PHARMACOLOGY OF COMMON ANTITHROMBOTICS KAMALES ARUMUGAM PRINCIPAL PHARMACIST ANTICOAGULATION WORKSHOP 19 TH SEP 2014

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1 PHARMACOLOGY OF COMMON ANTITHROMBOTICS KAMALES ARUMUGAM PRINCIPAL PHARMACIST ANTICOAGULATION WORKSHOP 19 TH SEP 2014

2 INTRODUCTION Thrombus pathology Antiplatelet Anticoagulants HIT Switching Anticoagulants Fibrinolytics

3

4

5 THROMBI PATHOLOGY ARTERIAL THROMBI VENOUS THROMBI FORMATION Artery Vein; tend to fragment creating an embolus INITIATION COMPOSITION Spontaneously or mechanical rupture of atherosclerotic plaques Mainly platelets, also contains fibrin & occasionally leukocytes & small amounts of coagulated erythrocytes Venous stasis or vascular injury after surgery or trauma Fibrin & erythrocytes KNOWN AS White thrombi Red thrombi MANIFESTS AS MI, Unstable angina, Ischaemic stroke, Peripheral artery disease e.g. acute limb ischaemia DVT, PE, AF related-thrombi

6 ANTITHROMBOTIC DRUGS

7 ANTIPLATELET DRUGS

8 ANTIPLATELET DRUGS

9

10 ANTIPLATELET DRUGS Aspirin P2Y 12 inhibitors: Clopidogrel Ticlopidine Thienopyridines Prasugrel Ticagrelor Dipyridamole Glycoprotein IIb/IIIa inhibitors: Abciximab Tirofiban Eptifibatide Antiplatelet drugs reduce mortality, risk of reinfarction & stroke

11 ASPIRIN MOA:

12 ASPIRIN ASPIRIN (ASA) PHARMACOKINETICS Action: rapid, peak plasma levels in 20 min Duration of action: 7-10 days Clearance: rapid Renal: caution in severe impairment; risk of bleeding & further deterioration of renal function INDICATIONS Acute MI, UA, Primary prevention of stroke & TIA, Secondary prevention of stroke, TIA & in IHD, Pain, Inflammation & fever DOSE Acute conditions: mg Long term: mg daily PRECAUTIONS ASA & NSAID allergies & aspirin-sensitive asthma Active peptic ulcer disease or other bleeding predispositions COMMON ADVERSE EFFECTS GI side effects (2 4x higher with ASA use; dose related) Asymptomatic blood loss Increased bleeding time PRACTICE POINTS No evidence that EC products decrease GI bleeding risk Patients with Hx of ASA-induced ulcer bleeding, clopidogrel causes more recurrent ulcer bleeding than ASA combined with PPI

13 ADP P2Y 12 RECEPTOR ANTAGONISTS Clopidogrel, Ticlopidine, Prasugrel The active metabolites selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y 12 receptor (irreversibly) and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation

14 ADP P2Y 12 RECEPTOR ANTAGONISTS CLOPIDOGREL (PLAVIX ) PHARMACOKINETICS Action: rapid, peak plasma levels in 45 min Duration of action: 7-10 days Metabolised extensively in the liver INDICATIONS Prevention of vascular ischaemic evens in pts with symptomatic atherosclerosis, NSTEACS (with ASA), adjuvant to reperfusion for STEMI (with ASA), Prevention of thromboembolism after placement of stent DOSE Loading dose: mg Long term: 75mg daily PRECAUTIONS COMMON ADVERSE EFFECTS Combining clopidogrel with inhibitors of CYP2C19 or genetic lack of CYP2C19 activity may decrease clopidogrel's effectiveness in reducing the risk of CV events (evidence is conflicting) Diarrhoea, GI ulcers, dyspepsia, brusing, TTP (very rare) PRACTICE POINTS Optimal duration of treatment in ACS & after placement of coronary stent is debated; longer treatment is recommended with a DES than with a BMS

15 ADP P2Y 12 RECEPTOR ANTAGONISTS TICLOPIDINE (TICLID ) PHARMACOKINETICS Action: peak plasma levels in 2 hours Duration of action: 7-10 days Metabolised extensively in the liver INDICATIONS DOSE Secondary prevention of ischaemic stroke and TIA in patients intolerant of or unresponsive to other antiplatelet drugs 250mg twice daily PRECAUTIONS COMMON ADVERSE EFFECTS Hematologic adverse reactions, including neutropenia, thrombocytopenia, TTP, aplastic anemia, agranulocytosis, pancytopenia, and leukemia, including fatalities, have been reported; monitoring recommended; therapy discontinuation may be necessary Diarrhoea, nausea, anorexia, vomiting, upper abdominal pain (tolerance may develop), mild-to-severe neutropenia PRACTICE POINTS Risk of neutropenia is greatest in the first 12 weeks of treatment; obtain FBC at baseline, then every 2 weeks for 4 months, then as indicated Stop ticlopidine if neutrophil count is <1.2x109/L or platelet count is <80x109/L; neutropenia is usually reversible on stopping ticlopidine

16 ADP P2Y 12 RECEPTOR ANTAGONISTS PRASUGREL (EFFIENT ) PHARMACOKINETICS Action: rapid, peak plasma levels in 30 mins Duration of action: 7 9 days; 5 days (depending loading/maintenance dose) Hydrolysed in the intestine INDICATIONS Prevention of atherothrombotic events (with ASA) in ACS (including STEMI and non-stemi) to be managed with PCI DOSE Give with low-dose ASA ( mg daily) Initially 60 mg, then 10 mg once daily >75 years or <60 kg: initially 60 mg, then 5 mg once daily PRECAUTIONS History of stroke or TIA contraindicated due to an increased risk of bleeding and stroke in trials Asian ethnicity may be at increased risk of bleeding COMMON ADVERSE EFFECTS PRACTICE POINTS Bleeding (may be severe and may cause anaemia) Hypersensitivity reactions (cross-reactivity can occur with other thienopyridines) In UA/NSTEMI patients, where coronary angiography is performed within 48 hours after admission, the loading dose should only be given at the time of PCI

17 ADP P2Y 12 RECEPTOR ANTAGONISTS Selective and reversibly binding P2Y 12 receptor antagonist that prevents ADP mediated P2Y 12 dependent platelet activation and aggregation

18 ADP P2Y 12 RECEPTOR ANTAGONISTS TICAGRELOR (BRILINTA ) PHARMACOKINETICS Action: rapid, peak plasma levels in 30 mins Platelet function recovery 3-4 days after cessation Metabolised in the liver by CYP3A4 INDICATIONS ACS (with aspirin) DOSE Give with low-dose ASA ( mg daily) Loading dose 180 mg, then 90 mg twice a day PRECAUTIONS Patients at risk of bradycardia (e.g. SSS without pacemaker, 2 nd or 3 rd -degree COMMON ADVERSE EFFECTS AV block) asymptomatic ventricular pauses Asthma, COPD ticagrelor may cause dyspnoea Weight <60 kg increases risk of bleeding Hyperuricaemia ticagrelor may increase uric acid concentration Treatment with CYP3A4 strong inhibitors contraindicated Bleeding (may be severe & cause anaemia), dyspnoea, nausea, diarrhoea, noncardiac chest pain, headache, raised uric acid concentration, raised creatinine concentration PRACTICE POINTS 12-month study: ticagrelor+asa more effective than clopidogrel+asa in preventing CV events in patients with ACS: Sig. reduction in MI & vascular death, but a non-sig. increase in stroke Incidence total major bleeding similar, rate of major IC haemorrhage was higher with ticagrelor

19 DIPYRIDAMOLE It inhibits the uptake of adenosine into the platelet & erythrocytes stimulate platelet adenylate cyclase & increase levels of platelet camp prevent activation and aggregation of platelet

20 DIPYRIDAMOLE DIPYRIDAMOLE PHARMACOKINETICS Action: peak 2 3 hours (CR) Extensively metabolized in the liver INDICATIONS Prevention of thromboembolism in patients with prosthetic heart valves (with warfarin) Secondary prevention of ischaemic stroke & TIA, including combination with ASA Cardiac stress testing (IV) DOSE Prevention of thromboembolism : PO mg daily in 3-4 doses Secondary prevention of stroke & TIA: PO 200mg CR twice daily PRECAUTIONS Vasodilatory effect (used with caution in patients with severe CAD) Beer s Criteria (short-acting dipyridamole): Not recommended, poorly tolerated & may cause orthostatic hypotension Aortic stenosis dipyridamole-induced vasodilation may increase pressure gradient across aortic valve and worsen organ perfusion. Unstable angina, recent MI use with caution; vasodilation may induce myocardial ischaemia. COMMON ADVERSE EFFECTS Headache, diarrhoea, nausea, vomiting, hot flushes, hypotension, tachycardia

21 GLYCOPROTEIN IIb/IIIa INHIBITORS Prevent binding of fibrinogen to platelet, by occupying glycoprotein IIb/IIIa receptor, thereby blocking platelet aggregation

22 GLYCOPROTEIN IIb/IIIa INHIBITORS ABCIXIMAB (REOPRO ) PHARMACOKINETICS Chimeric monoclonal antibody Action: within 10 mins Duration of action: Platelet function recovers over 48 hours Remains in the circulation for 15 days in a platelet-bound state INDICATIONS PTCA and intracoronary stenting Unstable angina refractory to treatment where PCI is planned DOSE PCI: IV bolus 250 mcg/kg before procedure, then 0.125mcg/kg/min for 12 hours Planned PCI in refractory unstable angina: Start hours before intervention; IV bolus of 250 mcg/kg, followed by infusion of 10 mcg/min; stop 1 hour after intervention PRECAUTIONS Abciximab infusion within 30 days increases risk & severity of thrombocytopenia Thrombocytopenia from previous abciximab increases risk of recurrence COMMON ADVERSE EFFECTS PRACTICE POINTS Bleeding, thrombocytopenia Give low-dose ASA & heparin infusion with abciximab Monitor baseline PT, APTT, CrCl, platelet count, Hb & HCT; after starting, monitor Hb & HCT at 12 & 24 hrs, & platelet count at 2 4 hrs & 24 hrs

23 GLYCOPROTEIN IIb/IIIa INHIBITORS EPTIFIBATIDE (INTEGRILIN ) PHARMACOKINETICS Action: immediate Duration of action: Return of platelet function 4 hours after stopping continuous inf Clearance: Renal INDICATIONS Unstable angina and non-stemi in high-risk patients Elective PCI with stenting DOSE PCI: IV bolus 180mcg/kg just before intervention, then 2nd bolus of 180mcg/kg 10 mins later. Start IV inf, 2mcg/kg/min, with first bolus until hospital DC or up to a max of hrs post intervention UA, non-stemi: IV bolus 180mcg/kg followed by 2mcg/kg/min IV inf for up to 72 hrs until initiation of CABG or DC from hospital. If PCI is performed during that time, continue inf for hrs after intervention for an overall max duration of 96 hrs PRECAUTIONS Renal: Same bolus but reduce inf to 1mcg/kg/min Hepatic: Avoid in patients with significant hepatic disease COMMON ADVERSE EFFECTS Bleeding, thrombocytopenia PRACTICE POINTS Give low-dose ASA and heparin infusion with eptifibatide Monitor PT, APTT, CrCl, platelet, Hb & HCT before treatment; monitor Hb, HCT and platelet within 6 hrs after start of treatment & at least once daily thereafter

24 GLYCOPROTEIN IIb/IIIa INHIBITORS TIROFIBAN (AGGRASTAT ) PHARMACOKINETICS Chimeric monoclonal antibody Action: rapid, within 30 mins Duration of action: Returns of platelet function within 8 hrs after discontinuation Clearance: Renal and biliary INDICATIONS DOSE PRECAUTIONS COMMON ADVERSE EFFECTS Unstable angina and non-stemi in high-risk patients IV 0.4mcg/kg/min for 30 minutes, followed by 0.1mcgkg/min for hrs Renal: Reduce dose by 50% when CrCl <30 ml/min Bleeding, thrombocytopenia PRACTICE POINTS Give low-dose ASA and heparin infusion with tirofiban Monitor PT, APTT, CrCl, platelet, Hb & HCT before treatment; monitor Hb, HCT and platelet within 6 hrs after start of treatment & at least once daily thereafter

25 ANTICOAGULANTS

26 ANTICOAGULANTS

27 ANTICOAGULANTS HISTORICAL DEVELOPMENT Oral Spoiled sweet clover Warfarin clinical use Dicoumarol discovered Warfarin / Vitamin K mechanism High / low dose Warfarin / INR Warfarin clinical trials Ximelagatran clinical trials Dabigatran Rivaroxaban Apixaban AZD s 1970s s 1990s Heparin discovered Heparin clinical use Continous heparin infusion/ aptt LMWH discovered LMWH clinical trials Pentasaccharide clinical trials Injection

28 ANTICOAGULANTS Heparins: UFH Enoxaparin Tinzaparin Warfarin Direct Thrombin Inhibitors: Dabigatran Bivalirudin Argatroban Lepirudin NA in Malaysia Melagatran Factor Xa Inhibitors: Fondaparinux Rivaroxaban Apixaban

29 HEPARIN (UFH) When heparin sodium is combined with antithrombin III (heparin cofactor), thrombosis is blocked through inactivation of Factor Xa and inhibition of prothrombin's conversion to thrombin (Factor IIa). This also prevents fibrin formation from fibrinogen during active thrombosis

30 HEPARINS HEPARIN (UFH) PHARMACOKINETICS Action: immediate Elimination T½: 1.5 hr (anticoagulation effect half-life) Metabolised in the liver; inactive metabolic products are excreted in the urine INDICATIONS Prevention of VTE & other thromboses in surgical and high-risk medical patients (including during procedures, eg haemodialysis) Treatment of VTE, ACS, peripheral arterial occlusion & disseminated intravascular coagulation (DIC) DOSE PRECAUTIONS COMMON ADVERSE EFFECTS Refer to PI/local protocols & indications for dose recommendations HIT Thrombocytopenia, bleeding, HIT, increased liver transferases PRACTICE POINTS Unexpectedly high APTT may be due to blood sample being taken from same limb as heparin infusion Preferred over LMWH in severe renal impairment Monitor APTT (6 hrs) after dose changes, platelet counts, HCT, signs & symptoms of bleeding

31 LMWH LMWH has greater capacity to potentiate factor Xa inhibition by antithrombin than thrombin because, with a mean molecular weight of , at least half of the LMWH chains are too short to bridge antithrombin to thrombin

32 LMWH ENOXAPARIN (CLEXANE ) PHARMACOKINETICS Action: anti-xa activity occurs 1 to 4 hours after injection Elimination T½: 4 5 hrs Metabolism: renal (40%) & hepatic INDICATIONS Prevention of VTE in surgical patients & in medical patients bedridden due to acute illness Treatment of venous thrombosis Prevention of extracorporeal thrombosis during haemodialysis Treatment of acute STEMI, non-stemi and unstable angina Treatment of PE DOSE Prophylaxis dose: mg once daily Treatment dose: 1mg/kg every 12 hrs Adjusted by weight & CrCl (if <30ml/min use 50% dose) PRECAUTIONS COMMON ADVERSE EFFECTS PRACTICE POINTS Caution in patients with renal impairment due to increased risk for bleeding; monitoring recommended (antifactor Xa) Bleeding, bruising and pain at injection site, hyperkalaemia, mild reversible thrombocytopenia, increased aminotransferases Consider heparin IV if an invasive procedure is anticipated as the anticoagulant effect diminishes more quickly after stopping

33 LMWH TINZAPARIN (INNOHEP ) PHARMACOKINETICS Action: peak plasma activity being observed after 4 to 6 hours Elimination T½: 1.5 hrs Excreted in urine primarily unchanged drug INDICATIONS Treatment of DVT and PE Prevention of postoperative DVT in patients undergoing general and orthopaedic surgery Prevention of extracorporeal thrombosis DOSE Prophylaxis dose: 75 anti Xa-units/kg/d or 3500 units/day Treatment dose: 175 anti Xa-units/kg/d PRECAUTIONS COMMON ADVERSE EFFECTS Caution in patients with renal or hepatic insufficiency; consider dose reduction Erythema, increased LFTs, localised pain, injection site hematoma

34 COMPARISONS BETWEEN UFH & LMWH ISSUES Bleeding incidence Protamine Renal impairment Severe HIT Osteoporosis General surgery (prevention) Orthopaedic surgery (prevention) DVT (treatment) NSTEACS VTE in cancer COMMENTS similar for heparin and LMWHs only partially effective in reversing effect of LMWHs risk of severe bleeding is higher with LMWHs lower with LMWHs; LMWHs should not be used as an alternative; cross-reactivity occurs in 90% of cases; incidence is even lower with danaparoid & it is used for treatment of HIT seems lower with LMWHs heparin & LMWHs have similar efficacy in preventing VTE LMWHs more effective than heparin or warfarin LMWHs as effective as heparin in preventing recurrent thromboembolism and in reducing overall mortality Enoxaparin appears to be slightly more effective than heparin in reducing the combined endpoint of death or MI but it increases the risk of major bleeding Long-term treatment with LMWHs (dalteparin) may be more effective than vitamin K antagonists

35 HIT Digital Ischemia in a Patient with Heparin-Induced Thrombocytopenia

36 HIT

37 HIT Occurs in <1% of patients with short-term use HIT should be suspected: Thrombocytopenia Thrombosis with thrombocytopenia Platelet count has fallen >50% Necrotic skin lesions at injection sites (heparin was started preceding 5-10 days) Diagnosis is initially made on clinical ground Assays with highest sensitivity and specificity may not be available & have slow turnaround time 1. Warkentin, TE, et al. Treatment and prevention of heparin-induced thrombocytopenia. ACCP Evidence-based clinical practice guidelines (8th edition) 2008;133 (6 Suppl): 340S..

38 HIT Delayed onset HIT has also occurred up to several weeks after stopping heparin May result in major ischaemic complications (eg stroke, limb ischaemia), bleeding or death Monitoring: Early recognition is important Baseline platelet count is a MUST Daily platelet count starting from Day 1 in patients with history of past heparin exposure within 3 months (occurs earlier if patient has been recently (<100 days) exposed to heparin) Otherwise, start on Day 4 Withhold heparin or LMWH if platelet count drops 30 50% below baseline and substitute alternative anticoagulant

39 HIT Treatment options: Lepirudin, Argatroban (both FDA approved) or Bivalirudin (limited data) Danaparoid (cross-reactivity 10%) Fondaparinux (weaker evidence) Warfarin alone should not be used Risk of causing venous limb gangrene and/or skin necrosis Safe to be use when patient is adequately and stably anticoagulated with a drug that reduces thrombosis & when platelet count is > 150,000/microL Prophylactic platelet transfusions should not be administered for patient with HIT who do not have active bleeding If heparin-induced thrombocytopenia (HIT) is confirmed, future use of heparin or LMWH is contraindicated

40 WARFARIN

41 ELIMINATION T½ OF VIT-K DEPENDANT PROTEINS PROTEIN T½ (hours) Factor VII 4 6 Factor IX 24 Factor X Factor II 60 Protein C 8 Protein S 30 Warfarin 40 (range 20 60)

42 LOADING DOSE VS MAINTENANCE DOSE

43 WARFARIN WARFARIN PHARMACOKINETICS Action: onset 24 hrs; peak 3 4 days; stabilised effect in days (ave days) Elimination T½: hrs (mean 40hrs) Metabolism: Hepatic (primarily via CYP2C9; minor pathway: CYP2C8, 2C18, 2C19, 1A2 & 3A4) INDICATIONS Prevention and treatment of VTE Prevention of thromboembolism in patients with prosthetic heart valves Prevention of stroke in patients with previous MI and increased embolic risk Prevention of stroke in non-valvular AF DOSE Follow local protocols & individualise according to TTR PRECAUTIONS Alcoholism contraindicated Compliance likely to be poor avoid unless supervised administration Protein C or protein S deficiency increases risk of skin necrosis COMMON ADVERSE EFFECTS Bleeding, skin necrosis (stop treatment), purple discolouration of toes, alopecia, fever, rash, nausea, vomiting, diarrhoea, hepatic dysfunction, allergic reactions, eg hypersensitivity PRACTICE POINTS Different brands are not bioequivalent and should not be interchanged Many drugs interactions; monitor the INR when changing drug treatment Consider use of a warning bracelet or necklace (Yayasan MedicAlert) Advise patients of the intended duration of anticoagulation, and the potential risks of stopping treatment without medical advice Review the need for continued warfarin treatment regularly

44 DIRECT THROMBIN INHIBITORS Reversibly inhibit both free and fibrin-bound thrombin, preventing conversion of fibrinogen to fibrin, preventing thrombus formation. Thrombin-induced platelet aggregation is also inhibited

45 DIRECT THROMBIN INHIBITORS DABIGATRAN (PRADAXA ) PHARMACOKINETICS Action: peak hrs Elimination T½: hrs Excretion: renal (primary); reduce dose in renal impairment INDICATIONS Prevention of VTE after elective total hip or knee replacement Non-valvular AF or high risk of stroke or systemic embolism DOSE Prevention of VTE after knee/hip replacement: initially 110mg within 1 4 hrs after surgery, then 220mg once daily; CrCl ml/min: 150 mg once daily Prevention of emboli in AF: 150mg BD; CrCl ml/min & >75 yrs: 110mg BD PRECAUTIONS GI haemorrhage within previous 12 months CI (more common than with warfarin in a clinical trial comparing their use in AF) Prosthetic heart valve CI COMMON ADVERSE EFFECTS Gastritis, dyspepsia, GI bleeding, oesophageal ulcers, increased liver enzymes & bilirubin PRACTICE POINTS Watch for drug interactions: verapamil, amiodarone, ketoconazole, P-gp inhibitors, clarithromycin, dronedarone, etc. Swallow capsule whole; oral bioavailability may be increased by 75 % when the pellets are taken without capsule shell; increased risk of bleeding

46 SWITCHING ANTICOAGULANTS (DABIGATRAN) SWITCHING From dabigatran to parenteral anticoagulant From parenteral anticoagulant to dabigatran From dabigatran to warfarin From warfarin to dabigatran RECOMMENDATIONS Prevention of VTE after knee/hip replacement: wait for 24 hours after the last dabigatran dose Prevention of emboli in AF: wait for 12 hours after the last dabigatran dose Start dabigatran within the 2 hours before the due time of the next dose of parenteral anticoagulant CrCl >50 ml/min: start warfarin 3 days before stopping dabigatran CrCl ml/min: start warfarin 2 days before stopping dabigatran CrCl ml/minute: start warfarin the day before stopping dabigatran Stop warfarin and start dabigatran when INR <2

47 FACTOR Xa INHIBITORS Selectively inhibit factor Xa, blocking thrombin production, conversion of fibrinogen to fibrin, and thrombus development

48 FACTOR Xa INHIBITORS FONDAPARINUX (ARIXTRA ) PHARMACOKINETICS Action: peak 3 hr Elimination T½: hr Excretion: renal (primary); may need to reduce dose in renal impairment INDICATIONS Prevention of VTE in high-risk orthopaedic surgery (hip fracture, knee or hip replacement) and abdominal surgery Treatment of VTE Treatment of high-risk unstable angina or non-stemi (NSTEACS) if PCI is not immediate DOSE PRECAUTIONS COMMON ADVERSE EFFECTS PRACTICE POINTS Prevention of VTE: 2.5mg SC once daily for 5 9 days; CrCl ml/min, 1.5mg once daily Treatment of VTE: <50 kg, 5mg SC once daily kg, 7.5mg SC once daily >100 kg, 10mg SC once daily >100 kg and CrCl ml/minute, initial 10mg SC, then 7.5mg SC once daily Treatment of high-risk NSTEACS: 2.5mg SC once daily Contraindicated when CrCl <30 ml/minute Thrombocytopenia, allergy NSTEACS additional dose of heparin must be given before an angiogram or PCI are performed

49 FACTOR Xa INHIBITORS APIXABAN (ELIQUIS ) PHARMACOKINETICS Action: peak 3 4 hrs Elimination T½: 12 hrs Excretion: hepatic & renal (30%) INDICATIONS Prevention of VTE following elective hip or knee replacement Non-valvular AF or high risk of stroke or systemic embolism DOSE Prevention of VTE after hip/knee replacement: 2.5mg BD Prevention of emboli in AF: 5mg BD PRECAUTIONS COMMON ADVERSE EFFECTS PRACTICE POINTS If at least 2 of: Weight <60 kg, age >80 years, SeCr>133 µmol/l, reduce dose to 2.5mg BD Nausea, thrombocytopenia, abnormal LFTs Apixaban is not indicated for patients with hip fracture (no clinical trial data

50 SWITCHING ANTICOAGULANTS (APIXABAN) SWITCHING From apixaban to parenteral anticoagulant (and vice versa) RECOMMENDATIONS Start at time of the next scheduled dose From apixaban to warfarin Give warfarin with apixaban for 2 days, then check INR before the next apixaban dose. Continue both drugs until INR >2. From warfarin to apixaban Stop warfarin and start apixaban when INR <2

51 FACTOR Xa INHIBITORS RIVAROXABAN (XARELTO ) PHARMACOKINETICS Action: peak 2 4 hrs Elimination T½: 5 12 hrs Excretion: Hepatic & renal (30%) INDICATIONS Prevention of VTE following elective hip or knee replacement Treatment of acute VTE and prevention of subsequent VTE Non-valvular AF or high risk of stroke or systemic embolism DOSE PRECAUTIONS COMMON ADVERSE EFFECTS Prevention of VTE after hip/knee replacement: 10mg once daily Treatment of acute VTE & prevention of subsequent VTE: 15mg BD for 3 weeks, then 20 mg once daily Prevention of emboli in AF: 20 mg once daily CrCl ml/minute: 15mg once daily Treatment with azoles (e.g. itraconazole) or HIV-PIs (e.g. ritonavir) CI Peripheral oedema, itch, skin blisters, muscle spasm PRACTICE POINTS Rivaroxaban & warfarin given together affect the INR more than additively: INR will be misleadingly high (e.g. up to 12) if measured <24 hours after the previous rivaroxaban dose; vitamin K treatment or reduction in warfarin dose is not required INR is not a measure of rivaroxaban's anticoagulant effect

52 SWITCHING ANTICOAGULANTS (RIVAROXABAN) SWITCHING From rivaroxaban to parenteral anticoagulant RECOMMENDATIONS Give first dose of parenteral anticoagulant when the next rivaroxaban dose would have been due. From rivaroxaban to warfarin Limited data. Give warfarin with rivaroxaban until INR >2; use standard warfarin dose for the first 2 days, then adjust dose according to INR. While both drugs are being taken, check INR at least 24 hours after the previous rivaroxaban dose. From parenteral anticoagulant to rivaroxaban Start rivaroxaban within the 2 hours before the due time of the next dose of parenteral anticoagulant or when an infusion is stopped. From warfarin to rivaroxaban Prevention of emboli in AF, stop warfarin and start rivaroxaban when INR <3 Treatment of DVT, stop warfarin and start rivaroxaban when INR <2.5

53 FIBRINOLYTICS

54 FIBRINOLYTICS

55 FIBRINOLYTICS Streptokinase binds plasminogen, which converts free plasminogen to plasmin. Alteplase, urokinase, recombinant urokinase (r-uk), reteplase and tenecteplase cleave plasminogen to produce plasmin, which catalyses the breakdown of fibrin

56 FIBRINOLYTICS Non- fibrin specific Streptokinase (SK) Urokinase (UK) Fibrin-specific Alteplase (r-tpa) Tenecteplase Reteplase NA in Malaysia

57 FIBRINOLYTICS STREPTOKINASE (STREPTASE ) PHARMACOKINETICS Action: peak 20 mins Elimination T½: 80 mins Excretion: degraded to peptides & excreted renally INDICATIONS Treatment of acute MI within 12 hours of onset, with persistent STsegment elevation or recent left bundle-branch block DOSE Systemic: single dose of 1.5 million IU IV over 60 mins Local intracoronary: bolus of 20,000 IU followed by a maintenance infusion of 2,000 IU to 4,000 IU/min over 30 to 90 mins PRECAUTIONS Development of antibodies thus not if administered more than 5 days, particularly between 5 days and 12 months after initial treatment & effect reduced in patients with recent streptococcal infections CI in severe active bleeding disorders or disease states with an increased risk of bleeding COMMON ADVERSE EFFECTS PRACTICE POINTS Hypotension, tachycardia, bradycardia (initial infusion), haemorrhage Allergic reactions pre-treat with Hydrocortisone 100mg Active heparinisation neutralised with protamine sulphate APTT <2x normal control value before thrombolytic is started Warfarin treatment the INR <1.3 before starting the streptokinase

58 FIBRINOLYTICS UROKINASE PHARMACOKINETICS Action: rapid Elimination T½: mins Excretion: Hepatic INDICATIONS Thrombosed IV cannulae, central venous catheters and haemodialysis shunts Peripheral arterial thromboembolism DVT, PE DOSE Adjust individually depending on the clinical condition PRECAUTIONS COMMON ADVERSE EFFECTS PRACTICE POINTS CI in severe active bleeding disorders or disease states with an increased risk of bleeding e.g. severe uncontrolled hypertension, severe hepatic disease, severe thrombocytopenia. Bleeding, including bleeding at injection sites, intracerebral bleeding, internal bleeding (e.g. GI, genitourinary), transient hypotension Stop heparin before giving urokinase; check APTT (should <2X the normal control value before beginning thrombolytic treatment & before reinstituting heparin

59 FIBRINOLYTICS ALTEPLASE (ACTILYSE ) PHARMACOKINETICS Action: rapid Elimination T½: 4 5 mins Excretion: Hepatic INDICATIONS Acute STEMI Massive pulmonary embolism Acute ischaemic stroke DOSE PRECAUTIONS COMMON ADVERSE EFFECTS Adjust individually depending on the clinical condition Due to an increased haemorrhagic risk, treatment with platelet aggregation inhibitors should not be initiated within the first 24 hours following thrombolysis with alteplase Bleeding, including bleeding at injection sites, intracerebral bleeding, internal bleeding (e.g. GI, genitourinary), transient hypotension PRACTICE POINTS Avoid IM injections & other invasive procedures during thrombolytic treatment In case of severe bleeding not controlled by local pressure, stop infusion of thrombolytic; fibrinogen, platelets, coagulation factors, tranexamic acid may be useful (or protamine if heparin has been used)

60 FIBRINOLYTICS PHARMACOKINETICS INDICATIONS DOSE PRECAUTIONS COMMON ADVERSE EFFECTS TENECTEPLASE (METALYSE ) Action: rapid Elimination T½: mins Excretion: Hepatic Acute STEMI Based on body weight, with a maximum dose of 10,000 units CI in severe active bleeding disorders or disease states with an increased risk of bleeding Bleeding, including bleeding at injection sites, intracerebral bleeding, internal bleeding (eg GI, genitourinary), transient hypotension PRACTICE POINTS Avoid IM injections & other invasive procedures during thrombolytic treatment In case of severe bleeding not controlled by local pressure, stop infusion of thrombolytic; fibrinogen, platelets, coagulation factors, tranexamic acid may be useful (or protamine if heparin has been used)

61 SUMMARY The development of various anti-thrombotic agents has great impact in prevention & treatment of thrombosis-related diseases. Such agents markedly reduced death from heart attacks, the risk of stroke in people with atrial fibrillation and the risk of major stroke in patients with mini-strokes, pulmonary embolism etc. Emergence of new agents provides more options and convenience for patients in the future.

62 REFERENCES 1. Australian Medicines Hanbook Andrew D Blann et al. ABC of antithrombotic therapy. An overview of antithrombotic therapy. British Medical Journal 2001;325: Patrono C et al. Antiplatelet drugs: American College of Chest Physicians evidence-based clinical practice guidelines (8 th ed). Chest.2008;118: Jefrey l, Weitz, et al. New Antithrombotic Drugs. ACCP Evidence-based clinical practice guidelines (8 th edition) 2008; 133:234S 256S 5. Warkentin, TE, et al. Treatment and prevention of heparin-induced thrombocytopenia. ACCP Evidence-based clinical practice guidelines (8 th edition) 2008;133 (6 Suppl): 340S. 6. Ann K.Wittkowsky. New oral anticoagulants: a practical guide for clinicians. J Thromb Thrombolysis. Published online: 04 November Zikria and Ansell. Oral anticoagulation with factor Xa and thrombin inhibitors: on the threshold of change. Current Opinion in Hematology 2009, 16: electronic Medicines Compendium (emc) [Internet database]. Stocks House, 9 North Street, Leatherhead, Surrey, England KT22 7AX. Updated periodically 9. Baskin, JL, et al. Thrombolytic therapy for central venous catheter occlusion. Haematologica May : ;doi: /haematol

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