New Oral Anticoagulants

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New Oral Anticoagulants

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  • Importance of clinical history
  • 1/3 active drug cleared by the kidneys.
    No accumulation of active drug when Cr clearance is >15mL/min
  • Using INR increases the discrepancy between results
  • Trouver des exemples avec Apixaban
  • Dual antiplatelet
    Rx
    ADP receptor blocker P2Y12 reversible
  • >30 000x selectivity for FXa over thrombin and other coagulation enzymes
    Licensed for stroke prevention and VTE prophylaxis after hip and knee replacement
    Phase III trials recently showed non-inferior effect to warfarin in acute VTE and significantly fewer bleeding complications
    T1/2 8-15 hours
  • Triniclot APTT HS
    Spiked plasma from 10 healthy subjects in concentration range 0-1000ng/mL
    Non-linear, flat dose response curves
    Individual dose response curves did not cross ie donor with shortest or longest APTT was same for each apixaban concentration.
  • WE use Sta Neoplastine
    PT: linear dose response effect but wide variation between different PT assays in absolute values
    Least sensitive reagent 0.02 increase in INR for each 100ng/mL in range 0-1000ng/mL. Mean increase INR was 0.15per 100ng/mL with most sensitive.
    At expected therapeutic peak concentration of 200ng/mL none of samples from 10 dnors had INR above normal range (>1.2) with least sensitive reagent.
    Concentration required to double PT calculated as 4000ng/mL for least sensitive, but difference was 5.6x between different PT assays.
  • A normal PT and APTT do not exclude a peak concentration of apixaban
    Broad range in APTT for healthy individuals at peak concentration illustrates difficulty in evaluating an individual APTT result
    Concentrations needed to double APTT were 5-6x higher than for rivaroxaban. And 2-7x higher to double PT than for rivaroxaban.
  • >30 000x selectivity for FXa over thrombin and other coagulation enzymes
    Licensed for stroke prevention and VTE prophylaxis after hip and knee replacement
    Phase III trials recently showed non-inferior effect to warfarin in acute VTE and significantly fewer bleeding complications
    T1/2 8-15 hours
  • Peak may be delayed until 6hrs after the first post-operative period
  • APTT more sensitive than PT
    UK NEQAS survey showed 40% variance in resposniveness to dabigatran of the 10 most frequently used APTT reagents. Variance between reagents was consistent up to concentration of 500ng/mL.
    60% variance between most frequently used thromboplastins in sensitivity to dabigatran on UK NEQAS exercise
    INR calculated from PT based on International sensitivity index. ISI designed for VKAs and not suitable for measurement of dabigatran.
  • Therapeutic dabigatran = 40-100s, but variation between labs based on different coagulometers.
    Falsely low results on fibrinogen on Clauss fibrinogen. Dose dependent effect.
    Now alternative reagents that do not underestimate fibrinogen.
    No effect on D-dimer assays, but likely to suppress D-dimer levels due to inhibition of thrombin.
    Coagulation factor and natural anticoagulant levels significantly effected by thrombin inhibitors and therefore not reliable if taking dabigatran
    Can measure antithrombin with Fxa based assay ( but not thrombin based)
  • Australia only 3 factor PCC but recent paper showed
    Recent study compared 4 and 3 factor PCC in healthy volunteers
    4F PCC reduced PT by 2.5-3.5s v 0.6-1s for 3F PCC
    But 3F reduced changes in thrombin generation assay >4F
    APCC 50 or 100 IU/kg reduced bleeding in tail incision model.
    Mouse model riva PCC 100iu/kg prevented ICH expansion without correcting PT
    Rat injury model PCC shortened APTT and clt time on TEG but did not decrease blood loss and similar results with rabbits and apixaban
  • Dialysis if APTT >80s, dabigatran >500ng/mL or impaired renal function
    4 hour haemodialysis reduces drug level by 60%
    Correct hypocalcaemia, acidosis and hypothermia.
    Activated charcoal not tested in clinical practice but one study apixaban may benefit even longer after ingestion due to entero-enteric recirculation
  • Discrepant effects, both potentially reverse, differences ?due to procoagulant factors in each
  • 1 and 2 in early clinical trials
    3 supposedly universal NOAC inhib
  • VKA can dDx anticoagulant failure v subtherapeutic anticoagulation as T1/2 is long and reliable measure in INR.
    Revise intensity, compliance and concordance.
    ODIs less able
  • LA testing with spiked samples showed rivaroxaban affected LAI (low PL) reagent more than apixaban, whereas dose response curves were similar for both with LA rich LA2 reagent.
    FP LAC ratios at rivaroxaban of >100ng/mL whereas lowest apixaban concentration that showed weak positive ratio was 600ng/uL.
  • New Oral Anticoagulants

    1. 1. NOACs Dr Carolyn Grove Clinical and Laboratory Haematologist Sir Charles Gairdner Hospital and PathWest Laboratory Medicine
    2. 2. Overview • Expected coagulation parameters in the setting of DOACs – Do these correlate with bleeding risk? • Treatment of bleeding Although NOACs are no longer novel, there is still surprisingly limited evidence on which to base Rx decisions
    3. 3. Coagulation Cascade PL – Platelet Membrane Phospholipid TF - Tissue Factor ‘a’ – active enzyme Rivaroxaban/Apixaban Dabigatran Mechanistically different from warfarin •Warfarin indirect effect by interfering with Vit K metabolism •Act at catalytic pocket of coagulation factors and inhibit their function
    4. 4. Tran et al, New Oral Anticoagulants: a practical guide IMJ 44 (2014)
    5. 5. Case 1 • Pre-op assessment • No other history Test Result Reference Range APTT 49.7s 29.5-40.5s INR 2.29 0.9-1.3 TCT 18.3s 15-23s Fibrinogen 4.35g/L 2-4.1g/L APTT 50:50 36.2s 29.5 - 40.5s INR 50:50 1.35 0.9-1.3
    6. 6. Case 1 Test Result Reference Range FX 69% 70-140% FII 71% 65-130% FV 32% 65-140% FVII 62% 65-135% FVIII 76% 50-200% FIX 58% 50-200% FXI 52% 65-140% Rivaroxaban 348ng/mL
    7. 7. Case 1: Discussion Points • What does the rivaroxaban level mean? • Is this a typical picture for coagulation parameters on therapeutic rivaroxaban?
    8. 8. Rivaroxaban • Peak levels within 3h of ingestion • Quantified by calibrated anti-Xa assays using rivaroxaban standards – 20mg OD dose: • Peak 290ng/mL (range 177-409 5-95th centile) • Trough 32ng/mL (range 5-155ng/mL) – 10mg OD dose: • Peak 125ng/mL (range 91-196) • Trough 9ng/mL (1-38)
    9. 9. PT APTT Tests: PT and APTT Principles…. Citrated blood Centrifuged -> Platelet poor plasma + Activator + Platelet substitute + Calcium ->Measure time to clot formation
    10. 10. Rivaroxaban and Coags Hillarp et al. Journal of Thrombosis and Haemostasis, 9: 133-139
    11. 11. Rivaroxaban and routine coagulation assays • PT more suitable than APTT for assessing anticoagulation intensity – Linear over broad range and high sensitivity – Marked variability between reagents (3x) – Can be used to determine relative degree of anticoagulation if sensitivity of PT known • Normal PT ratio with most reagents excludes a therapeutic intensity of anticoagulation due to rivaroxaban – Some degree of anticoagulation not excluded – Intensity ≤ prophylactic dose of LMWH
    12. 12. Ex vivo experiment with rivaroxaban (10 mg) Asmis, L.M. et al Thrombosis Research 129 (2012) 492-498
    13. 13. Rivaroxaban • TT, fibrinogen not affected • No effect on D-dimer assay – Suppression of D-dimer levels due to inhibition of thrombin generation • LAC assay is sensitive to low levels of rivaroxaban
    14. 14. Case 2 78 y.o. man A&E 0-1 D/C Coronary angiography and drug eluting stent Ticagrelor + aspirin -40 -8 Right upper lobectomy and wedge lower lobe resection -7 AF+ HD instability -5 Chest pain No new changes on angiogram -4 Start apixaban 5mg bd
    15. 15. A&E • Dyspnoea and collapse • New right pleural effusion and right anterior chest wall haematoma • Apixaban last dose 17hours ago • Hb 123, plt 579, INR 2.7, APTT 41.7s • Apixaban 139.7ng/mL
    16. 16. Management Case 2 • Stop antiplatelet and apixaban Rx • 25IU/kg prothrombinex • 1U platelets • Apixaban 36 hours post dose 55.9ng/mL • INR 2.8, APTT 52.9, normal liver and renal function • Factors – VII = 25% – X = 54% – XI = 38% • Vitamin K 10mg IV with normalisation of coag profile and factors
    17. 17. Case 2 Discussion Points • Were the apixaban levels and time course for drug clearance typical? • Were the abnormalities in coagulation profiles consistent with apixaban therapy?
    18. 18. Apixaban Levels 10mg single dose fasted v fed Frost C et al. Br J Clin Pharmacol. 2013 Feb;75(2):476-87
    19. 19. Apixaban levels • APPRAISE-1 study ACS 10mg bd doses – 2.5mg bd dose • Peak 68ng/mL (38 / 98 5th /95th percentile) • Trough 57ng/mL (18 / 97 5th /95th percentile) – 5mg bd dose • Trough 107ng/mL (56 / 203 10th /90th percentile) – 10mg bd dose • Peak 267ng/mL (122 / 412 5th /95th percentile) • Trough 221ng/mL (30 / 412 5th /95th percentile) • Our lab limits of detection 20-999 ng/mL
    20. 20. Apixaban Hillarp, A et al. Journal of Thrombosis and Haemostasis (2014), 12: 1-9 At peak of 200ng/mL most responses were within the reference interval for APTT for that reagent. Even at peak 1000ng/mL APTT still within reference limit for several samples.
    21. 21. Apixaban concentration to double APTT Hillarp, A et al. Journal of Thrombosis and haemostasis, 12: 1-9
    22. 22. Apixaban and INR Hillarp, A et al. Journal of Thrombosis and haemostasis, 12: 1-9
    23. 23. Hillarp, A et al. Journal of Thrombosis and Haemostasis, 12: 1-9
    24. 24. Apixaban • Cannot use APTT or PT to screen for apixaban activity – They may be normal even with peak apixaban levels • Concentration needed to double – APTT = 2200 - 4700ng/mL (5-6x rivaroxaban) – PT = 700 - 3900ng/mL (2-7x rivaroxaban) • Linear dose response curves for chromogenic anti-FXa assays – this is the way to check if drug on board • If markedly deranged PT/APTT consider other causes Hillarp, A et al. Journal of Thrombosis and Haemostasis, 12: 1-9
    25. 25. • No obvious explanation for differences between rivaroxaban and apixaban in vitro.
    26. 26. Case 2 Discussion Points • Were the apixaban levels and time course for drug clearance typical? • Were the abnormalities in coagulation profiles consistent with apixaban therapy?
    27. 27. Case 3 • CHADS score 4 • Previous bleeding on warfarin • Changed to dabigatran • Presented by ambulance after first dose rivaroxaban (reason for change unclear) • Felt tongue swelling and tightness in throat immediately after first dose
    28. 28. Case 3 Test Result +4hrs Result + 14 Reference Range APTT 73.1 32.2 29.5-40.5s INR 4.3 1.7 0.9-1.3 TCT >120 15-23s Fibrinogen 3.4 3.38 2-4.1g/L Rivaroxaban 490 102.3 Dabigatran 226 64
    29. 29. Dabigatran • Peak 2h post ingestion • 150mg bd dose – mean peak plasma concentration 175ng/mL with range 117- 275ng/mL (25th -75th percentile range) • Our lab 50-500ng/mL
    30. 30. Dabigatran • APTT curvilinear dose-response with dabigatran – Steep increase at low concentrations – linearity above dabigatran of 200ng/mL • Above 100ng/mL the APTT is invariably prolonged • A normal APTT ratio likely excludes a therapeutic intensity of anticoagulation – Can’t exclude some effect – Intensity no more than with prophylactic LMWH • Even at 200ng/mL the PT is not prolonged or prolonged <3s with some reagents.
    31. 31. Dabigatran • TT linear concentration response to dabigatran – most assays too sensitive – high variability above 25ng/mL dabigatran – sensitive method to determine if dabigatran present • Normal TT excludes dabigatran • Dabigatran quantitative assay – Hemoclot thrombin inhibitor assay – Essentially a diluted TT (1/8). – Linear dose-response curve to 1000ng/mL.
    32. 32. Test Dabigatran Rivaroxaban Apixaban PT Insensitive Sensitive Insensitive APPT Sensitive Less sensitive Insensitive TT V. Sensitive No effect No effect Drug level Dilute TT Anti-Xa with calibrator Anti-Xa with calibrator Significant anticoagulant effect unlikely TT and APTT normal PT normal (with sensitive thromboplastin) Low drug level Summary But remember significant variability between assays.
    33. 33. Tran et al, New Oral Anticoagulants: a practical guide IMJ 44 (2014)
    34. 34. Tran et al, New Oral Anticoagulants: a practical guide IMJ 44 (2014)
    35. 35. Bleeding on DOA • Same RF for bleeding as warfarin • Increased bleeding from the GI system • Higher risk in renal impairment • Lower rate of ICH • No specific antidote
    36. 36. ThrombosisBleeding Problems of Haemostasis Treat the problem without creating the opposite one Somewhat more complicated of late?
    37. 37. Evidence for pro- haemostatic agents • Conflicting and limited • No clinical trials in bleeding patients – aPCC (FEIBA) and four factor PCC have been shown to reduce bleeding in some animal models • Variable effect on coag parameters in animals, healthy volunteers and spiked plasma samples – FEIBA more consistent impact on haemostatic changes • unknown if this translates to superior clinical efficacy – PCC (50IU/kg of 4 factor agent) reversed laboratory effects of rivaroxaban, but not dabigatran – rVIIa less consistent effect
    38. 38. Animal bleeding models • Apparent dissociation between effect on lab tests and bleeding tendency which is drug specific • Mouse tail bleeding model – Oral dabigatran = mean plasma level 200ng/mL – PCC at 14.3ug/kg plus rFVIIa at 3mg/kg corrected the prolonged APTT but did not reduce blood loss • Rabbit kidney incision model with dabigatran – Higher dose PCC up to 50ug/kg – no effect on APTT – increased thrombin generation in a dose-dependent manner – reduced blood loss • Rabbit hepato-splenic incision model – 5mg/kg rivaroxaban – treated before injury with 40ug/kg PCC or 150ug/kg rFVIIa. – both partially corrected PT, APTT and ETP and rFVIIa corrected the prolonged lag time – neither reduced bleeding
    39. 39. Tran et al, New Oral Anticoagulants: a practical guide IMJ 44 (2014)
    40. 40. WATAG
    41. 41. Clot lysisClot formation Thrombin Plasmin Normal Haemostasis Closely linked and carefully regulated processes Correct calcium, hypothermia, acid-base balance
    42. 42. At present • Opinion based recommendations • Limited data for efficacy • Off license use • Potential thrombotic complications need to be balanced – Guidelines for use in life threatening bleeding only • Urgent measurement of the intensity of anticoagulation to determine contribution of NOAC • Recognize contributory coagulopathy unrelated to NOAC
    43. 43. Specific antidotes • Dabigatran monoclonal antibody – highly specific, rapid dose-dependent decrease in blood loss in rat tail injury model, sustained for up to 6hrs and complete reversal of anticoagulant effect on lab assays • PRT4445 – universal reversal agent for Xa inhibitors. – recombinant Xa that is haemostatically inactive and binds Xa inhibitors • Per977 – synthetic small molecule that binds NOACs – reduced blood loss in rat tail injury model – corrects aPTT and anti-Xa in ex vivo human blood
    44. 44. Other issues • Identification of Rx failure • Short T1/2 so measurement of the intensity of anticoagulation after the event will not reliably discriminate treatment failure from inadequate anticoagulation v inadequate compliance • Drug monitoring • Fixed dosing is effective and safe despite wide ranges for peak and trough concentrations (ie wide therapeutic range) – Group specific outcome of ODI patients in clinical trials is non-inferior to warfarin. No published evidence base for monitoring and dose adjustment for routine patients. • Estimates that same dose of ODI can result in a 30% difference in thrombin generation inhibition and therefore suggested thrombosis more likely in low responders and bleeding more likely in high. • Implication that dose adjustment would improve individual patient clinical outcomes to be tested
    45. 45. Questions?
    46. 46. • Fixed dose group-specific outcomes: – Assumed overall trial results generalisable to all patients in trial and similar future patients – Estimates that same dose of ODI can result in a 30% difference in thrombin generation inhibition and therefore suggested thrombosis more likely in low responders and bleeding more likely in high. – Implication that dose adjustment would improve individual patient clinical outcomes has not been tested – Group specific outcome of ODI patients in clinical trials is at least non-inferior to warfarin, therefore monitoring and dose adjustment for routine patients is not advisable until evidence base for such a practice.
    47. 47. Test Thrombin inhibitor Clinical Utility Fxa inhibitors Clinical Utility PT ++ No +++ Qualitative APTT +++ Qualitative + Uncertain TT ++++ Limited Not affected No Dilute plasma TT +++ Quantitative Not affected No Fibrinogen Not affected for high thrombin concentration reagents No Not affected No D-dimer Not affected No Not affected No RVVT ++ No ++ No Chromogenic anti Xa Not affected No +++ Quantitative Clotting factors False low with clot-based assays. Positive Testing not recommended False low with clot-based assays. Positive Testing not recommended
    48. 48. Dabigatran experience • RE-LY trial – Both doses of dabigatran had lower risks of intra and extra cranial bleeding cg warfarin in those <75years – Patients >75 years had lower risk of ICH, but similar or higher rate of extracranial bleeds that warfarin – Added single anti-platelet agent inceased major bleeding risk HR 1.6 – Dual antiplatelet therapy HR 2.31 – Post marketing reports on dabigatran for AF report similar bleeding rates as the phase III trial ASH abstract 2012: post hoc analysis of major bleeding from 5 pahse III trails lower 30 day mortality with dabigatran that warfarin most patients with major bleeding treated with supportive measures only without factor concentrates.
    49. 49. GI bleeding • Rivaroxaban and dabigatran 1.5 fold increased risk GI bleeding cf warfarin • Mechanism possibly incomplete absorption and local effects on gut mucosa rather than systemic anticoagulation effect as with warfarin. • Apixaban has less GI bleeding – Possibly as more frequent dosing so reduced peak.
    50. 50. Hillarp, A et al. Journal of Thrombosis and haemostasis, 12: 1-9
    51. 51. Coagulation: Step 1: Initiation • Initiation of clotting occurs when disruption of the endothelium exposes activated factor VII (VIIa) in blood to tissue factor on subendothelial cells (smooth muscle cells and fibroblasts) • FVIIa-TF complex activates other clotting proteins (esp. FX and FIX) • Small amount of thrombin is formed
    52. 52. Coagulation: Step 2: Propagation • Thrombin (IIa) activates platelets which release further coagulation proteins • Thrombin activates coagulation proteins required for its own production • Large scale production of thrombin takes place on platelet surface
    53. 53. Summary of haemostasis after disruption of vascular endothelium • Platelets bind to subendothelial collagen to initiate primary closure of the vessel wall defect • Tissue factor in subendothelium combines with FVII in blood to form the FVIIa-TF complex • FVIIa-TF complex activates other clotting proteins leading to thrombin production • Large scale production of thrombin takes place on the platelet surface • Thrombin converts fibrinogen to fibrin • Fibrinolysis is activated to localise the clot to the site of injury
    54. 54. Dagibatran etexilate (Pradaxa) • Prodrug of dabigatran • Low oral bioavailability – Breaking the capsule can significantly increase bioavailability – Food does not effect bioavailability but take with food to minimise dyspepsia • Until metabolised to dabigatran, is a substrate for P-glycoprotein efflux transporter – interacts with drugs that induce this pathway. • Binds thrombin active site and blocks free and clot bound thrombin. • Predominantly renal excretion – Contraindicated if CrCl <30ml/min • If dose missed, take within 6 hours or omit if >6hours have elapsed.
    55. 55. Rivaroxaban • Inactivates free and clot-associated factor Xa • OD dosing, bioavailability 80%, 90% protein bound – Oral absorption excellent for 10mg does but higher doses taken with food to improve bioavailability • Predominantly eliminated by liver • No accumulation of drug when CrCl >15ml/min but dose reduction to 15mg OD if CrCl 15-30ml/min • Kinetics effected by drugs that affect P-glycoprotein and cytochrome P45o3A4, but not CYP2C9 • If dose missed take next dose within 12 hours but does omitted if >6hrs elapsed
    56. 56. Apixaban • Bioavailability 50% • Extremes of body weight effect bioavailability • Metabolised through liver • Does not accumulate in mild-moderate renal impairment • CYP3A4 metabolism and P-glycoprotein substrate
    57. 57. • Meta-analysis in AF – Trend toward reduced major bleeding (RR 0.86) – Significant reduction in ICH compared to warfarin (RR0.46) – Major GI bleeding more common with dabigatran and rivaroxaban than warfarin • Meta-analysis in VTE – Rivaroxaban reduced the risk of major bleeding compared with warfarin – Other DOA did not

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