Antiagregating agents and anticoagulants

Antiagregating agents and anticoagulants

Causes of arterial thrombosis a) Unstable atherosclerotic plaque (crucial factor for arterial thrombosis) b) Endothelial dysfunction (more frequent - women middle age) c) Generalised hypercoagulaton For arterial thrombosis is decisive activation of thrombocyte homeostasis

Pathophysiology of acute coronary syndromes Soft plaque plaque disruption occlusive thrombus perfusion decrease ischemia necrosis

Venous thrombosis a) Blood velocity decreased (coagulation factors activaton) b) endothelial dysfunction c) generalized hypercoagulation For venous thrombosis is decisive secondary homeostasis activation

Antiplatelet therapy

TROMBOCYTE normal activation

ADHESION contact phase binding through vwf to subendothelial collagen trombocyte

ADHESION - stabilization phase binding through fibronectine, collagen, laminine and vwf subendothelial space trombocyte

THROMBOCYTE ADHESION

ACTIVATION - thrombocyte and ADP pathway (degranulation and GP IIb/IIIa receptor expresion). subendothelial space

ADHESION AND THROMBOCYTE AGREGATION bivalent proteins

Primary thrombus farmation and fibrin polymerization

ANTIPLATELET AGENTS 1) ADHESION BLOCKADE - GP Ib/IIa, vwf antagonists (clinical trials) 2) ACTIVATION BLOCKADE - inhibition - TXA 2., ADP, serotonine., thrombin activation (inhib. COX, TXA 2 recept., ticlopidin, clopidogrel) 3) PLATELET STABILISATION ( cyclic nukleotides) - camp (dipiridamol) or cgmp (NO donors) 4) ANTI-AGGREGATION (GP Iib/IIIa inhibition) - peptides (abciximab, eptifibatid), - fibans 1st. generation (tirofiban), 2. generation

Thromocyte adhesion, activation and aggregation ticlopidinc clopidogrel rec. ADP hrombine rec. heparine ridogrel thrombocyte rec. TXA2 ketanserin naftidrofuryl GPIb vwf collagen serotonine rec. GP Ia abciximab tirofiban eptifibatid IIb/IIIa IIb/IIIa vwf fibrinogen inhib. vwf IIb/IIIa IIb/IIIa Activation COX a TX synt. release TXA 2 ASA indobufen dazoxiben Vessel wall

Thromboxane activation inhibitors a) Cyclooxygenase inhibition (COX 1 ): - irreversible inhibition: ASA - reversible inhibition: indobufen, NSA, sulfinpyrazone b) Tromboxane syntase inhibition: dazoxibene, ozagrel c) TXA 2 receptors antagonists : ridogrel, nidrogrel

Acetylsalicylic acid (ASPIRIN, ASA) ireversible acetylation COX 1 (up to 7 days) farmacoeconomy highly effective optimal dose 100-350 mg (75-2000 mg) 10-20% population ASA resistent indication: acute coronary ischemia (IM, unstable angina) secondary prevention (after IM, stroke, TIA, peripheral occlusion, arterial intervention) primary prevention high risk patients hypertension a diabetes

ASA mechanism of action Phospholipase - PLA2 trombocyte endothel COX-1 ASA indobufen arachidonic acid PGG 2 / PGH 2 COX-2 activated endothel COX-2 inhib. TXA 2 PGE 2 PGF 2a PGI 2

Cardiovascular mortality/morbidity decrease after ASA unstable angina 15 13,8% 10 8,3% 10,2% 5,8% placebo ASA 15 10 myocardial infarction MI acute 14.4% 10.6% placebo ASA 11.7% 9.3% 5 3,5% 2,1% 5 2.2% 1.0% 0 0 CV events CV mortality nonfatal IM MI chronic placebo ASA CV events CV events nonfatal stroke stroke or TIA placebo ASA 20 17.1% 25 21.0% 15 13.5 20 14.6% 10 5 9.4% 8.1% 6.5% 4.7% 15 10 5 8.4% 6.3% 10.2% 6.6% 0 CV events CV mortality unstabile stroke 0 CV events CV mortality nonfatal stroke

ASA - CV MORTALITY AND MORBIDITY (IM, STROKE) (ANTIPLATELET TRIALIST COLLABORATION) STUDIES 3 primary prev. 20 cerebral 11 MI 11 AMI 12 AP 20 CABG/PTCA 28 peripheral 51 DVT 30 others 189 total Br Med J 1994 EVENTS 1176 1916 2270 2783 398 245 444 67 283 9789 COHORT 27210 9530 15529 18126 3450 3057 3864 4771 3948 90297 ANTIPLATELET AGAINST CONTROL 0.0 0.5 1.0 1.5 2.0 effect 2p < 0.00001 RRR ± SD 12 ± 6 % 24 ± 5 % 24 ± 4 % 26 ± 4 % 39 ± 9 % 33 ± 13 % 25 ± 10 % 42 ± 19 % 44 ± 10 % 25 ± 2 %

RESISTANCE TO ASA - antiaggegation effect decreased - multifactorial etiology - higher incidence of thrombotic events - 5% non-responders - 20% semi-responders

Competitive COX-1 inhibitors indobufen, sulfinpyrazon, Comparable effect to ASA not proven Not recomended for therapy

Thienopyridines O S N Cl ticlopidin (1. generation) S N C Cl clopidogrel (2. generation) O C H 3 C H 3 O O S O N F prasugrel (3. generation)

ADP activation inhibitors (thienopyridines) irreversibile block ADP activation More effective than ASA, Potenciation of ASA ticlopidine slow onset, agranulocytoses. clopidogrel faster onset, leukopenia rare potenciation of fibrinolysis indikations: acute coronary sy, sec. prevention., PTCA Very high price in comparison with ASA

TICLOPIDINE thienopyridine derivative, slow onset, full effect after 8-11 days Inhibition of ADP platelet activation (induced by collagen, adrenaline) ireversible effect for thrombocyte life span (effect disappears after 10-14 days) dose 2x250 mg

TICLOPIDINE Indication: alergy or bad tolerance ASA CV events during ASA treatment PTCA, PTA (4 weels) Adverse events: GIT dyscomfort (with meal) neutropenia 0,5-1,0% (check blood count WBC!)

CLOPIDOGREL irreversible blockade platelet activation (and aggregation) mediated by ADP faster onset safer (rare neutropenia) dosage: 75 mg daily, first dose 300 mg, effect after 4-6 h., steady state after 3-7 d expensive

CLOPIDOGREL Effect - potentiation by ASA indications: acute coronary syndrome (up to 6-12 m after attack), coronary interventions (PTCA + stent, prim. PTCA) secundary prevention of atherosclerosis (not very effective) PTCA Percutaneous Transluminal Coronary Angioplasty

CV mortality (MI/stroke) changes after treatment with clopidogrel N: 12 562

ASA and clopidogrel secondary prevention- CV mortality/morbiditu (CAPRIE) stroke 7,3% MI - 3,7% Peripheral vascular disease 23,8% Total decrease 8,7% ASA better clopidogrel better

krevní průtok (% poklesu) ASA - clopidogresl combination - potentiation 0-20 -40 klopidogrel + ASA -60-80 klopidogrel ASA placebo -100 0 5 10 15 20 25 30 35 40 45 50 1. Herbert JM et al. Thromb Haemost 1998; 80: 512 18. t (min.)

PRASUGREL thienopyridin ireversible block P2Y12 receptors Pro-drug metabolic activation resistance rare peroral, onset of actiity during 30 min faster onset.

PRASUGREL thienopyridin indications: acute coronary syndrome (up to 6-12 m after attack), coronary interventions (PTCA + stent, prim. PTCA) secundary prevention of atherosclerosis (not very effective)

příhody (%) Clopidogrel against prasugrelu mortality (12 měs.) - 15 10 CV+, IM, stroke clopidogrel prasugrel 12.1 9.9 o 19% NNT = 46 5 0 prasugrel bleeding clopidogrel 1.8 0 30 60 90 180 270 360 450 2.4 dny NNH = 167

F Ticagrelor HO O N N N HN N N S F HO OH non-thienopyridine - P2Y 12 receptor block reversibile receptor inhibition peroral, quick onset (1-2 h) safer, but short acting very promissing for subacute treatment

10 Comparison of ADP receptor inhibitors acute CV events 0-10 15%* 19%* 16%* -20 CURRENT klopidogrel 75 vs 150 mg TRITON prasugrel PLATO ticagrelor

GPIIb/IIIa receptor antagonists

Mechanism of action GP IIb/IIIa antagonists

GP IIb/IIIa antagonists - accute coronary syndrome, including interventions (most effective) - economy more expensive (app. 1000 US $) - peptides: abciximab (REOPRO) - antibodies eptifibatide (INTEGRILIN) - cyclic peptide - nonpeptide (fibans) 1. generation: parenteral - tirofibane (AGGRASTAT) peroral (orbo-, xemilo-, sibrafiban, ) 2. generation: higher affinity to receptors, other effects (roxi-, cromo-, frada-, lefradafiban)

GP IIb/IIIa inhibitors - mechanism of proagregating activity receptor conformational changes inactive active binding inhibitor fibrinogen GP IIb/IIIa GP IIb/IIIa site GP IIb/IIIa trombocyte

Abciximab (ReoPro) - Monoclonal antibody combination of 2 fragments - Specific binding to IIb/IIIa receptor - Long lastin effect (fading for 14 days) - High affinity to receptors Optimal effect for prevention and treatment of thrombotic complications after coronary interventions High price

small peptides IIb/IIIa peptide antagonists eptifibatid Imitate aminoacid sequention of fibrinogene chain (arginin-glycin-aspartin) Shorter effect in comparison with abciximab eptifibatid (cyclic heptapeptide) Main indication acute coronary events (nonq-mi) high risk patients

Non-peptide GP IIb/IIIa antagonists Tirofibane synthetic nucleoside analogue Injections Quick oncet of action Short acting - effect 4 8 hours Derived from Viper venom Indications non-stabile angina, PTCA

IIb/IIIa receptor antagonists clinical use PTCA Percutaneous Transluminal Coronary Angioplasty Acute coronary syndrom, mainly MI PTCA with thrombotic complicatons (local) Pharmacological treatment of non-q MI at risk patients Pharmacological treatment of AMI

NEW ANTIPLATELET AGENTS TRIFLUSAL (inhibition platelet COX), similar to ASA, better tolerability RIDOGREL (combination - block TXA 2 receptor and synthesis.), better than ASA (AMI) TROMBOSTATIN (oligopeptide, blocking thrombocyte thrombin receptor PAR-1, bradykinine degradating product), preclinical testing ANAGRELID - nonspecific inhibition of platelet activation (ADP, thrombin, collagen), for acute corronary syndrome only

Rational use of antiplatelet therapy Ischemic hearth disease acut form only (i.e. MI ) ASA, clopidogrel, eptifibatide, tirofiban (ticlopidine) Secondary prevention atherosclerosis after MI, stroke, TIA ASA, clopidogrel, event. ticlopidine) stable AP, silent ischemia, peripheral ischemia ASA, clopidogrel, event. ticlopidine Primary prevention of high risk patinets ASA After revascularisation interventions (stent) - ASA, clopidogrel, ticlopidine, abciximab, event. eptifibatid or tirofiban Atrial fibrilation (when anticoagulants are contraindicated) ASA

Anticoagulants

Secondary homeostasis erytrocytes trapping

coagulation system internal system external system XIa VIIa/TF ANTICOAGULATION IX IXa IX VIII VIIIa VIIIi VIIa/TF X Xa X V Va Vi act. protein C prot. S prot. C prothrombin thrombin XIII thrombomodulin fibrinogen fibrin fibrin net plazmin fibrin degradation product

ANTICOAGULANTS possibility for action thrombin inhib. - direct (hirudines, ximelagatran, agatroban, efegatran) - indirect (heparine, LMWH others) f. Xa inhibitors direct (xabans) - indirect (heparine, LMWH, pentasacharids - fondaparinux) 5) vitamine K dependent factors inhibition (vitamine K antagonists)

ANTICOAGULANTS mechanism of action 1. Thrombin inhibitors - direct /hirudines,ximelagatran, gatroban, efegatran) - indirect (heparines, LMWH) 2. Factor Xa inhibitors direct (xabans) - indirect (heparine, LMWH, pentasacharids - fondaparinux) 3. vitamin K dependent factors inhibition (vitamine K antagonists)

coagulation system internal system external system ANTICOAGULATION XIa VIIa/TF heparines, pentasacharides IX IXa IX VIII VIIIa VIIIi VIIa/TF i X Xa X V Va Vi act. protein C prot. S prot. C prothrombin htrombin XIII thrombomodulin fibrinogen fibrin fibrin net plazmin fibrin degradation product heparines, hirudins, ximelagatran

THROMBIN INHIBITORS a) indirect (heparine, LMWH) - no inhibition for thrombin bind to fibrin or f.xa b) direct (hirudines, competitive and noncompetitive inhibitors) - strong antithrombotic effect

INDIRECT THROMBIN INHIBITORS DIRECT TROMBIN INHIBITORS AT III TROMBIN Catalyt. site MELAGATRAN Reversible blockade of catalytic site THROMBIN LMWH, UFH ATIII mediated blockade of catalytic site for heparine activation HIRUDINE reversible blockade of fibrine catalytic and binding site THROMBIN

HEPARINE - UFH Sulphonyl-mucopolysacharide Continuous infusion necessary (sc. aplication uncertain) dosage prediction questionable (binding, variable farmacokinetic) Inability to inactivate thrombin bind to fibrin Neutralised by platelet factor 4 Induced trombocytopenie (HIT), bleeding Average effective dose 30 thousands IU 24h Neutralised by protamin sulfate Replaced in most indications by LMWH

Mechanism of action AT III Fibrinogen binding site THROMBN AT III catalytic site for f. Xa a thrombin TROMBIN f.xa UFH UFH, LMWH UFH LMWH AT III THROMBIN TROMBIN b i n d i n g AT AT III III AT III f.xa PENTASACHARIDS

Heparine fractionisation heparin (UFH) pentasacharids LMWH

Low molecular weight heparins (LMWH) Heparin depolymerisation (15 sacharides units) Higher inhibition fxa and lower thrombin (LMWH with longer chain higher trombin inhibition) Inability to inhibit thrombin bind to fibrin Longer effect Predictable effekt Good s.c. resorptione Lower incidence of trombocytopenie (HIT) Incomplete neutralization by protamine

Low molecular weight heparins (LMWH) mol.weight anti-xa/anti-iia UFH heparin Heparin 12 15 000 1,0 dalteparin Fragmin 6 000 2,7 enoxaparin Clexane 4 200 3,8 nadroparin Fraxiparin 4 500 3,6 parnaparin Fluxu 5 000 3,7 reviparin Clivarin 4 000 3,5 tinzaparin Logiparin 6 000 1,9

% distribuce Diferences between LMWH 10 15 20 25 sacharide iunits enoxaparin bemiparin reviparin parnaparin nadroparin dalteparin tinzaparin

PENTASACHARIDES - f.xa INHIBITORS selective factor Xa block, analog from pentasacharid sequence of heparinu, activate ATIII advatages: easy dosing, longer effect, predictable effect AT AT III III disadvantage: no antidote known AT III f.xa fondaparinux: prevention and treatment of perioperative TED and AKS better prophylaxisthan LMWH in DVT registered and reimbursed indaparinux: aplication 1x weekly

Hirudin, bivalirudin, lepirudin, desirudin direct trombin inhibitors reversibile blockade of the catalytic and binding side of fibrin proteins, parenteral aplication relat. shorter effect (30-150 min) indication: heparin induced trombocytopenia - HIT (antibodies vs. compl. heparin and PF4) AKS, intervention (PTCA,..) DVT, pulmonary embolia TROMBIN

Hirudin, bivalirudin, lepirudin, desirudin hirudin natural protein Hirudo officinalis bivalirudin, lepirudin, desirudin analogs with better resorption, longer halflife and higer afinity to trombin High cost, practically rarely used metaanalysis show only not signif. lower mortality in AKS compared with standart therapy (ASA, LMWH)

Gatrans direct thrombin inhibitors

Dabigatran (Pradaxa) Direct binding to thrombin catalytic center without AT thrombin inhibition (free and even bind to fibrin) dabigatran fibrinová síť trombin katalyt. místo

Dabigatran Peroral (bioavailability of pro-drug 6%) Low variability response (not necessary monitoring of effect) Renal elimination Hepatic metabolism

Dabigatran Direct reversible thrombin inhibition peroral Quick onset (max. effect after 1 hour) Long lasting effect ( 2x daily) Indication: prevention and treatment TE comparable to LMWH For stroke prevention better than warafarin

kumulativní riziko Dabigatran vs warfarin atrial fibrialtion - thrombotic comlications (RELY) 0.05 0.04 0.03 0.02 warfarin dabigatran 2x110 mg dabigatran 2x150 mg RR 0.91 (95% CI: 0.74 1.11) p<0.001 (NI) p=0.34 (Sup) RRR 34% RR 0.66 (95% CI: 0.53 0.82) p<0.001 (NI) p<0.001 (Sup) 0.01 0.0 0 0.5 1.0 1.5 2.0 2.5 roky Connolly SJ., et al. NEJM

Ximelagatran oral prodrug with conversion to melagatran excellent resorption and bioavailability reversibile inhibitor of trombin 2x daily, without monitoring need lower variability compared to warfarin (less interactions) TROMBIN Indication: prevention anad FT treatment, longterm anticoagulation in TED prevention

Xabans direct inhibition of f. Xa rivaroxaban, apixaban, otamixaban, edoxaban,

Rivaroxaban (Xarelto) Reversible inhibition of f. Xa (even bind to fibrin) Direct effect without AT Strong inhibition of thrombin activaton, but not thrombin activity rivaroxaban f. Xa katalyt. místo

Rivaroxaban peroral t 1/2 6-9 hours, 1-2x daily Small variability in response Prevention of TE after ortopedic operations, atrial fibrilation, DVT treatment comparable to enoxaparine

incidence (%) Rivaroxaban enoxaparin hip operations 4 20 3 TEN total RRR 70% TEN severe RRR 88% enoxaparin rivaroxaban 2 10 1 TEN sympt. bleeding 0 3.7% 1.1% 2.0% 0.2% 0.5% 0.3% 0.1% 0.3%

kumulativní výskyt (%) Rivaroxaban vs warfarin atrial fibrilation stroke prevention 6 5 4 rivaroxaban warfarin výskyt příhod 1.71 2.16 warfarin 21% 3 2 1 rivaroxaban HR (95% CI): 0,79 (0,66, 0,96 P-value Non-Inferiority: <0.0 0 0 120 240 360 480 600 720 840 960 Days Studie ROCKET AF

Apixaban direct f. Xa inhibition Peroral and injections Standard effect, no monitoring t 1/2 8-12 hours, 1-2x daily Low risk of interactions

Apixaban For prevention of TE after ortopediv operatins better than enoxaparine For prevention of strojke during atrial fibrialtion better than ASA and warfarin

COAGULATION SYSTEM internal pathway external pathway ANTICOAGULATION SYSTEM XIa VIIa/TF heparin, pentasacharides IX IXa IX VIII VIIIa VIIIi VIIa/TF X Xa X V Va Vi akt. prot. C prot. S prot. C protrombin trombin XIII trombomodulin fibrinogen fibrin fibrin net plazmin degradation fibrin products heparin, hirudines,ximelagatran

vitamin K warfarin

Vitamin K antagonist- WARFARIN - Synthesis inhibition of vitamin K dependrnt factors (coagul. and anticoagul.) - Currentlythe only registered orally effective anticoagul. - good bioavailab., plasma protein binding - 5x effective stereoizomer metabol. CYP 2C9 - Signif. interindivid. variability metabol., interaction with food and other drugs, vit. K in food - Monitoring the (INR) effect is essential - First stage of treatment procoagul. effect (inhib. synt. anticoagul. factors), suuitable combination with LMWH

COAGULATION SYSTEM internal pathway external pathway ANTICOAGULATION SYSTEM XIa VIIa/TF IX IXa IX VIII VIIIa VIIIi VIIa/TF X Xa X V Va Vi act. prot. C prot. S prot. C protrombin trombin XIII trombomodulin fibrinogen fibrin fibrin net plasmin degradation fibrin products antivitamines K tpa

warfarin KUMATOX - jed na potkany a myši

CYP2C9 Polymorfism via CYP2C9 metabolism 15-20% of drugs - ASA and NSAIDs, warfarin, sulphonamides, phenitoin, barbiturates, - activation of AT 1 rec. blockers (sartanes) > 30 types of polymorfism: slow, medium and quick metabolism Impact of CYP2C9*2 (10-20% population) CYP2C9*3 (6-9% population) slow metabol. significanz slow down degradation of warfarin (5-27x clearence), risc of bleeding

poměr rizika Narrow therapeutic window warfarinu 15 rrisk trombembolisme terapeutic window Risk of bleeding 10 5 3 1 1.0 1.5 2.0 3.0 4.0 7.0 INR INR < 2.0 - INR > 4.0

Warfarin indications Prevention of embolism Atrial fibrialtion Valvular prosthesis Chronic thromboembolis Pulnomal artery embolism Trombofilic disiease

Warfarin contraindications Coagulopathy, High risk of bleeding - Gastric ulcer Crohn disease, High hypertension gravidity

Bleeding during warfarin treatment WARFARIN Stop treatment vitamin K 1 p.o. (1-10 mg), event. i.v.. Fresh frozen plazma i.v. Prothromplex human coagulation factors II (prothrombin), VII, IX, X -?? Riziko krvácení po 7. dekádě, u jaterní či renální insuf., po iktu, při anamnéze krvácení, u diabetu,

Arterial trombosis treatment - fibrinolysis activation

FIBRINOLYSIS SCHEME Tissue-type (t-pa) plasmin Urokinase type (u-pa) activators plasminogen activators inhibitors PAI-1 PAI-2 PAI-3 plasminogen Plazmin inhibitors plasmin 2 -antiplasmin 2 -makroglobulin FIBRIN fibrin degradation products

Fibrin and fibrinolysis polymerisation scheme fibrinogen trombin faktor XIIIa Fibrin dimer fibrin polymer plasmin fibrin net Fibrin degradation products

Advantages and disadvantages of essential fibrinolytics streptokinases: effective, cost effective, antigenic, hypotension release r-tpa: quick and very effective, nonantigenic, select. short term effect, very expensive anistreplases: quick effect (bolus), long lasting (APSAC) antigenic, average price urokinases: effective, bolus, neantigenic, expensive

Fibrinolytics derivatives from t-pa (longer lasting effect, higher specificity to fibrin) alteplasis lanoteplasis TNK reteplasis

Trombolysis efect related to delay from onset of MI attack Reduced Mortality (%)

ANTI-PLATELET TREATMENT POSSIBILITIES 1) adhesis inhibitors: monocl. antibodies versus vwf and platelet rec.gpi 2) activation inhibitors: a) tromboxan activation blockers: COX blockers (ASA, indobufen) TX rec. inhibitors (ridogrel) tromboxan-synthasis inhibitor (dazoxiben) b) ADP rec. blockers: tiklopidin, klopidogrel c) serotonin rec. blockers: naftidrofuryl, ketanserin d) trombin rec. blocker: inhibitory trombinu e) multipotent platelet rec. blockers: (anagrelid) 3) agregation inhibitors: GPIIb/IIIa rec. antag. (abciximab, integrilin, epitifibatid, II. generation: roxifiban, lotrafiban, fradafiban) 4) platelet stabilisation : via camp (dipyridamol) or cgpm (NO donators)