Cattaneo le urgenze in ematologia 21 maggio 2011

Farmaci antiaggreganti

Marco Cattaneo

Clinica MedicaOspedale San Paolo – Università degli Studi di Milano

P2Y12TxA2-R

TxA2 ADP

GPIIb/IIIa

GPIIb/IIIa

PLATELET

Adhesiveprotein

GP IIb/IIIaAntagonists

P2Y12TxA2-R

PGH2

ArachidonicAcid

COX-1

Tx synthase

ASPIRIN

TxA2

Thienopirydines

PLATELET

deltagranule

Characteristics of the ideal antithrombotic agent

•Potent antithrombotic effect•Low risk•Predictable pharmakodynamic profile, making monitoring unnecessary•Rapid onset•Rapid onset•Rapid offset*•Availability of an antidote•No interaction with food or adjunctive medicines commonly used•Low cost* For safety reasons, a drug with rapid offset is generally preferable to a drug with long-lasting effects, although the use of the latter might minimize the negative effects of poor compliance.

Kaplan-Meier estimates of mortality during the first 30 days among patients who developed and those who did not develop major bleeding

Eikelboom, J. W. et al. Circulation 2006;114:774-782

“Responders”

Thr

ombo

sis

Inhi

bitio

n of

hem

osta

sis

(%)

Reletionship between inhibition of platelet aggregationand the risk of thrombosis or bleeding

“Non Responders”

Ble

edin

g

Thr

ombo

sis

Inhi

bitio

n of

hem

osta

sis

(%)

Characteristics of the ideal antithrombotic agent

•Potent antithrombotic effect•Low risk•Predictable pharmakodynamic profile, making monitoring unnecessary•Rapid onset•Rapid onset•Rapid offset*•Availability of an antidote•No interaction with food or adjunctive medicines commonly used•Low cost* For safety reasons, a drug with rapid offset is generally preferable to a drug with long-lasting effects, although the use of the latter might minimize the negative effects of poor compliance.


“Responders”

Ble

edin

g

Thr

ombo

sis

Inhi

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n of

hem

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(%)


Ble

edin

g

Thr

ombo

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Time of treatment

Inhi

bitio

n of

hem

osta

sis

(%)

INR-Specific Incidence of All Adverse Events (All Episodes of Thromboembolism, All Major Bleeding Episodes, and Unclassified Stroke)

Thrombosis Bleeding

Cannegieter S et al. N Engl J Med 1995;333:11-17


“Responders”

Ble

edin

g

Thr

ombo

sis

Inhi

bitio

n of

hem

osta

sis

(%)


Ble

edin

g

Thr

ombo

sis

Time of treatment

Inhi

bitio

n of

hem

osta

sis

(%)

ANTICOAGULANT

Need for laboratorymonitoring

“Evolution” of antithrombotic treatment

monitoring

No Need for laboratorymonitoring

ANTIPLATELET


ANTICOAGULANT


“Evolution” of antithrombotic treatment

monitoring

No need for laboratorymonitoring

monitoring

No Need for laboratorymonitoring

ASPIRINASPIRIN

Prevalence of “Aspirin resistance”

But:Hillarp et al, 2003 122 Arachidonic acid-induced WB aggregation 0.8%Tantry et al, 2005 223 Arachidonic acid-induced PRP aggregation 0.4%Fontana et al, 2006 96 Serum TxB2 1.0%Frelinger et al, 2006 680 Serum TxB2 1.0%

(uncompliant orunder-dosed)

Campbell & Steinhubl, 2005

THIENOPYRIDINESTHIENOPYRIDINES

specificreceptor

ADP

P2Y12 IP receptor

ADPagonist prostacyclin

GsGiGq

Platelet aggregation

δ

stabilization

cAMP

PI3K AC

N

ClHSHOOCN

ClS

Ticlopidine

ACTIVE METABOLITESTHIENOPYRIDINES

N

OCH3

ClHSHOOCN

O

S

CH3

ClClopidogrel

specificreceptor

P2Y12 IP receptor

agonist prostacyclin

GsGiGq

ADP

N

OCH3

ClSHOOC

S

Platelet aggregation

δ

cAMP

AC

Prevalence of resistance toantiplatelet agents

• Aspirin (serum TxB2) ≈ 0-5% (*)• Clopidogrel (P2Y -specific assays) ≈ 30%• Clopidogrel (P2Y12-specific assays) ≈ 30%

(*) mostly due to non-compliance

Schematic representation of the metabolismof clopidogrel

Mega, J. L. et al. Circulation 2009;119:2553-2560

ORs for MACE, according to CYP2C19*2 allele (n=11,959),and PPI use (n=46,037)

Hulot et al, JACC 2010

Risk for cardiovascular death, myocardial infarction, or stroke for subtypes of PPIs.Time-dependent, propensity score–matched Cox proportional hazards analysis.

Charlot M et al. Ann Intern Med 2010;153:378-386

Kaplan–Meier Estimates of the Probability of Remaining Free of Primary Cardiovascular Events, According to Study Group.

Bhatt DL et al. N Engl J Med 2010. DOI: 10.1056/NEJMoa1007964

Other factors affecting the response to clopidogrel

Higher response Lower response

Age √Body weight √Body weight √Diabetes mellitus √Renal failure in diabetes m. √Smoking √

Response variability (“resistance”) to Clopidogrel

The solution?The solution?

“Tailored treatment”:increase the dose of Clopidogrel in poor responders

(based on the results of plateletplatelet functionfunction teststests))

IsIs itit the right the right approachapproach??

“Responders”

Who would dare arguing against?


Laboratory monitoring of clopidogrel therapyQuestions that need to be answered

• Which test of platelet function?• Is it really effective?• Is it the solution for all patients?• Is it safe?• Is it safe?• Is it cost-effective?

Studio GRAVITASStudio GRAVITAS

GRAVITAS Trial - Profile

Price, M. J. et al. JAMA 2011;305:1097-1105

Cumulative Kaplan-Meier Estimates of the Time to the First Adjudicated Occurrence of the Primary Efficacy End Point

Price, M. J. et al. JAMA 2011;305:1097-1105

Response variability (“resistance”) to Clopidogrel

Another solution?

Change the drug!

Another solution?

N

ClHSHOOC

N

OCH3

HOOC

N

ClS

Ticlopidine

N

OCH3

ACTIVE METABOLITESTHIENOPYRIDINES

N

F

O

HSHOOC

N

ClHSHOOCN

S ClClopidogrel

N

F

O

S

O

OCH3

Prasugrel

Schematic representation of the metabolismof clopidogrel and prasugrel

Mega, J. L. et al. Circulation 2009;119:2553-2560

Prasugrel 60+10

Clopidogrel 600+75

Inhibition of ADP (20µM)-induced platelet aggregation

Clopidogrel 300+75

Payne et al, J Cardiovasc Pharmacol 2007

Reletionship between IPA by Clopidogrel 300 mg orPrasugrel 60 mg in response to 20 µM ADP 24 h after the loading dose

“Responders”

Brandt et al, Am Heart J 2007


Cumulative Kaplan-Meier Estimates of the Rates of Key Study End Pointsduring the Follow-up Period, in TRITON-TIMI 38

Wiviott S et al. N Engl J Med 2007

Effects of Prasugrel and Clopidogrel active metabolites (AM)on human platelet aggregation induced by ADP (10 µM)

Sugidachi et al, JTH 2007

Reletionship between drug-induced inhibition of hemostasisand the risk of thrombosis or bleeding

“Responders”

Inhi

bitio

n of

hem

osta

sis

(%)

Ble

edin

g

Thr

ombo

sis


Inhi

bitio

n of

hem

osta

sis

(%)

Ble

edin

g

Thr

ombo

sis

Reletionship between IPA by Clopidogrel 300 mg orPrasugrel 60 mg in response to 20 µM ADP 24 h after the loading dose

“Responders”

Ble

edin

g

Thr

ombo

sis

Brandt et al, Am Heart J 2007


Ble

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g

Thr

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Short-acting, direct P2Y12 antagonists

(Cangrelor) (Ticagrelor)

Clopidogrel 75 mg qd

80

100Day 1 Day 14

AZD6140 100 mg bid

80

100Day 1 Day 14

80

DISPERSE Study: Faster and More Consistent IPA With AZD6140 Than With Clopidogrel (Final Extent)

Husted S. Presented at ESC 2005.

Time, h

20

40

60

2 4 8 12 2 4 8 12 24

Time, h

20

40

60

2 4 8 12 2 4 8 12 24

IPA (%; 20 {micro}mol/L ADP, final extent) by protocol time and treatment

Gurbel, P. A. et al. Circulation 2009;120:2577-2585

Cumulative Kaplan-Meier Estimates of the Time to the First Adjudicated Occurrence of the Primary Efficacy End Point

Wallentin L et al. N Engl J Med 2009;361:1045-1057

Incidence of the primary end-point and non-CABG relatedTIMI-major bleeding events in patients who received ticagrelor vs patients

who received clopidogrel in the PLATO trial.

Events Ticagrelorno/total

(%)

Clopidogrelno/total

(%)

Hazard Ratio

(95% C.I.)

p

Primary end point 864/9333 1014/9291 0.84 <0.001Primary end point (composite of vascular

death, myocardial infarction or stroke)

864/9333(9.8)

1014/9291(11.7)

0.84(0.77-0.92)

<0.001

Non-CABG-related major bleedings, TIMI criteria

221/9235(2.8)

177/9186(2.2)

1.25(1.03-1.53)

0.03

Wallentin and PLATO Investigators, NEJM 2009

Major Efficacy End Points at 12 Months

Wallentin L et al. N Engl J Med 2009;361:1045-1057

Held et al, JACC 2011

Short-acting, direct P2Y12 antagonists

(Cangrelor) (Ticagrelor)

ELINOGREL

• Elinogrel is direct-acting, competitive, reversible P2Y12 non-nucleotide antagonist

• IC50 ~2-3 µM in ADP aggregation (PRP)

• Highly selective for P2Y12 (does not inhibit P2Y1 or other purinergic receptors)

• Oral bioavailability ~50%

• T1/2 ~12 h (BID drug) (Elimination: 50% renal, 50% hepatic)

• Tmax 2-6 h

INNOVATE PCI - Adverse EventsClopidogrel

N=208

Pooled elinogrel 100 mg N=201

Pooled elinogrel 150 mg N=207

Any SAE 11.1% 14.9% 12.6%

Drug d/c due to AE or SAE 7.2% 7.5% 10.1%

Dyspnea* 4.3% 15.4% 12.1%

0.5% 1.0% 0.5%Bradycardia 0.5% 1.0% 0.5%

Syncope 0.5% 1.5% 0.5%

ALT/AST > 3x^ 1.0% 4.0% 4.8%

ALT/AST > 5x 0.5% 2.0% 3.4%

* Dyspnea was generally mild, transient, and infrequently led to discontinuation

^ Most cases occurred within first 60 days and were asymptomatic; All cases resolved, even when treatment

was continued; No Hy’s Law cases.

Dyspnea in PLATO trial

All patientsTicagrelor(n=9,235)

Clopidogrel(n=9,186) p value*

Dyspnea, % Dyspnea, %

Any

With discontinuation of study treatment

13.8

0.9

7.8

0.1

<0.001

<0.001

CangrelorCangrelor and and dyspnoeadyspnoea

• CHAMPION PCI: a dyspnoea adverse event was reported in 1.0% of patients receiving cangrelor and 0.4% of patients receiving only clopidogrel (P = 0.001)clopidogrel (P = 0.001)

• CHAMPION PLATFORM: a dyspnoea adverse event was reported in 1.4% of patients receiving cangrelor and 0.5% of patients receiving placebo (P = 0.002)

Cattaneo le urgenze in ematologia 21 maggio 2011

Health & Medicine

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