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 Worldwide 1 Pulmonary Disease 6.3 Injuries AIDS 9 9.7 Cancer 12.6 Infectious Disease 19.3 Atherothrombosis* 22.3 0 5 10 15 20 25 30 Causes of Mortality (%) * Atherothrombosis defined as ischemic heart disease and cerebrovascular disease. 1 The World Health Report 2001. Geneva. WHO. 2001.
Years Atherothrombosis Significantly Shortens Life Atherothrombosis reduces life expectancy by around 8-12 years in patients aged over 60 years 1 20 Average Remaining Life Expectancy at Age 60 (Men) 16 12-7.4 years -9.2 years -12 years 8 4 0 Healthy History of Cardiovascular Disease History of AMI History of Stroke Analysis of data from the Framingham Heart Study. Peeters A, et al. Eur Heart J. 2002;23:458-466.
Clinical Manifestations of Atherothrombosis Cerebral Ischemic stroke Transient ischemic attack Cardiac Myocardial infarction Angina pectoris (stable, unstable) Peripheral Arterial Disease Critical limb ischemia, claudication
Common Underlying Atherothrombotic Disease Process Atherothrombotic Stroke Unstable Angina MI PAD Plaque Rupture Platelet Adhesion, Activation, and Aggregation Thrombus Formation Atherothrombotic Events (MI, Stroke, or CV Death) 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.
Risk of a Second Atherothrombotic Event Increased Risk vs General Population (%) Original Event MI Stroke MI Stroke PAD 5-7 times greater risk (includes death)* 2-3 times greater risk (includes angina and sudden death)* 4 times greater risk* 3-4 times greater risk (includes TIA) 9 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.
Atherothrombosis: A Generalized and Progressive Process Thrombosis Atherosclerosis Unstable angina MI Ischemic stroke/tia Critical leg ischemia Intermitent claudication CV death ACS Stable angina/ Intermittent claudication 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 Unstable Stable Few SMCs Thin fibrous cap Inflammatory cells More SMCs Thick fibrous cap Lack of inflammatory cells Eroded endothelium Activated macrophages Intact endothelium Foam cells Libby P. Circulation. 1995;91:2844-2850.
Plaque Rupture Andrew Farb, MD by permission.
Risk Factors for Plaque Rupture Local Factors Atheromatous Core (size/consistency) Cap Fatigue Cap Thickness/ Consistency Cap Inflammation Smoking Diabetes Mellitus Homocysteine Cholesterol Systemic Factors Fibrinogen Impaired Fibrinolysis Fuster V, et al. N Engl J Med. 1992;326:310-318. Falk E, et al. Circulation. 1995:92:657-671. Plaque Rupture
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 dijagnoze 1 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 Acute Plaque Rupture ACS (UA/NSTEMI/STEMI) Clinical Subclinical Presence of Multiple Coronary Plaques Persistent Hyperreactive Platelets Vascular Inflammation 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.
Hemostatic Plug Formation PRIMARY AGGREGATION Platelet Aggregation Clotting Hemostatic Clot SECONDARY COAGULATION Thrombin Fibrin 0 min 10 min 5 min Adapted from Ferguson JJ, et al. Antiplatelet Therapy in Clinical Practice. 2000:15-35.
Platelets Role in Thrombosis Platelet 1. Platelet Adhesion GP Ib 2. Platelet Activation Plaque rupture ASA, Clopidogrel/Ticlopidine Activated Platelet GP IIb/IIIa TxA2 GP IIb/IIIa Inhibitors Fibrinogen ASA, acetylsalicyclic acid. Cannon and Braunwald, Heart Disease. 2001.
Activated Platelet Clopidogrel Ticlopidine To neighboring platelet IV Gp IIb/IIIa Inhibitors Gp IIb/IIIa fibrinogen receptor Activation COX Aspirin Thrombin Serotonin Epinephrine Collagen Adhesive proteins thrombospondin fibrinogen p-selectin vwf Coagulation factors factor V factor XI PAI-1 Degranulation Inflammatory factors platelet factor 4 CD 154 (CD 40 ligand) PDGF Platelet agonists ADP ATP serotonin calcium magnesium TXA, thromboxane; PDGF, platelet-derived growth factor.
Patients (%) 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. Platelet Hyperreactivity Following ACS Predicts 5-Year Outcomes 50 Death Cardiac Events 40 *RR=1.6 30 (CI 0.7-3.5) 24.1 20 14.9 *RR=1.6 (CI 0.5-5.5) 10.3 10 6.4 *RR=3.1 (CI 1.6-5.8) 46.2 *RR=5.4 (CI 2.2-13.4) 34.6 0 Negative (n=94) Intermediate (n=29) Platelet Aggregability Status Positive (n=26)
erapija 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 P2Y 12 (ADP) receptor blockers (clopidogrel, etc.) block the binding of adenosine diphosphate (ADP) to a platelet receptor P2Y 12, 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 crossbridging 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 (P2Y 12 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 P2Y 12 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 ~130,000 bolesnika liječenih klopidogrelom u 10 kliničkih ispitivanja ~130 milijuna bolesnika liječenih u svakodnevnoj kliničkoj praksi Publicirana ispitivanja Indikacija u STEMI Indikacija u AF ACTIVE CURRENT CURRENT Indikacija u UA/NSTEMI COMMIT CCS2 CHARISMA CHARISMA COMMIT CCS2 COMMIT CCS2 CLARITY CLARITY CLARITY CLARITY CHARISMA COMMIT CCS2 CLARITY Indikacija nakon IM, CVI ili dokazane PAB CARESS CARESS CARESS CARESS CARESS MATCH MATCH MATCH MATCH MATCH MATCH CARESS MATCH CREDO CREDO CREDO CREDO CREDO CREDO CREDO CREDO CURE (PCI-CURE) CURE (PCI-CURE) CURE (PCI-CURE) CURE (PCI-CURE) CURE (PCI-CURE) CURE (PCI-CURE) CURE (PCI-CURE) CURE (PCI-CURE) CURE (PCI-CURE) CLASSICS CLASSICS CLASSICS CLASSICS CLASSICS CLASSICS CLASSICS CLASSICS CLASSICS CLASSICS CAPRIE CAPRIE CAPRIE CAPRIE CAPRIE CAPRIE CAPRIE CAPRIE CAPRIE CAPRIE CAPRIE 1996 2000 2001 2002 2004 2004 2005 2005 2006 2009 2009 1. Data on file 2. IMS data MAT 12/10 Godina publikacije
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 krvarenja u bolnici usko koreliraju sa smrtnošću nakon PCI Peterson ED ACC 2007 Mehta SR ACC 2007 PCI-perkutana koronarna intervencija
Događaji (%) COMMIT: klopidogrel smanjuje kombinirani ishod smrti, IM ili CVI za 9% u STEMI 10 8 Placebo (10.1%) klopidogrel (9.3%) RRR=9% P=0.002 6 Hour to entry Clopidogrel Placebo Odds ratio & 95% CI (22,958) (22,891) Clopid. better Placebo better 4 0-6 7-12 776 (9.3%) 672 (9.7%) 904 (10.9%) 735 (10.7%) 2 13-24 ALL 666 (8.8%) 2125 (9.3%) 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 Chen ZM. Lancet 2005;366:1607 21 0 0 7 14 21 28 Dani od randomizacije
Kumulativni rizik CURRENT OASIS 7: Klopidogrel dvostruka vs standardna doza: primarni ishod - PCI bolesnici CV smrt, IM ili moždani udar 0.0 0.01 0.02 0.03 0.04 Klopidogrel standardna doza Klopidogrel dvostruka doza HR 0.86 95% CI 0.74-0.99 P=0.039 14% RRR 0 3 6 9 12 15 18 21 24 27 30 Dani Mehta SR, et al. Lancet 2010;376:1233 1243
Kumulativni rizik CURRENT OASIS 7: Klopidogrel dvostruka vs standardna doza Stent tromboza (potvrđena angiografski) 0.0 0.004 0.008 0.012 Klopidogrel standardna doza Klopidogrel dvostruka doza HR 0.54 95% CI 0.39-0.74 P=0.0001 46% RRR 0 3 6 9 12 15 18 21 24 27 30 Mehta SR, et al. Lancet 2010;376:1233 1243 Dani
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
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 Prasugrel vs klopidogrel: TRILOGY ACS bez razlike u događajima nema razlike u kompozitnim događajima (KV smrt, IM, CVI) između prasugrela i klopidogrela u prvoj godini Medikamentozno liječeni visokorizični bolesnici sa UA/NSTEMI (bez revaskularizacije)
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
ESC smjernice za liječenje NSTEMI - P2Y12 inhibitori a50% inhibicija agregacije trombocita 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 42 of Cardiology (ESC). ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent STsegment elevation. European Heart Journal. Published online 26 August 2011
TIKAGRELOR: Prvi i jedini odobreni CPTP TIKAGRELOR pripada novoj kemijskoj skupini; ciklopentil-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 P2Y 12 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 P2Y 12 receptor ADP mjesto vezanja BRILIQUE P2Y 12 receptor na trombocitu 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 Aktivan oblik Intermedijarni metabolit Predlijek Klopidogrel: PREDLIJEK ZAHTJEVA PRETHODNU PRETVORBU U AKTIVAN OBLIK Prilagođeno iz Schomig A. N Engl J Med. 2009;361:1108 1111.
Inhibicija agregacije trombocita (IPA) TIKAGRELOR - Brz početak djelovanja 100 80 * * * * BRILIQUE (n=54) 60 Klopidogrel (n=50) 40 * 20 *P<0.0001 BRILIQUE vs klopidogrel BRILIQUE Klopidogrel Placebo Placebo (n=12) 0 Udarna doza 0 2 4 6 8 10 12 14 16 18 20 22 24 Vrijeme (sati) BRILIQUE 180-mg udarna doza kod stabilnih CAD pacijenata Klopidogrel 600-mg udarna doza kod stabilnih CAD pacijenata Veza između IPA i kliničke aktivnosti još nije potvrđena Prilagođeno iz Gurbel PA, et al. Circulation. 2009;120:2577 2585.
Klinička farmakologija: TIKAGRELOR i klopidogrel TIKAGRELOR Klopidogrel Kemijska klasa CPTP tienopiridini Reverzibilna inhibicija P2Y 12 receptora DA NE PD varijabilnost CYP2C19 genotipa NE DA Doziranje 2 puta dnevno (bid) jednom dnevno (qd) Srednja inhibicija agregacije trombocita nakon 30 min Srednja inhibicija agregacije trombocita nakon 2 sata 41% 8% 89% 38% Gurbel PA, et al. Circulation. 2009;120:2577 2585. Sažetak opisa svojstava lijeka Brilique (BRILIQUE) PLAVIX [Uputa o lijeku, Hrvatska]..
TIKAGRELOR ima dvostruki mehanizam djelovanja: antitrombocitni učinak i pojačan adenozinski odgovor Trombocit ENT-1 Eritrocit Adenozin AC camp ADP A 2A P2Y 12 Gs Aktivacija/agregacija trombocita Gi Tikagrelor Inhibicija receptora P2Y 12 1,2 Antitrombocitni učinak Inhibicija ENT-1 transportera 3,4,5 Poboljšan lokalni adenozinski odgovor može rezultirati:* Dodatna inhibicija agregacije/aktivacije trombocita Kardioprotekcija 6 Vazodilatacija 5,7,8 Modulacija upale Dispneja 7 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. 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.
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.