The new oral anticoagulants & the future of haemostasis laboratory testing. Alcohol: the good, the bad and the ugly

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1 The new oral anticoagulants & the future of haemostasis laboratory testing Emmanuel J Favaloro Diagnostic Haemostasis Laboratory, Institute of Clinical Pathology & Medical Research, ICPMR, Pathology West, NSW 2145 Australia Alcohol: the good, the bad and the ugly

2 3 Anticoagulants / antithrombotics Many clinical indications Main existing agents: Vitamin K antagonists (VKAs) such as warfarin (very common): Prophylaxis, treatment of pulmonary embolism (PE), venous thrombosis and its extension, thromboembolic complications assoc with atrial fibrillation (AF); coronary occlusion adjunctive treatment. Unfractionated heparin (common / less common): Prophylaxis and treatment of thromboembolic disorders, e.g. thrombophlebitis, PE and occlusive vascular disease. Also used to prevent thromboembolic complications arising from cardiac and vascular surgery, frostbite, dialysis and other perfusion procedures. Low molecular weight heparin (common): Prevention of venous thromboembolism (surgical, acutely unwell bedridden medical patients), extracorporeal thrombosis during haemodialysis. Treatment of established deep vein thrombosis (DVT); unstable angina, non-q-wave MI (with aspirin); acute ST-segment elevation MI (STEMI) (+ thrombolytic) Garcia DA, et al. Chest 2012;141(Suppl 2):e24S e43s Favaloro et al. Pathology 2011; 43: Current routine tests and current anticoagulant monitoring Prothrombin time / International Normalised Ratio (PT / INR). Vitamin K antagonists (VKAs) such as warfarin (very common) Therapeutic range (INR): Heart valves ; other indications Activated Partial Thromboplastin Time (APTT). Unfractionated heparin (uncommon) Therapeutic range: s (~ x baseline or 0.3 to 0.7 U/mL heparin by anti-xa assay). Thrombin Time (TT). Unfractionated heparin (uncommon) No therapeutic range: TT is prolonged by unfractionated heparin. Anti-Xa assay. Unfractionated heparin and/or low molecular weight heparin (uncommon) Therapeutic ranges: 0.3 to 0.7 U/mL (unfractionated heparin) to U/mL (low molecular weight heparin). Favaloro & Adcock. Semin Thromb Hemost 2008;34: Cuker. Semin Thromb Hemost 2012;38: Favaloro et al. Pathology 2011; 43:

3 PT, APTT & TT: INR & VKAs: Anticoagulant control points NB: INR = (PT/MNPT) ISI 5 Favaloro et al. Pathology 2011; 43: Favaloro et al. Pathology 2011; 43:

4 Heparin - anticoagulant control points: New oral anticoagulants / antithrombotics Many coming Main agents & current indications (Australia): Dabigatran (etexilate; Pradaxa; Boehringer Ingelheim Pty Ltd): Direct thrombin inhibitor: Venous thromboembolic event (VTE) prevention in adults after major lower limb orthopaedic surgery (elective total hip, knee replacement); stroke, systemic embolism prevention in nonvalvular AF with greater than or equal to 1 additional stroke risk factor. Rivaroxaban (Xarelto; Bayer Ltd): Direct Factor Xa inhibitor: VTE prevention in adults after major orthopaedic surgery of lower limbs (elective total hip, knee replacement); prevention of stroke, systemic embolism in nonvalvular AF + at least 1 additional stroke risk factor; treatment of DVT, prevention of recurrent DVT, PE. Apixaban (Eliquis; Bristol-Myers Squibb Pharmaceuticals): Direct Factor Xa inhibitor: Venous thromboembolic event prevention in adults following elective total hip, total knee replacement surgery. 7 Favaloro et al. Pathology 2011; 43: Favaloro et al. Pathology 2011; 43: MIMS 4

5 New oral anticoagulants / antithrombotics New oral anticoagulants & anticoagulant control points: 9 Garcia et al. Blood : Favaloro et al. Pathology 2011; 43:

6 New oral anticoagulants vs heparin anticoagulant control points: Alcohol: Some positive effects for moderate intake Evidence for beneficial effects to coronary system Termed the French Paradox in 1992 (low incidence of cardiovascular disease in French people despite relatively high dietary intake of saturated fats). Most evidence relates to positive effects of red wine Some negative effects for excess intake Chronic heavy alcohol consumption and binge drinking associated with increased risk of cardiovascular effects Other adverse health outcomes (e.g. liver disease, mental disturbances, memory loss) Antisocial effects (increased aggression, violence, etc) 11 Favaloro et al. Pathology 2011; 43:

7 Alcohol: Alcohol:

8 New oral anticoagulants / antithrombotics Current routine tests and new anticoagulant drugs Have been developed without need for monitoring Clinical trials limited laboratory testing & defined patient populations (many conditions excluded) Marketing strategy - no monitoring required Post release - real world settings Many adverse events & some deaths no monitoring required / limited laboratory testing - how to assess? Plethora of subsequent publications regarding testing Why test? NOT drug monitoring (not like Warfarin) Patient presents with adverse events (i.e. thrombosis or haemorrhage) Patient known to be on anticoagulant: drug failure or patient compliance? Patient unknown to be on anticoagulant: unconscious trauma acute bleeding Either case: necessity of immediate reversal of anticoagulation? Patients requiring surgery (known / unknown to be on anticoagulant)? Patients with renal failure & known to be on anticoagulant? Patient types excluded in clinical trials & known to be on anticoagulant? Prothrombin time / International Normalised Ratio (PT / INR). INR not designed for use with the new oral anticoagulants PT variably prolonged by both Dabigatran and Rivaroxaban depending on reagent & drug level In general, PT more sensitive to Rivaroxaban than Dabigatran. Many PT reagents relatively insensitive to Dabigatran Activated Partial Thromboplastin Time (APTT). APTT variably prolonged by both Dabigatran and Rivaroxaban depending on reagent & drug level In general, APTT more sensitive to Dabigatran than Rivaroxaban. Many APTT reagents relatively insensitive to Rivaroxaban. Thrombin Time (TT). Standard TT over sensitive to Dabigatran but unresponsive to Rivaroxaban. Anti-Xa assay. Standard anti-xa assay over sensitive to Rivaroxaban but unresponsive to Dabigatran. No therapeutic range for these anticoagulants with any test or test reagent 15 Favaloro et al. Pathology 2011; 43: Favaloro et al. Clin Chem Lab Med 2011; 49(5): Harenberg J, et al. Semin Thromb Hemost 2012;38:16-22 Harenberg J, et al. Semin Thromb Hemost 2012;38: Favaloro et al. Pathology 2011; 43:

9 Current routine tests and new anticoagulant drugs - PT Current routine tests and new anticoagulant drugs - APTT 1. In general, PT more sensitive to Rivaroxaban than Dabigatran 2. Not all PT reagents sensitive to Rivaroxaban 3. No therapeutic range for these anticoagulants with any test or test reagent 1. In general, APTT more sensitive to Dabigatran than Rivaroxaban 2. Not all APTT reagents equally sensitive to Dabigatran 3. No therapeutic range for these anticoagulants with any test or test reagent 17 Harenberg J, et al. Semin Thromb Hemost 2012;38:16-22 Harenberg J, et al. Semin Thromb Hemost 2012;38: Harenberg J, et al. Semin Thromb Hemost 2012;38:16-22 Harenberg J, et al. Semin Thromb Hemost 2012;38:

10 New anticoagulant drugs and non-routine tests Prothrombin induced clotting time (PICT). Sensitive to both Dabigatran & Rivaroxaban. Reagents not widely available & standardisation unclear. Result depends on way test is performed. Test not widely available No therapeutic range for these anticoagulants with this test New anticoagulant drugs and non-routine tests Dilute Russell Viper Venon Time (drvvt). Sensitive to both Dabigatran & Rivaroxaban. Reagents widely available but test is not standardised for this application. Thrombin Generation (TG). Sensitive to both Dabigatran & Rivaroxaban. Reagents available but test is not standardised for this application. Research application but not routine testing. No therapeutic range for these anticoagulants with these tests or reagents 19 Harenberg J, et al. Semin Thromb Hemost 2012;38:16-22 Harenberg J, et al. Semin Thromb Hemost 2012;38:

11 New anticoagulant drugs - recommendations 1 New anticoagulant drugs - Westmead 21 Assess / consider need for testing in your lab or network. Discuss with clinicians. Are there any requests for testing. Should this testing be performed on site or sent away? Economics, staffing, instrumentation, availability after-hours and on weekends? Assess sensitivity of your current assays for both Dabigatran & Rivaroxaban. Standards easily available. Easy to assess sensitivity of current assays to these drugs. At least PT & APTT; if available, also TT & drvvt. Assess clotting times and normalised ratios (CT/CT of normal plasma) 22 Data not shown: Standard TT - Rivaroxaban insensitive; Dabigatran - oversensitive (even lowest drug dose = max TT). Standard anti-xa - Dabigatran insensitive; Rivaroxaban - oversensitive (even lowest drug dose = beyond assay detection range). Data Shown: PT, APTT & drvvt Clotting time data difficult to interpret in terms of effect given different baselines. Ratio data easier to interpret in terms of effect. Results not entirely within expectations. Apparent sensitivity Rivaroxaban drvvt > PT > APTT Apparent sensitivity Dabigatran drvvt ~ APTT > PT (but, possible dodgy point high drug level?) Presumably reagent dependent effects for PT & APTT. Data should be repeated for confirmation and drug evaluation range extended. (Key staff member on maternity leave; recent tender finalised & network will probably change routine PT & APTT reagents). 11

12 23 New anticoagulant drugs - recommendations 2 Follow the recommendations of experts. Australasian Society of Thrombsis and Haemostasis (ASTH) working group - recommendations for testing in progress. Others in progress/published Example: Consensus Document of FCSA, SIMeL, SIBioC and CISMEL (Italian Federation of Thrombosis Services; Italian Society of Laboratory Medicine; Italian Society of Clinical Biochemistry; Italian committee for standardization of laboratory tests): Dabigatran - recognises that this prolongs PT (but responsiveness poor) and prolongs APTT (better responsiveness, but non-linear); thus recommends modified TT or ECT. Rivaroxaban - recognises that this prolongs PT & APTT (linearly responsive), & drvvt (non-linearly responsive), or can be measured by anti-xa assay (but standard assay too sensitive); recommends PT (not INR) or modified anti-xa assay. Tripodi et al. Clin Chem Lab Med 2012, in press. 24 New anticoagulant drugs - Other considerations Interferences: Patients with certain haemostatic conditions (especially LA), may be difficult to assess (especially clot based tests) Beware usual pre-analytical issues (e.g., under-filled tubes, clotted samples, etc) & analytical interferences (e.g., lipaemia, icteria, haemolysis) Complications: Cannot properly measure many haemostasis analytes whilst patients are on anticoagulant drugs including Dabigatran & Rivaroxaban (e.g., antithrombin, fibrinogen, activated protein C resistance, protein C/S, LA). Drug levels / test results dependent on timing of dose (consider drug half-lives) Practicalities: Most routine labs only measure PT & APTT. ECT & (modified) TTs including HEMOCLOT (for Dabigatran) will not be difficult to set up on most coagulation analysers. (Modified) anti-xa (for Rivaroxaban) less easy to manage, but feasible if instrument includes a chromogenic detection system 12

13 New anticoagulant drugs - potential algorithm Basic coagulation assay panel PT APTT TT All normal Consider timing of tests in relation to last dose of OAC Consider specific individual test sensitivities to each OAC Significant OAC activity can be excluded Acknowledgments/Thanks: PT prolonged > APTT prolonged TT normal APTT prolonged > PT prolonged TT prolonged or non-clottable Suggestive of rivaroxaban effect (exclude warfarin effect, liver disease, etc) Confirmatory assay: anti-xa using specific rivaroxaban assay/standard (HEMOCLOT & ECT normal; drvvt prolonged) Suggestive of dabigatran effect (exclude heparin effect, low fibrinogen, etc) RCPA Haematology QAP staff, Westmead lab staff, Soma Mohammed, Roslyn Bonar, AIMS NSM 2012 organisers. Confirmatory assay: HEMOCLOT using specific dabigatran assay/standard (anti-xa normal; ECT prolonged; drvvt prolonged; fibrinogen normal unless dabigatran levels very high)