anti platelet and thrombolytic drugs (1)

8/2/2019 Anti Platelet and Thrombolytic Drugs (1)

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LIFEBLOOD

THE

ThrombosisCHARITY

Antiplatelet and thrombolytic drugs


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Antithrombotic drugs

Fibrinolytics


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Fibrinolytics


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Fibrinolytics


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Fibrinolytics


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The role of platelets


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Antiplatelet drugs


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Acetylsalicylic acid mechanism of action


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Acetylsalicylic acid pharmacokinetics

Rapid absorption of aspirin occurs in thestomach and upper intestine, with the peakplasma concentration being achieved 15-20minutes after administration

The peak inhibitory effect on plateletaggregation is apparent approximately onehour post-administration

Aspirin produces the irreversible inhibition ofthe enzyme cyclo-oxygenase and thereforecauses irreversible inhibition of platelets for therest of their lifespan (7 days)


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Acetylsalicylic acid major use

Secondary prevention of transient ischaemicattack (TIA), ischaemic stroke and myocardialinfarction

Prevention of ischaemic events in patients withangina pectoris

Prevention of coronary artery bypass graft(CABG) occlusion


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ADP-receptor antagonists mechanismof action


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ADP-receptor antagonists pharmacokinetics

Both currently available ADP-receptorantagonists are thienopyridines that can beadministered orally, and absorption isapproximately 80-90%

Thienopyridines are prodrugs that must beactivated in the liver


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ADP-receptor antagonists major use

Secondary prevention of ischaemiccomplications after myocardial infarction,ischaemic stroke and established peripheralarterial disease

Secondary prevention of ischaemiccomplications in patients with acute coronarysyndrome (ACS) without ST-segment elevation


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Dipyridamole mechanism of action


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Dipyridamole pharmacokinetics

Incompletely absorbed from the gastrointestinaltract with peak plasma concentration occuringabout 75 minutes after oral administration

More than 90% bound to plasma proteins

A terminal half-life of 10 to 12 hours

Metabolised in the liver

Mainly excreted as glucuronides in the bile;

a small amount is excreted in the urine


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Dipyridamole major use

Secondary prevention of ischaemiccomplications after transient ischaemic attack(TIA) or ischaemic stroke (in combination withaspirin)


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GPIIb/IIIa-receptor antagonists mechanism of action


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GPIIb/IIIa-receptor antagonists pharmacokinetics

Available only for intravenous administration

Intravenous administration of a bolus dosefollowed by continuous infusion produces constantfree plasma concentration throughout the infusion.At the temination of the infusion period, freeplasma concentrations fall rapidly forapproximately six hours then decline at a slowerrate. Platelet function generally recovers over the

course of 48 hours, although the GP IIb/IIIaantagonist remains in the circulation for 15 days ormore in a platelet-bound state


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GPIIb/IIIa-receptor antagonistsmajor use

Prevention of ischaemic cardiac complicationsin patients with acute coronary syndrome(ACS) without ST-elevation and during

percutaneous coronary interventions (PCI), incombination with aspirin and heparin

GPIIb/III i


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GPIIb/IIIa-receptor antagonists major drawbacks

Can only be administered by intravenousinjection or infusion and are complicated tomanufacture

Oral drugs have been investigated but were noteffective and have therefore not reached themarket

Th b l i d


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Thrombolytic drugs mechanism of action

Th b l i d


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Th b l i d


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Th b l ti d


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Th b l ti d h ki ti


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Thrombolytic drugs pharmacokinetics

The plasma half-life of the third generation drugs is14-45 minutes, allowing administration as a singleor double intravenous bolus. This is in contrast tosecond generation t-PA, which with a half-life of 3-

4 minutes, must be administered an initial bolusfollowed by infusion

Th b l ti d j


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Thrombolysis in patients with acute myocardialinfarction (MI)

Thrombolysis in patients with ischaemic stroke

Thrombolysis of (sub)acute peripheral arterialthrombosis

Thrombolysis in patients with acute massivepulmonary embolism

Thrombolysis of occluded haemodialysis shunts

Thrombolytic drugs major use

Th b l ti d j d b k


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Thrombolytic drugs major drawbacks

Treatment is limited to acute in-hospitaltreatment. There is a high risk of bleedinginherent in this treatment

Patients using anticoagulants arecontraindicated for treatment with thrombolytics


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PCI and platelet activation

The early response to arterial wall injury isplatelet activation and depositionover theinjured arterial surface, creating the substrate

forthrombosis

Stent implantation appears to be associatedwith greater platelet activation than balloon

angioplasty alone

The magnitude of platelet activation isassociatedwith an increased risk for adverse

clinical events after coronaryinterventionKabbani SS: Circulation. 2002;104:181


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Myocardial necrosis after PCI

Myocardial necrosis, assessed by CK-MBelevation, is relatively frequent after coronaryintervention, occurring in up to 40% of cases

Klein LW: J Am Coll Cardiol. 1991; 17: 621626Abdelmeguid AE: Circulation. 1996; 94: 1528

1536

Brener SJ: Eur Heart J. 2002; 23: 869

876Nallamothu BK: J Am Coll Cardiol. 2003; 42:

Although most patients remainasymptomatic with no changes in cardiacfunction, even a mild release of CK-MB isassociated with higher mortality duringfollow-up


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The ARMYDA 2 Study


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To evaluate whether aggressive antiplatelet therapywithclopidogrel in patients undergoing PCI will reduce

periprocedural MI and improve outcome

The ARMYDA-2 StudyAntiplatelet therapy for Reduction ofMYocardial Damage during Angioplasty

Patti, G. et al. Circulation2005;111:2099-


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255 pts with stable CAD or non-ST ACS,randomized to 300 or 600 mg of Clopidogrel 4-8 h

before PCI

Primary end point: A composite of death, MI or TVR at 30days

non-ST-elevation MI - 25%

complex lesions - 75%

DES - 20%Patti, G. et al. Circulation2005;111:2099-

ARMYDA-2 Study

Antiplatelet therapy for Reduction ofMyocardial Damage during Angioplasty


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ARMYDA-2: Number of events

Event Clopidogrel300 mg

Clopidogrel600 mg

Death 0 0

Target vesselrevascularization

0 1

MI 15 5

ARMYDA-2 STUDY Results: 30 day


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Patti, G. et al. Circulation2005;111:2099-2106

ARMYDA-2 STUDY Results: 30-dayoccurrence of death, MI, or TVR in patients receiving

600-mg versus the 300-mg loading regimen of

clopidogrel

The primary endpoints occurred in:

4% of pts with 600mg versus

12% with 300 mg


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ARMYDA-2 STUDY Results: Comparison ofpostprocedural elevation of CK-MB and troponin I in the 2

study arms

ARMYDA 2 STUDY R lt


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ARMYDA-2 STUDY Results:

Baseline and peak values of CK-MB, troponin I, andmyoglobin

ARMYDA 2 STUDY R lt


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Pretreatment with 600-mg loading dose of clopidogrelsignificantly reduced the risk of periprocedural MI(OR 0.48; 95% CI 0.15 to 0.97; P=0.044)


ARMYDA-2 STUDY Results:Multivariable analysis

P f h


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Percentage of patients with anyelevation of CKMB/troponin I

Marker Clopidogrel300 mg

(%)

Clopidogrel600 mg

(%)

p

CKMB 26 14 0.036

TroponinI

44 26 0.004


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Bleeding events

Event Clopidogrel300 mg

Clopidogrel600 mg

Major bleed(Hgb>5g/dL)

0 0

Minor bleed(Hgb


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The ARMYDA-2 trialConclusions:

Pretreatment witha 600-mg loading dose ofclopidogrel given 6 hours before theprocedure issafe and, as compared with the 300-mg dose,

reduces

periprocedural MI and improves short-termprognosis in patients undergoing PCI

The low risk of this pharmacological regimen

may support itsroutine use in patients beforeplanned coronary angioplastyand may influencepractice patterns with regard to antiplatelet

therapy before PCI

The activemetabolite exerts its antiplatelet effect


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CLOPIDOGREL

ASA COX

ADP

ADP

C

GPllb/llla(Fibrinogen receptor)

Collagen thrombin

TXA2

Activation

TXA2

COX (cyclo-oxygenase)ADP (adenosine

diphosphate)TXA2 (thromboxane A2) Jarvis B, Simpson K. Drugs2000; 60:

The active metabolite exerts its antiplatelet effectby noncompetitiveinhibition of the platelet ADP

receptor subtype P2Y12

Clopidogrel: An

inactiveprodrug requires in vivoconversion in the liver

by the cytochrome P450(CYP) 3A4 enzyme

system


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A prodrug that needs to bemetabolized to an activecompound that targets the plateletGi-coupled adenosinediphosphate (ADP) P2Y12 receptor

Clopidogrel is oxidized in a cytochrome P450 (CYP)

monooxygenase-dependent way to 2-oxo-clopidogrel,an intermediatemetabolite that is further hydrolyzed tothe active thiol metaboliteof clopidogrel

The active metabolite irreversibly binds tothe P2Y12receptor

The major circulatingmetabolite of clopidogrel is acarboxylic acid derivate thatcompletely lacks

The thienopyridine

clopidogrel


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Absorption (oral): rapid, not affected by food or

antacids

Metabolism: rapid and extensive hepatic metabolism

Half-life: 8 hours (but has an irreversible effect on

platelets, with a lifespan of approximately 710 days)

Excretion: 50% in urine and 46% in feces, after 5

days

Pharmacology of Clopidogrel

Jarvis B, Simpson K. Drugs2000; 60: 34


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Clopidogrel Dosing

1977: The75-mg once-daily dose was approved by theFDA after the CAPRIE trial showedsuperior reduction ofadverse cardiovascular events with clopidogrelversusaspirin

The 75-mg once-daily dose had been used in CAPRIE

because it produced inhibition of platelet aggregationequivalentto that produced by ticlopidine 250 mgadministered twice daily

2002: FDA approval for the 300-mg loading dose inpatients with ACS after the CURE trial demonstrated areduction of adverse cardiovascular events withdualanti latelet thera versus as irin

Loading Dose


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Loading DoseWithout a loading dose, clopidogrel 75 mg dailyinduces inhibitionof ADP-induced platelet aggregation

as early as 2 hours afterthe first dose but requires 3to 7 days to achieve maximal inhibitionof plateletaggregation

The 3- to 7-day delay can be shortenedto 6 hourswith a loading dose of 300 mg

With 600 mg loading (as compared with the300-mg dose):

the maximal platelet inhibition is achievedat 2 hours

the level of inhibition of plateletaggregation is increased

the numberof low responders decreasedBates ER: Circulation2005;111:2557-2559

Hochholzer W: Circulation2005;111:2560-2564


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The benefit of a higher loading

doseThe advantage of using the higher loading doseis the maximal drug effect during theperiprocedural periodwhen pretreatment has not

been given, a common occurrence with

ad hoc PCI

The clinical benefit is measuredby lowerbiomarker-defined periprocedural MI rates, as has

been

seen with periprocedural platelet inhibitionwith GP IIb/IIIa inhibitor agents, and with the 600mg Clopidogrel pre-treatment in the ARMYDA-2trial

Sh ld i h h i l id l


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Should patients who are on chronic clopidogreltherapy receive the 600 mg pretreatment

regimen?

Many patients presentingfor PCI are alreadytreated with clopidogrel.Should these patientsreceive the 600-mg pretreatment regimen?

The answer is yes!

Additional, significantinhibition of platelet

aggregation is achieved when a 600-mg dose isadministeredto patients already receivingclopidogrel 75 mgdaily

F th l t l t i hibiti b hi d ith


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Further platelet inhibition can be achievedwith600-mg Re-loading in patientswith chronic

clopidogrel therapy

Adnan KastratiCirculation. 2004;110:1916-1919

In both groups, 600 mg clopidogrelloading significantly inhibitedADP-induced expression of GP IIb/IIIa and

P-selectin

receptorsIn the chronic therapy group, loadingwith 600 mg clopidogrelyielded furtherinhibition of platelet aggregation in

addition to that achieved by themaintenancedose of 75 mg/d, from5214% to 3312% (P


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Abciximab offersno additional benefit inthe setting of Clopidogrel pretreatment

Kastrati A: N Engl J Med2004;350:232-238


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Study design and objectives

2159 patients with CAD who underwent a PCI:

All patients were pretreated with a 600-mg dose of

clopidogrel at least two hours before the procedure

N=1079 - abciximab

N=1080 - placebo

Primary end point:

Composite of death, MI, and urgent TVR within 30 days



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Results: 4% event rate in both patient

groups



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conclusion

In patients at low and intermediate risk whoundergo elective PCI after pretreatment

with a 600-mg loading dose of clopidogrel at least

two hours before the procedure, the additional useof abciximab is associated with no clinicallymeasurable benefit within the first 30 days


Ab i i b ff dditi l b fit i th


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Randomized Clinical Trial of Abciximab in Diabetic PatientsUndergoing Elective PCI After Treatment With a High Loading

Dose of Clopidogrel

Julinda Mehilli, Circulation. 2004;110:3627-3635

Abciximab offersno additional benefit in thesetting of Clopidogrel pretreatment in

Diabetics

Study: 701 diabetic patients with CAD who underwent

elective PCI after pretreatment with a 600-mg doseof clopidogrel >2 hours before the procedure

351 patients - abciximab

350 patients - placebo

Primary end point: composite of death and MI at 1 year


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There is no significant impact of abciximab on the riskof death and MI in diabetic patients undergoing PCIafter pretreatment with a 600-mg loading dose ofclopidogrel at least 2 hours before the procedure

Conclusion

s:

Mehilli J, Circulation

2004;110:3627-3635


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How High Should We Go?

Absorption, Metabolization, and Antiplatelet Effectsof 300, 600, and 900-mg Loading Doses of

Clopidogrel:

Results of the ISAR-CHOICE (Intracoronary Stenting andAntithrombotic Regimen: Choose Between 3 High Oral Doses

for Immediate Clopidogrel Effect) Trial

Nicolas von Beckerath: Circulation 2005;112: 2946 - 2950

Primary end point:

Maximal ADP-induced (5mol/L) plateletaggregation 4 hours after administrationof

clopidogrel

Antiplatelet Effects of 300 600 and


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Antiplatelet Effects of 300-, 600-, and900-mg Loading Doses of Clopidogrel

Sixty patients with suspected ordocumented CADadmitted for coronary angiography were included

They wereallocated to clopidogrel loading doses of

300, 600, or900 mg in a double-blinded,randomized manner

Plasma concentrationsof the active thiolmetabolite, unchanged clopidogrel, and theinactivecarboxyl metabolite of clopidogrel were determined

before and serially after drug administrationNicolas von Beckerath: Circulation 2005;112: 2946 - 2950


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von Beckerath, N. et al. Circulation2005;112:2946-2950

Plasma concentrations

Loading with 600 mg resultedin higher plasmaconcentrationsof active metabolite, clopidogrel,and carboxylmetabolite

compared with loading with 300mg (P0.03)

With 900 mg, no furtherincrease in plasma concentrations

of activemetabolite andclopidogrel (P0.38) was achieved

active metabolite

clopidogrel

carboxyl metabolite

300 mg(blue)

600 mg (red)

900 mg

M xim l ADP i d d pl t l t ti 4 h s ft


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Maximal ADP-induced platelet aggregation 4 hours afteradministration of a 300-, 600-, and 900- mg loading

dose

von Beckerath, N. et al. Circulation2005;112:2946-2950

An increaseof the clopidogrel loadingdose from 600 to 900 mg does not

result in further suppression ofplatelet aggregationcaused by a

failed increase in plasmaconcentration of the drug

This suggeststhat intestinalabsorption becomes the bottleneck

when singledoses exceeding 600 mgare administered


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Should we split the high dose?

Administering 900 mg Clopidogrelin 2separate doses may allow more completeabsorption and,consequently, additional platelet

inhibition compared with 600mg

However, the practicability of such anapproach as a pretreatmentbefore PCI is limited

Nicolas von Beckerath Circulation. 2005;112:2946-2950

What can we reasonableconclude about


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What can we reasonable conclude aboutantiplatelet therapy and PCI?

1. augmentingaspirin with additional antiplatelet therapyreduces myonecrosisafter PCI

2. according to the information currently available,if

clopidogrel is selected, the dose should be 600 mgand thedrug should be administered at least 2 hoursbefore PCI

3. for the types of patients evaluated thus far,

intravenous GPIIb/IIIa inhibitors appear unnecessarywhen clopidogrel hasbeen administered

4. if circumstances restrict clopidogrelpretreatment,intravenous GP IIb/IIIa is a reasonable alternative


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Thank You

anti platelet and thrombolytic drugs (1)

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