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Update on the New Oral Anticoagulants Eliot Williams, MD PhD Division of Hematology & Medical Oncology.

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Presentation on theme: "Update on the New Oral Anticoagulants Eliot Williams, MD PhD Division of Hematology & Medical Oncology."— Presentation transcript:

1 Update on the New Oral Anticoagulants Eliot Williams, MD PhD Division of Hematology & Medical Oncology

2 Nothing to disclose

3 History of anticoagulant therapy 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2010 Anticoagulant in spoiled sweet clover (K.P. Link) First clinical use of 4-hydroxycoumarin (O. Meyer et al) Warfarin mechanism elucidated (J. Suttie) Warfarin dosing/INR Warfarin clinical trials Heparin discovered by medical student (McLean) Clinical use of heparin Requirement for plasma cofactor discovered (K. Brinkhous) Cont infusion of heparin; aPTT monitoring LMWH (J. Hirsch) LMWH trials Fondaparinux trials

4 New oral anticoagulants Dabigatran (Pradaxa ® ) – thrombin inhibitor –FDA approval 2010: stroke prevention in non- valvular Afib Rivaroxaban (Xarelto ® ) – Xa inhibitor –FDA approval 2010/11: postop VTE prophylaxis, stroke prevention in Afib, treatment of VTE Apixaban (Eliquis ® ) – Xa inhibitor –FDA approval 2012: stroke prevention in Afib; approved 2014 for VTE prophylaxis after major orthopedic surgery Edoxaban – Xa inhibitor –Not yet FDA approved

5 Anticoagulant drug mechanisms Ansell, 2011 HTRS meeting Indirect inhibitors Direct inhibitors

6 Edoxaban

7 Pharmacology of oral anticoagulant drugs WarfarinNew agents Bioavailability99%6-80% (some active drug in large bowel) Tmax72-96 hours2-4 hours Half-life40 hours5-17 hours MetabolismCytochrome P450Biliary/Renal Drug InteractionsManyNot so many Food InteractionsYesNo Genetic VariationMajor effectsMinor effects (?) MonitoringPT/INRNone ReversalVit K/PCC/FFPPCC? Dialysis?

8 Cost per month of oral anticoagulants Rivaroxaban (20 mg/day) : $290 Dabigatran (150 mg bid): $290 Apixaban (5 mg bid): $147 Warfarin (7.5 mg/day): $31 Source: UWHC Pharmacy

9 Dabigatran Dose –Stroke prevention in A fib: 110-150 mg bid 110 mg dose not available in US For patients with CrCl 15-30: 75 mg bid Not recommended for CrCl < 15 or dialysis dependent –Postop VTE prophylaxis*: 150-220 mg once daily –Prevention of recurrent VTE*: 150 mg bid Less than 10% absorbed; relatively high rate of GI side effects Crosses the placenta – do not use during pregnancy Drug may degrade over time after exposure to air – must be kept in original packaging Unused tablets should be discarded after 90 days * Not FDA-approved indication

10 Rivaroxaban Dose: –Stroke prevention in Afib: 15-20 mg once daily –Post op VTE prophylaxis: 10 mg once daily –Acute VTE treatment: 15 mg twice daily –Secondary prevention of VTE: 20 mg once daily –Acute coronary syndrome*: 2.5-5 mg twice daily Use with caution in moderate renal impairment (CrCL 30-49); 15 mg/day dose recommended –Avoid use if CrCl < 30 (not dialyzable) Avoid use in severe liver disease *Not FDA-approved indication

11 Apixaban Dose: –Stroke prevention in Afib: 5 mg bid 2.5 mg bid if age >80, weight 1.5 –Post op VTE prophylaxis*: 2.5 mg bid –Secondary prevention of VTE*: 2.5-5 mg bid –Treatment of acute VTE*: 10 mg bid –Secondary prevention of VTE*: 5 mg bid Avoid use in severe liver disease (75% biliary excretion) *Not FDA-approved indication


13 NEW ORAL ANTICOAGULANTS VS WARFARIN IN NON-VALVULAR ATRIAL FIBRILLATION All randomized; RE-LY unblinded All designed as non-inferiority trials Primary outcome was stroke or embolism All funded by drug manufacturer TrialDrug being compared # subjectsCHADS 2 (mean) TTR (median) RE-LYDabigatran (two doses) 18,1132.167% ROCKET-AFRivaroxaban14,2643.558% ARISTOTLEApixaban18,2012.166% ENGAGE AF-TIMI 48 Edoxaban (two doses) 21,1052.868% NEJM 2009; 361: 1139NEJM 2011; 365:883NEJM 2011; 365:981

14 NEW ORAL ANTICOAGULANTS VS WARFARIN: RISK OF STROKE OR EMBOLISM Dabigatran 150 mg bid Rivaroxaban 20 mg qd Apixaban 5 mg bid Edoxaban 60 mg qd Combined Ruff et al, Lancet 2013


16 NEW ORAL ANTICOAGULANTS VS WARFARIN: RISK OF MAJOR BLEEDING Ruff et al, Lancet 2013 Dabigatran 150 mg bid Rivaroxaban 20 mg qd Apixaban 5 mg bid Edoxaban 60 mg qd Combined

17 Bleeding rates with dabigatran vs warfarin as a function of age Circulation 2011;123:2363 Intracranial bleeding lower with dabigatran at all ages Extracranial bleeding rates higher with dabigatran above age 75 Warfarin D 110 D 150 Warfarin D 150 D 110

18 Dabigatran use associated with higher risk of coronary events ←Risk lower with dabigatran Risk higher with dabigatran→ Arch Intern Med 2012;172:397

19 LESSONS FROM AF TRIALS WITH NEW ORAL AGENTS Main result: New agents at least as effective as warfarin, can be given without routine monitoring Other/unexpected findings: –Reduction in intracranial bleeding –Higher MI rates (dabigatran) –Higher rates of GI bleeding (active drug in lower intestine) –Extracranial bleeding risk higher in older patients

20 Relative efficacy and safety of apixaban vs warfarin, according to adequacy of individual INR control Wallentin et al, Circulation 2013 Favors apixaban Favors warfarin The benefit of switching from warfarin to a NOAC appears to be greatest in patients with relatively poor INR control

21 Can the new oral agents be used in patients with mechanical valves? Randomized trial of dabigatran vs warfarin in patients with mechanical valves showed more thrombotic complications (5% vs 0) and more bleeding (4% vs 2%) with dabigatran (Eikelboom et al, NEJM 2013; 369:1206) DO NOT USE NOACs IN PATIENTS WITH MECHANICAL VALVES


23 Efficacy of NOACs for treatment of acute VTE is comparable to warfarin meta-analysis of phase 3 trials J Thromb Haemost 2014;12:320

24 Safety of NOACs for treatment of acute VTE is superior to warfarin meta-analysis of phase 3 trials J Thromb Haemost 2014;12:320

25 NOACs for treatment of VTE Efficacy comparable to warfarin Modest safety advantage Practical advantages –No monitoring –No injections –No transitioning – single agent treatment –Shorter hospital stay


27 NOACs vs LMWH after total hip or knee arthroplasty A systematic review of the literature Ann Intern Med 2013;159:275 Mortality Symptomatic DVT Nonfatal PE Major bleeding Dabigatran vs LMWHXa inhibitors vs LMWH Less thrombosis, more bleeding with NOACs


29 New oral anticoagulants plus antiplatelet therapy in ACS: meta-analysis Arch Intern Med 2012; 172:1537 Favors NOA Favors placebo Non-significant decrease in overall mortality, large increase in risk for major bleeding

30 Monitoring

31 Effects of NOACs on routine coag tests PT/INR and PTT are relatively insensitive to the effects of these drugs –Reagent-dependent – results will vary among labs Normal PT and PTT do not rule out significant blood level of NOAC If PT or PTT elevated → assume significant blood levels of NOAC Thrombin time very sensitive to dabigatran effect – normal TT implies no drug on board –Rivaroxaban & apixaban do not affect TT

32 Measuring blood levels of NOACs Dabigatran: –Modified thrombin time assay (Hemoclot ® ) Rivaroxaban and apixaban: –Anti-Xa activity (similar to LMWH assay) Neither assay FDA-approved or widely available now When to consider measuring drug level: –Detect/quantify overdose –Screen for drug accumulation (eg, impaired renal or liver function) –Assure low drug level prior to surgery  Limited usefulness for assessing compliance due to short drug half-lives

33 REVERSAL? No specific antidote for any of the new OACs –New agents in development may solve this problem Activated charcoal will reduce drug absorption if administered within a few hours of ingestion Rivaroxaban & apixaban effect may be reversed by giving prothrombin complex concentrate (PCC) (limited data) Dabigatran is dialyzable –60% removed/3 hours, with rebound effect Case reports suggest that recombinant factor VIIa (NovoSeven™) is ineffective vs dabigatran (Thromb Haemost 2012;108:585)

34 Risk-benefit profile of NOACs vs warfarin remains favorable in patients with moderate renal insufficiency (GFR < 50) Meta-analysis of 9 phase III trials J Thromb Haemost 2014;12:337 Thrombotic eventsMajor bleeding % of drug excreted by kidneys → VKA better NOAC better VKA better NOAC better

35 Transitioning

36 Transitioning to NOACs Unfractionated heparin to NOAC: –Start NOAC when UFH infusion stopped LMWH to NOAC: –Start NOAC 2 h before next scheduled sq dose of LMWH Warfarin to NOAC: –When INR < 2.0

37 Transitioning from NOACs NOAC to parenteral anticoagulant: –CrCl >30: start 12 hours after last NOAC dose –CrCl <30: start 24 hours after last NOAC dose NOAC to warfarin: –CrCl >50: start warfarin 3 days before NOAC stopped –CrCl 31-50: start warfarin 2 days before NOAC stopped –CrCl 15-30: start warfarin 1 day before NOAC stopped  Remember that NOACs can prolong PT/INR

38 When to stop drug before surgery Stop NOAC at least 3 drug half-lives prior to surgery –Dabigatran: 42-51 h –Rivaroxaban: 15-27 h –Apixaban: 24-48 h Allow more time if: –Age > 75 –Impaired renal or liver function –High bleeding risk

39 Who are the best candidates for new oral anticoagulants? Patients who have unstable INR on warfarin not due to poor compliance Reasonably good renal & hepatic function No mechanical valve Not pregnant (drugs cross placenta) < 75 years old No history of lower GI bleeding Not at high risk for ACS (dabigatran)

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