Advances in Anticoagulation

Transcription

1 May 18, 2017 Advances in Anticoagulation Wei Ling Lau, MD Assistant Professor, Nephrology University of California, Irvine

2 Talk Outline High stroke risk in CKD population Warfarin off-target effects on MGP Emerging use of NOACs (New Oral Anticoagulants) in CKD Apixaban (Eliquis) FDA approved in ESRD! Limited Evidence

3 Increased stroke risk in CKD For every 10 ml/min/1.73 m 2 decline in renal function, stroke risk increases by 7% ESRD patients have the highest stroke risk with 3-5 times higher mortality than the non- CKD population A-fib increases stroke risk 5-fold and prevalence of a-fib is up to 27% in ESRD Masson Nephrol Dial Transplant 2015 p1162 USRDS 2009 Wang AJKD 2014 p604 Boriani Europace 2015 p1169

4 Further tipping the scales? Bleeding in ESRD BP variability Platelet dysfunction Intra-dialytic heparin BBB disruption Brain microbleeds Rate of hemorrhagic stroke in HD population 75 per 10,000 person-years; >5 fold higher than in general population National Health Insurance Research Database for ; Wang AJKD 2014 Lau, Huisa, Fisher Transl Stroke Res 2017

5 Unfractionated heparin Low molecular weight heparins (factor Xa inhibitors) Enoxaparin (Lovenox) Fondaparinux (Arixtra) Direct thrombin inhibitors Argatroban Bivalirudin (Angiomax) Factor Xa inhibitors Apixaban (Eliquis) Rivaroxaban (Xarelto) Edoxaban (Savaysa) Direct thrombin inhibitor Dabigatran (Pradaxa) Vitamin K antagonist Warfarin (Coumadin)

6 Off-target effects: warfarin and vascular calcification warfarin CUA Tantisattamo ATVB 2015;35:237 Lau, Ix; Semin Nephrol. 2013; Meissner; Dermatology 214(4):278-82

7 General population: warfarin reduces stroke risk with a-fib by 64% Hart et al. Ann Intern Med : Warfarin was the only oral anticoagulant available in the US ESRD population: warfarin has no effect or may increase stroke risk; increases major bleeding; no mortality benefit Dahal et al. Chest 2016 Tan et al. BMC Nephrology 2016

8 Intrinsic pathway Extrinsic pathway

9 Apixaban (Eliquis) FDA-approved in ESRD! Limited Evidence Since 2009 there have been 4 large Phase III trials comparing NOACs with warfarin in a-fib (over 71,000 patients); CKD 4/5 patients were excluded RE-LY (dabigatran) ROCKET-AF (rivaroxaban) ARISTOTLE (apixaban) ENGAGE AF-TIMI 48 (edoxaban) Pelliccia et al. Int J Cardiology 2016 Wang J Clin Pharm 2016 p628 Apixaban was FDAapproved for use in ESRD patients in 2014 based on a single-dose pharmacokinetic study in 8 HD patients

10 Phase 1 studies in dialysis patients Drug Dabigatran (Pradaxa) Apixaban (Eliquis) Rivaroxaban (Xarelto) Mechanism of action Direct thrombin inhibitor Factor Xa inhibitor Factor Xa inhibitor n Dosing strategy Removal by HD mg day 1, 110 mg day 2, 75 mg day 3 (equiv. blood levels to 150 mg BID) 50% with 4-hr dialysis; Minor redistribution, increase ~15% after HD 8 Single dose 5 mg Negligible (~ 6.7% recovered from dialysate) mg after each HD (dose is 20 mg daily in non-ckd patients) Negligible Khadzhynov Thromb Haem 2013 p596 Wang J Clin Pharm 2016 p628 De Vriese AJKD 2015 p91

11 Package insert: Apixaban 5 mg BID in ESRD (regular dose)

12 January 2017 online Seven patients received apixaban 2.5 mg twice daily for 8 days... Significant accumulation of the drug was observed. Only 4% of the drug was removed during dialysis. After a 5-day washout period, five patients received 5 mg apixaban twice daily for 8 days.. trough levels increased to 218 ng/ml (P=0.03), above the 90th percentile for the 5-mg dose in patients with preserved renal function. Apixaban 2.5 mg twice daily in patients on hemodialysis resulted in drug exposure comparable with that of the standard dose (5 mg twice daily) in patients with preserved renal function and might be a reasonable alternative to warfarin for stroke prevention in patients on dialysis. Apixaban 5 mg twice daily led to supratherapeutic levels in patients on hemodialysis and should be avoided.

13 What do we do at the HD unit? Discuss with our patients Discuss with prescribing doc Alert RN and technicians D/C heparin, re-introduce initial bolus if necessary Use minimal apixaban dose: 2.5 mg BID Monitor for clotting of circuit (Kecn, drip chambers, venous and arterial pressures, dialyzer streaks) Current dosing guidelines: in HD patients use 5 mg BID; decrease dose to 2.5 mg BID if weight <60 kg or age 80 y/o

14 No specific antidotes available for the factor Xa inhibitors (and not dialyzable) Dabigatran (Pradaxa) Idarucizumab 5g IV bolus Hemodialysis Apixaban Rivaroxaban Edoxaban NO REVERSAL AGENT AVAILABLE Activated prothrombin complex concentrates (apcc) e.g., Factor eight inhibitor bypassing activity (FEIBA) 8 units/kg PCC e.g., KCentra units/kg

15 Level <0.1 (UCI lab) no inhibitor present Dr. Richard Newman (Professor of Pathology)

16 ESRD patients are at high risk for cardiovascular and thrombosis events AND major bleeding. Anticoagulation in ESRD is controversial (survival, stroke). Warfarin (the only available oral anticoagulant for >50 years) may promote cardiovascular morbidity in CKD. We now have new oral anticoagulants! Apixaban (Eliquis) is approved for use in ESRD! But data is lacking re: safety and dose adjustment, and no antidote available We need more studies in ESRD to examine anticoagulation strategies and outcomes.