min for 60 min for thrombolysisthrombolysis..

Drugs Loading Dose IV Infusion Dosage/Duration

Streptokinase 250,000 IU/30 min. 100,000 IU/hr for 24-72 hr

Alteplase • 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)

ThrombolyticThrombolytic drugs in PADdrugs in PAD

Drugs Loading Dose IV Infusion Dosage/Duration

Streptokinase 250,000 IU over 30 min 100,000 IU/hr for 24 hr

Alteplase 100 mg given over a period of 2–5 h

After successful thrombolytic, heparin must be start.

ThrombolyticThrombolytic drugs in Prosthetic valvedrugs in Prosthetic valve

European Heart Journal Supplements (2001) 3 (Supplement Q), Q22–Q26

ThrombolyticThrombolytic in Massive PEin Massive PE

ThrombolyticThrombolytic therapy is indicated in therapy is indicated in patients with massive PE, as shown by patients with massive PE, as shown by shock and/or hypotension.shock and/or hypotension.The use of The use of thrombolyticthrombolytic therapy in patients therapy in patients with with submassivesubmassive PE (RV PE (RV hypokinesiahypokinesia) is ) is controversial.controversial.ThrombolyticThrombolytic therapy is not indicated in therapy is not indicated in patients without right ventricular overload. patients without right ventricular overload.

Task Force Report, Eur Heart J 2000;21:1301

Drugs Loading Dose IV Infusion Dosage/Duration

Streptokinase 250,000 IU/30 min. 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.

ThrombolyticThrombolytic drugs in PEdrugs in PE

General contraindicationGeneral contraindication

ContraindicationsContraindicationsAortic dissectionAortic dissectionHypersensitivityHypersensitivity. . CrossCross--sensitivity with sensitivity with anistreplaseanistreplase and and streptokinase may occurstreptokinase may occur. . Active internal bleedingActive internal bleedingHistory of History of cerebrovascularcerebrovascular accident, accident, Recent CNS trauma or surgery, neoplasm, or Recent CNS trauma or surgery, neoplasm, or arteriovenousarteriovenous malformationmalformation. . Severe uncontrolled hypertension and known Severe uncontrolled hypertension and known bleeding tendenciesbleeding tendencies..PregnancyPregnancy

PrecautionsPrecautions

Recent Recent ((within 10 dayswithin 10 days) ) major surgery, major surgery, trauma, GI or GU bleedingtrauma, GI or GU bleeding. . Severe hepatic or renal diseaseSevere hepatic or renal disease. . SubacuteSubacute bacterial bacterial endocarditisendocarditis or acute or acute pericarditispericarditis. . Use cautiously in geriatric patientsUse cautiously in geriatric patients. . Safety not established in pregnancy, Safety not established in pregnancy, lactation, or childrenlactation, or children..

Drugs InteractionDrugs Interaction

Concurrent use with aspirin, Concurrent use with aspirin, NSAIDsNSAIDs, , warfarinwarfarin, heparins, , heparins, abciximababciximab, , ticlopidineticlopidine, , or or dipyridamoledipyridamole may increase the risk of may increase the risk of bleeding, although these agents are bleeding, although these agents are frequently used together or in sequencefrequently used together or in sequence. . Risk of bleeding may also be increased by Risk of bleeding may also be increased by concurrent use with concurrent use with cefamandolecefamandole, , cefotetancefotetan, , cefoperazonecefoperazone, , plicamycinplicamycin, and , and valproicvalproic acidacid..

MonitoringMonitoring

MonitoringMonitoringEfficacyEfficacy

AMIAMIAnginalAnginal free, arrhythmia, ST free, arrhythmia, ST segment resolution, enzyme, segment resolution, enzyme, imagingimaging

PEPEBP, BP, OxyginationOxygination

PADPADPain free, color, pulse, imagingPain free, color, pulse, imaging

Prosthetic valveProsthetic valveHF, ClickHF, ClickEchocardiographyEchocardiography

StrokeStrokeNeuroNeuro deficitedeficite

Side effectSide effectBleedingBleeding

Internal: GI, CNS, othersInternal: GI, CNS, othersExternal: puncture sitesExternal: puncture sites

Hypersensitive reactionHypersensitive reaction

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

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