Trombociti i koronarna bolest

Prof. dr. sc. Mislav Vrsalović FESC, FSVM

Trombociti - interdisciplinarni pristup Zagreb, 11. studenoga 2017.

Atherothrombosis* is the

Leading Cause of Death Worldwide1

* Atherothrombosis defined as ischemic heart disease and cerebrovascular disease. 1 The World Health Report 2001. Geneva. WHO. 2001.

22.3

19.3

12.6

9.7

9

6.3

0 5 10 15 20 25 30

Atherothrombosis*

Infectious Disease

Cancer

Injuries

Pulmonary Disease

AIDS

Causes of Mortality (%)

Atherothrombosis Significantly

Shortens Life

Analysis of data from the Framingham Heart Study.

Peeters A, et al. Eur Heart J. 2002;23:458-466.

Atherothrombosis reduces life expectancy by around

8-12 years in patients aged over 60 years1

Average Remaining Life Expectancy at Age 60 (Men)

0

4

8

12

16

20

Healthy

Years

History of AMI

-9.2

years

History of Cardiovascular Disease

-7.4

years

History of Stroke

-12

years

Cerebral Ischemic stroke

Transient ischemic attack

Cardiac Myocardial infarction

Angina pectoris (stable, unstable)

Peripheral Arterial Disease

Critical limb ischemia, claudication

Clinical Manifestations of Atherothrombosis

Common Underlying Atherothrombotic

Disease Process

MI, myocardial infarction; PAD, peripheral arterial disease; CV, cardiovascular.

Ness J, et al. J Am Geriatr Soc. 1999;47:1255-1256.

Schafer AI. Am J Med. 1996;101:199-209.

Atherothrombotic Events (MI, Stroke, or CV Death)

Plaque

Rupture

Platelet

Adhesion,

Activation, and

Aggregation

Thrombus

Formation

MI Atherothrombotic

Stroke PAD Unstable Angina

Risk of a Second Atherothrombotic Event

Increased Risk vs General Population (%)

Original Event MI Stroke

MI 5-7 times

greater risk

(includes death)*

3-4 times greater risk

(includes TIA)

Stroke 2-3 times

greater risk (includes angina and sudden

death)*

9 times

greater risk

PAD 4 times

greater risk*

2-3 times greater risk

(includes TIA)

* Death documented within 1 hour of an event attributed to CHD.

Note:This chart is based on epidemiologic data and is not intended to provide a direct basis for

comparison of risks between event categories.

MI, myocardial infarction; TIA, transient aschemic attack, PAD, peripheral artery disease.

Adult Treatment Panel II. Circulation. 1994;89:1333-1363.

Kannel, WB. J Cardiovasc Risk. 1994;1:333-339.

Wilterdink, JI, et al. Arch Neurol. 1992;49:857-863.

Crique, MH, et al. N Engl J Med. 1992;326:381-386.

Unstable

angina

MI

Ischemic

stroke/TIA

Critical leg

ischemia

Intermitent

claudication

CV death

ACS

Atherosclerosis

Stable angina/

Intermittent claudication

Atherothrombosis: A Generalized and

Progressive Process

Thrombosis

Adapted from Libby P. Circulation. 2001;104:365-372.

Atherothrombosis: Thrombus Superimposed on

Atherosclerotic Plaque

Adapted from Falk E, et al. Circulation. 1995;92:657-671.

Characteristics of Unstable and

Stable Plaque

Thin

fibrous cap

Inflammatory

cells

Few

SMCs

Eroded

endothelium Activated

macrophages

Thick

fibrous cap

Lack of

inflammatory

cells

Foam cells

Intact

endothelium

More

SMCs

Libby P. Circulation. 1995;91:2844-2850.

Unstable Stable

Plaque Rupture

Andrew Farb, MD by permission.

Impaired Fibrinolysis

Fibrinogen Diabetes Mellitus

Cholesterol

Smoking Cap Fatigue

Atheromatous Core (size/consistency)

Cap Inflammation

Homocysteine

Plaque Rupture

Cap Thickness/

Consistency

Systemic Factors Local Factors

Risk Factors for Plaque Rupture

Fuster V, et al. N Engl J Med. 1992;326:310-318.

Falk E, et al. Circulation. 1995:92:657-671.

Akutni

koronarni

sindrom

Smrtnost bolesnika s AKS je i dalje visoka

Smrtnost bolesnika s AKS-om kod kojih je napravljena PCI u prvoj godini

nakon dijagnoze1

AKS – akutni koronarni sindrom; NAP – nestabilna angina pektoris

NSTEMI – infarkt miokarda bez ST elevacije; STEMI – infarkt miokarda sa ST elevacijom

- Svakih 12 sati u Hrvatskoj umru najmanje 2 osobe zbog AKS-a.2

ACS: Tip of the Atherothrombotic “Iceberg”

ACS, acute coronary syndrome; UA, unstable angina; NSTEMI, non-ST-segment elevation myocardial

infarction; STEMI, ST-segment elevation myocardial infarction.

Adapted from Goldstein JA. J Am Coll Cardiol. 2002;39:1464-1467.

Clinical

Subclinical

Presence of Multiple Coronary Plaques

Vascular Inflammation

Persistent Hyperreactive

Platelets

Acute Plaque Rupture ACS (UA/NSTEMI/STEMI)

Hemostatic Plug Formation

Thrombin

AGGREGATION

Fibrin

Hemostatic

Clot

Clotting Platelet Aggregation

0 min 10 min 5 min

SECONDARY

PRIMARY

COAGULATION

Adapted from Ferguson JJ, et al. Antiplatelet Therapy in Clinical Practice. 2000:15-35.

1. Platelet Adhesion

2. Platelet Activation

Platelet

GP Ib

Plaque rupture Activated Platelet

GP IIb/IIIa

ASA, acetylsalicyclic acid.

Cannon and Braunwald, Heart Disease. 2001.

TxA2

Fibrinogen

GP IIb/IIIa Inhibitors

ASA, Clopidogrel/Ticlopidine

Platelets Role in Thrombosis

Thrombin Serotonin Epinephrine Collagen Activation

Activated

Platelet

COX

Degranulation

Aspirin

Gp IIb/IIIa

fibrinogen

receptor

To neighboring

platelet

Clopidogrel

Ticlopidine

Platelet agonists

ADP ATP serotonin calcium magnesium

Adhesive proteins

thrombospondin

fibrinogen

p-selectin

vWF

Coagulation factors

factor V factor XI PAI-1

Inflammatory factors

platelet factor 4

CD 154 (CD 40 ligand)

PDGF

IV Gp IIb/IIIa Inhibitors

TXA, thromboxane; PDGF, platelet-derived growth factor.

Platelet Hyperreactivity Following ACS

Predicts 5-Year Outcomes

Platelet Aggregability Status

0

10

20

30

40

50 Death

Cardiac Events

10.3

6.4

14.9

24.1

46.2

34.6

Pati

en

ts (

%)

*RR=1.6

(CI 0.5-5.5)

Negative

(n=94)

*RR=1.6

(CI 0.7-3.5)

*RR=5.4

(CI 2.2-13.4)

*RR=3.1

(CI 1.6-5.8)

Intermediate

(n=29)

Positive

(n=26)

ACS, acute coronary syndrome.

* Relative risk compared to group with negative aggregation.

Adapted from Trip MD, et al. N Engl J Med. 1990;322:1549-1554.

Terapija AKS

Antiishemijski lijekovi

Antikoagulansi

-UFH ili LMWH

-fondaparinux

-bivalirudin

Antiagregacijska th.

-ASK

-klopidogrel

-Gp IIb/IIIa inhibitori

Revaskularizacija

Antitrombocitna terapija: klopidogrel – preko 10 godina životnog iskustva na širokom spektru

bolesnika

10 kliničkih ispitivanja uključijući preko 130.000 bolesnika

Učinkovitost i sigurnost klopidogrela dokazana je na preko 130

milijuna bolesnika u svijetu

Okosnica antitrombocitne terapije

Prasugrel i tikagrelor – novi antitrombotici

Approved 2011

Antiplatelet Mechanism of Action

Aspirin blocks cyclooxygenase, the enzyme that mediates the first step in the biosynthesis of prostaglandins and thromboxanes from arachidonic acid, preventing platelet aggregation

The P2Y12 (ADP) receptor blockers (clopidogrel, etc.) block the binding of adenosine diphosphate (ADP) to a platelet receptor P2Y12, thereby inhibiting activation of the glycoprotein (GP) IIb/IIIa complex and platelet aggregation

Anti-GP IIb/IIIa antibodies and receptor antagonists inhibit the final common pathway of platelet aggregation (the cross-bridging of platelets by fibrinogen binding to the GP IIb/IIIa receptor)

Aspirin

Platelets do not synthesize new enzymes functional defect induced by aspirin persists for the life of the platelet (nonreversible)

In ACS, including Unstable Angina and NSTEMI: reduction in the combined endpoints of subsequent nonfatal MI, nonfatal stroke, and vascular death Give first dose in ACS of 162-325mg, crushed or chewed, as soon as possible in ACS

ASA has rapid and immediate antithrombotic effect

Discharge patient on ASA 75-100mg daily and to be continued indefinitely for secondary prevention

Side effects: GI intolerance, worsening of preexistent bleeding

Primary Prevention

1. Benefit of ASA must be weighed against risk of bleeding 1. Risk of bleeding likely to outweigh benefits in patients w/ Framingham 10 year risk scores < 10%

2. Consider in patients with DMII and those with CKD as well as patients w/ Framingham risk scores > 10%

ADP receptor antagonists (P2Y12

receptor blockers) Ticlopidine: rarely used anymore due to risk of thrombocytopenia, neutropenia, GI upset and TTP-HUS

Clopidogrel: DAPT with Clopidogrel and ASA was superior compared to ASA alone in patients w/ NSTEMI 3 limitations to the use of clopidogrel Delayed onset of action

Large individual variability in platelet response due to mutation in CYP2C19 allele decreased platelet inhibition and increase in ischemic events

Inhibitory effect on platelets is Irreversible

Prasugrel: more rapid onset of action and achieves higher degrees of platelet inhibition than clopidogrel Compared with Clopidogrel, 19% reduction in cardiovascular

death/MI/stroke when given at time of planned PCI, however bleeding risk greatly increased (including life-threatening bleed)

Contraindicated in patients w/ history of stroke, age > 75 years, or weight < 60 kg

Ticagrelor

Binds reversibly to the P2Y12 platelet

receptor

More rapid onset of action than clopidogrel

More intense platelet inhibition than

clopidogrel

Data reveals better *efficacy* than clopidogrel

with reduction in cardiovascular death, MI,

stroke in patients with ACS

Klopidogrel: preko 10 godina kliničkog

iskustva

Indikacija

nakon IM, CVI ili

dokazane PAB

Publicirana ispitivanja

Godina publikacije

CAPRIE

1996

CAPRIE CAPRIE CAPRIE

CLASSICS CLASSICS CLASSICS

CURE

(PCI-CURE)

CURE

(PCI-CURE)

CREDO

2000 2001 2002

CAPRIE CAPRIE CAPRIE CAPRIE CAPRIE

CLASSICS CLASSICS CLASSICS CLASSICS CLASSICS

CURE

(PCI-CURE)

CURE

(PCI-CURE)

CURE

(PCI-CURE)

CURE

(PCI-CURE)

CURE

(PCI-CURE)

CREDO CREDO CREDO CREDO CREDO

2004 2004 2006 2005 2005

MATCH MATCH MATCH MATCH MATCH

CLARITY CLARITY CLARITY CLARITY

COMMIT

CCS2

COMMIT

CCS2

COMMIT

CCS2

CHARISMA CHARISMA

CARESS

2009

CARESS CARESS CARESS CARESS

MATCH

CREDO

CURE

(PCI-CURE)

CLASSICS

CAPRIE CAPRIE

CLASSICS

CURE

(PCI-CURE)

CREDO

MATCH

CLARITY

COMMIT

CCS2

CHARISMA

2009

CARESS

CURRENT CURRENT

ACTIVE

Indikacija u

UA/NSTEMI

Indikacija u

STEMI

Indikacija u AF

~130,000 bolesnika liječenih klopidogrelom u 10 kliničkih ispitivanja

~130 milijuna bolesnika liječenih u svakodnevnoj kliničkoj praksi

1. Data on file

2. IMS data MAT 12/10

Klopidogrel: manje združenih događaja

KV smrti, IM ili CVI nakon PCI

Meta analiza PCI-CURE, PCI-CLARITY i CREDO: konzistentan povoljan učinak liječenja klopidogrelom

na KV smrti, IM ili moždani udar nakon PCI: 28% smanjenje događaja u bolesnika koji nisu primali GP

IIb/IIIa inhibitor u vrijeme PCIa i 31% smanjenje događaja u bolesnika liječenih GP IIb/IIIa inhibitorom

Sabatine MS et al. Am Heart J 2008;155:910–917.

KV-kardiovaskularni, IM-infarkt miokarda, MU-moždani udar, PCI-perkutana koronarna intervencija

Klopidogrel: bez signifikantnog povećanja broja

TIMI velikih ili manjih krvarenja nakon PCI

Meta-analiza PCI-CURE, PCI-CLARITY i CREDO: Primjena klopidogrela nije bila povezana sa

signifikantnim porastom kompozitnog ishoda TIMI major i minor krvarenja, bez obzira na primjenu

GP IIb/IIIa inhibitora

Sabatine MS et al. Am Heart J 2008;155:910–917.

Zašto je krvarenje važno?

Smrtnost i krvarenje u bolnici nakon PCI

Peterson ED ACC 2007

Mehta SR ACC 2007 PCI-perkutana koronarna intervencija

• krvarenja u bolnici usko koreliraju sa smrtnošću nakon PCI

COMMIT: klopidogrel smanjuje

kombinirani ishod smrti, IM ili CVI za 9%

u STEMI D

og

ađ

aji

(%

)

Chen ZM. Lancet 2005;366:1607–21

klopidogrel (9.3%)

RRR=9%

P=0.002

Placebo (10.1%)

0 0 7 14 21 28

2

4

6

8

10

Dani od randomizacije

Clopidogrel Placebo Odds ratio & 95% CI

Clopid. better Placebo better (22,958) (22,891)

Hour

to entry

0-6

7-12

13-24

ALL

776 (9.3%)

672 (9.7%)

666 (8.8%)

2125 (9.3%)

904 (10.9%)

735 (10.7%)

666 (8.7%)

2311 (10.1%) 9% SE 3

(2P = 0.002)

0.4 0.6 0.8 1.0 1.2 1.4 1.6

CURRENT OASIS 7:

Klopidogrel dvostruka vs standardna doza:

primarni ishod - PCI bolesnici

Dani

Ku

mu

lati

vn

i ri

zik

0.0

0

.01

0

.02

0

.03

0

.04

0 3 6 9 12 15 18 21 24 27 30

Klopidogrel standardna doza

Klopidogrel dvostruka doza

HR 0.86

95% CI 0.74-0.99

P=0.039

14%

RRR

CV smrt, IM ili moždani udar

Mehta SR, et al. Lancet 2010;376:1233–1243

CURRENT OASIS 7:

Klopidogrel dvostruka vs standardna doza Stent tromboza (potvrđena angiografski)

0 3 6 9 12 15 18 21 24 27 30

Dani

Ku

mu

lati

vn

i ri

zik

0.0

0

.00

4

0.0

08

0

.01

2 Klopidogrel standardna doza

Klopidogrel dvostruka doza

46%

RRR

HR 0.54

95% CI 0.39-0.74

P=0.0001

Mehta SR, et al. Lancet 2010;376:1233–1243

Što je s novim antitrombocitnim lijekovima?

• učinkovitost: početak djelovanja

• sigurnost: krvarenja

Prasugrel vs klopidogrel: PCI bolesnici smanjenje događaja uz veći rizik od krvarenja

TRITON TIMI: Wiviott, N Engl J Med 2007;357:2001-15

Prasugrel vs klopidogrel: “TRILOGY ACS”

bez razlike u događajima

Medikamentozno liječeni visokorizični bolesnici sa UA/NSTEMI

(bez revaskularizacije)

nema razlike u

kompozitnim

događajima (KV smrt,

IM, CVI) između

prasugrela i

klopidogrela u prvoj

godini

http://www.theheart.org/article/1437675.do?utm_medium=email&utm_source=20120825_ESC2012_en_world&utm_campaign=newsletter;

http://spo.escardio.org/sessiondetails.aspx?eevtid=54&fp=401&doc=webcast

Tikagrelor vs klopidogrel:

smanjenje događaja uz veći rizik od ne-CABG

krvarenja i fatalnih intrakranijalnih krvarenja

PLATO: Walletin, N Engl J Med 2009;361:1-13

Ograničenja prilikom upotrebe novih

antitrombotičkih lijekova

PRASUGREL

• u bolesnika s visokim rizikom od

krvarenja, osobito:

- bolesnici stariji od 75 godina

- bolesnici lakši od 60 kg

• kontraindikacija - CVI/TIA u

anamnezi

TIKAGRELOR • kontraindikacija – intrakranijalno

krvarenje u anamnezi

• posebna upozorenja – povećani

rizik od krvarenja

- Povećani rizik od ne-CABG

krvarenja (AKS bolesnici na

tikagreloru i ASK)

• češća pojava dispneja (oprez

kod bolesnika s astmom i

KOPB-om)

• suradljivost - 2 tbl. na dan

(doza održavanja)

MU-moždani udar, TIA-tranzitorna ishemična ataka; ASK-acetilsalicilna kiselina

42

ESC smjernice za liječenje NSTEMI

- P2Y12 inhibitori

Grupa I , razina B

The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without ST-segment elevation of the European

Society of Cardiology (ESC). ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-

segment elevation. European Heart Journal. Published online 26 August 2011

a50% inhibicija agregacije trombocita

TIKAGRELOR: Prvi i jedini odobreni CPTP

TIKAGRELOR

pripada novoj kemijskoj skupini; ciklo-pentil-triazolo-pirimidina (CPTP)

je aktivna supstanca, ne zahtjeva prethodnu pretvorbu u aktivan oblik

je selektivni antagonist receptora adenozin difosfata (ADP)

Vezuje se direktno i reverzibilno na P2Y12 receptore i na taj način sprječava ADP-om posredovanu aktivaciju i agregaciju trombocita

Tienopiridini (klopidogrel) zahtjevaju prethodnu pretvorbu u aktivan oblik i vezuju se ireverzibilno za P2Y12 receptor

P2Y12 receptor

na trombocitu

BRILIQUE

ADP mjesto

vezanja

Husted S, et al. Eur Heart J. 2006;27:1038–1047.

Gurbel PA, et al. Expert Opin Drug Metab Toxicol. 2009;5(8):989–1004.

Van Giezen JJ, et al. J Thromb Haemost. 2009;7:1556–1565.

TIKAGRELOR: Nije potrebna prethodna aktivacija

BRILIQUE:

NIJE POTREBNA PRETHODNA

AKTIVACIJA LIJEKA

Klopidogrel:

PREDLIJEK – ZAHTJEVA PRETHODNU

PRETVORBU U AKTIVAN OBLIK

Aktivan oblik

Intermedijarni metabolit

Predlijek

Prilagođeno iz Schomig A. N Engl J Med. 2009;361:1108–1111.

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20 22 24

TIKAGRELOR - Brz početak djelovanja

*

*

* *

*

BRILIQUE (n=54)

Klopidogrel (n=50)

Placebo (n=12)

Prilagođeno iz Gurbel PA, et al. Circulation. 2009;120:2577–2585.

BRILIQUE 180-mg udarna doza kod stabilnih CAD pacijenata

Klopidogrel 600-mg udarna doza kod stabilnih CAD pacijenata

Inh

ibic

ija a

gre

ga

cij

e t

rom

bo

cit

a (

IPA

)

Udarna doza

Vrijeme (sati)

BRILIQUE

Klopidogrel *P<0.0001 BRILIQUE vs

klopidogrel Placebo

Veza između IPA i kliničke aktivnosti još nije potvrđena

Klinička farmakologija: TIKAGRELOR i klopidogrel

Gurbel PA, et al. Circulation. 2009;120:2577–2585.

Sažetak opisa svojstava lijeka Brilique (BRILIQUE)

PLAVIX® [Uputa o lijeku, Hrvatska]..

TIKAGRELOR Klopidogrel

Kemijska klasa CPTP tienopiridini

Reverzibilna inhibicija P2Y12 receptora DA NE

PD varijabilnost CYP2C19 genotipa NE DA

Doziranje 2 puta dnevno (bid) jednom dnevno (qd)

Srednja inhibicija agregacije trombocita

nakon 30 min 41% 8%

Srednja inhibicija agregacije trombocita

nakon 2 sata 89% 38%

TIKAGRELOR ima dvostruki mehanizam djelovanja:

antitrombocitni učinak i pojačan adenozinski odgovor

Inhibicija receptora P2Y12 1,2

Antitrombocitni učinak

Inhibicija ENT-1 transportera3,4,5

Poboljšan lokalni adenozinski

odgovor može rezultirati:*

Dodatna inhibicija

agregacije/aktivacije

trombocita

Kardioprotekcija6

Vazodilatacija5,7,8

Modulacija upale

Dispneja7

Figure adapted from Nylander S, et al. (2013).

AC, adenylyl cyclase; ADP, adenosine diphosphate; cAMP, cyclic adenosine monophosphate; ENT, equilibrative nucleoside transporter.

References in slide notes.

Eritrocit

Adenozin

cAMP

Trombocit

ADP

ENT-1

Tikagrelor

AC

Gi Gs

A2A P2Y12

Aktivacija/agregacija trombocita

1. van Giezen JJJ, et al. J Thromb Haemost 2009;7:1556–1565.

2. Wallentin L. Eur Heart J 2009;30:1964–1977.

3. Nylander S, et al. J Thromb Haemost 2013;11:1867–1876.

4. Armstrong D, et al. J Cardiovasc Pharmacol Ther; In press.

5. van Giezen JJJ, et al. J Cardiovasc Pharmacol Ther 2012;17:164–172.

6. Wang K, et al. Thromb Haemost. 2010;104:609-17.

7. Wittfeldt A, et al. J Am Coll Cardiol 2013;61:723–727.

8. Alexopoulos D, et al. Circ Cardiovasc Interv 2013;19:5121–5126.

TIKAGRELOR: Smanjenje kardiovaskularne

smrtnosti u bolesnika s AKS-om

ARR – apsolutno smanjenje rizika; RRR – relativno smanjenje rizika; HR – omjer rizika

NNT – potreban broj liječenih osoba da bismo spriječili jedan događaj

CI – interval pouzdanosti

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

TIKAGRELOR ne pokazuje značajne razlike u cjelokupnom

broju teških, smrtonosnih i po život opasnih krvarenja

Učestalost krvarenja definirano po PLATO-u i TIMI-ju *

* TIMI – tromboliza kod infarkta miokarda

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