Anti Platelet and Thrombolytic Drugs (1)
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Transcript of 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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Antithrombotic drugs
Fibrinolytics
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Antithrombotic drugs
Fibrinolytics
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Antithrombotic drugs
Fibrinolytics
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The role of platelets
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The role of platelets
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The role of platelets
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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 mechanism of action
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Acetylsalicylic acid mechanism of action
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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 mechanismof action
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ADP-receptor antagonists mechanismof action
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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 mechanism of action
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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 mechanism of action
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GPIIb/IIIa-receptor antagonists mechanism of action
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GPIIb/IIIa-receptor antagonists mechanism of action
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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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Thrombolytic drugs mechanism of action
Th b l i d
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Thrombolytic drugs mechanism of action
Th b l ti d
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Thrombolytic drugs mechanism of action
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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Patti, G. et al. Circulation2005;111:2099-2106
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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Patti, G. et al. Circulation2005;111:2099-2106
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)
Patti, G. et al. Circulation2005;111:2099-2106
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
Kastrati A: N Engl J Med2004;350:232-238
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Results: 4% event rate in both patient
groups
Kastrati A: N Engl J Med2004;350:232-238
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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
Kastrati A: N Engl J Med2004;350:232-238
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