Direct Oral Anticoagulants Eliot Williams, MD PhD Division of Hematology & Medical Oncology

History of anticoagulant therapy Oral thrombin and Xa inhibitors Warfarin mechanism elucidated (J. Suttie) Warfarin clinical trials Anticoagulant in spoiled sweet clover (K.P. Link) First clinical use of 4-hydroxycoumarin (O. Meyer et al) Warfarin dosing/INR 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2010 Parenteral anticoagulants – heparin early 20th C. Incredible shrinking drug; heparin derivatives still drugs of choice for treatment of acute VTE, in-hospital prophy Oral anticoagulants – Wisconsin connection Heparin discovered by medical student (McLean) Clinical use of heparin Cont infusion of heparin; aPTT monitoring LMWH trials Requirement for plasma cofactor discovered (K. Brinkhous) LMWH (J. Hirsch) Fondaparinux trials

Direct oral anticoagulants Dabigatran (Pradaxa®) – thrombin inhibitor FDA approval 2010: stroke prevention in non-valvular Afib; approved 2014 for VTE treatment 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 FDA approval for VTE treatment 2014 Edoxaban (Savayasa®) – Xa inhibitor FDA approval 1/2015: stroke prevention in Afib; treatment of acute VTE

Anticoagulant drug mechanisms Indirect inhibitors Direct inhibitors Indirect vs direct inhibitors. Parenteral vs oral. Thrombin vs Xa. Note that warfarin doesn’t block actions of clotting factors but just lowers blood levels. Rivaroxaban Apixaban Edoxaban Ansell, 2011 HTRS meeting

Dabigatran given as pro-drug. Edoxaban

Pharmacology of oral anticoagulant drugs Warfarin DOACs Bioavailability 99% 6-80% (some active drug in large bowel) Tmax 72-96 hours 2-4 hours Half-life 40 hours 5-17 hours Metabolism Cytochrome P450 Biliary/Renal Drug Interactions Many Not so many Food Interactions Yes No Genetic Variation Major effects Minor effects (?) Monitoring PT/INR None Reversal Vit K/PCC/FFP PCC? Dialysis?

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 About 10x as expensive as warfarin, but much cheaper than LMWH. Source: UWHC Pharmacy

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 VTE treatment/prevention of recurrent VTE: 150 mg bid (following LMWH or heparin Rx) 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

Rivaroxaban Dose: Stroke prevention in nonvalvular 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 Treatment trials have used higher/BID doses of R initially

Apixaban Dose: Stroke prevention in nonvalvular Afib: 5 mg bid 2.5 mg bid if age >80, weight < 60 kg, or serum creatinine > 1.5 Post op VTE prophylaxis: 2.5 mg bid Treatment of acute VTE: 10 mg bid x 7 days, then 5 mg bid Secondary prevention of VTE: 2.5 mg bid Lowest dependence on renal excretion of new agents Avoid use in severe liver disease (75% biliary excretion) Less dependent on renal excretion – safer in pts with renal insuff? Less safe in pts with liver dz? *Not FDA-approved indication

Edoxaban Dose: Stroke prevention in Afib: 60 mg/d 30 mg/d if CrCl 15-50 or body wt ≤ 60 kg Post op VTE prophylaxis*: 30 mg/d Treatment of acute VTE: 60 mg/d (following LMWH or heparin Rx) Avoid use if CrCl > 95 ml/min (excessive excretion decreases efficacy) Less dependent on renal excretion – safer in pts with renal insuff? Less safe in pts with liver dz? *Not FDA-approved indication

DOACS for ATRIAL FIBRILLATION

DIRECT ORAL ANTICOAGULANTS VS WARFARIN IN NON-VALVULAR ATRIAL FIBRILLATION Drug being compared # subjects CHADS2 (mean) TTR (median) RE-LY Dabigatran (two doses) 18,113 2.1 67% ROCKET-AF Rivaroxaban 14,264 3.5 58% ARISTOTLE Apixaban 18,201 66% ENGAGE AF-TIMI 48 Edoxaban 21,105 2.8 68% All randomized; RE-LY unblinded All designed as non-inferiority trials Primary outcome was stroke or embolism All funded by drug manufacturer NEJM 2009; 361: 1139 NEJM 2011; 365:883 NEJM 2011; 365:981 NEJM 2013;369:2093

DOACS 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

DOACS VS WARFARIN: SECONDARY EFFICACY AND SAFETY OUTCOMES Ruff et al, Lancet 2013

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

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

Bleeding rates with dabigatran vs warfarin in atrial fibrillation: a “real-world” study JAMA Intern Med 2015;175:18

Bleeding rates with dabigatran vs warfarin in atrial fibrillation: a “real-world” study Favors warfarin→ JAMA Intern Med 2015;175:18

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

LESSONS FROM AF TRIALS WITH DOACS 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

Relative efficacy and safety of apixaban vs warfarin, according to predicted adequacy of individual INR control Favors apixaban Favors warfarin The benefit of switching from warfarin to a DOAC appears to be greatest in patients with relatively poor INR control This is patient-level data comparing outcomes with apixaban and warfarin (in Afib) vs adequacy of anticoagulant control in warfarin pts vs matched controls. Bottom group is all adverse outcomes (bleeding or clotting), note that the benefit of apixaban greatest when warfarin control is worst Wallentin et al, Circulation 2013

Can DOACs 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 DOACs IN PATIENTS WITH MECHANICAL VALVES

DOACS for TREATMENT OF VTE

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

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

Efficacy and safety of alternative treatments for acute VTE vs LMWH/VKA Unfractionated heparin + VKA inferior to LMWH + VKA Single-agent rivaroxaban and apixaban appear safer than LMWH + VKA JAMA 2014;312:1122-35

Safety and efficacy of DOACs for initial and extended treatment of VTE A systematic review Gómez-Outes et al, J Cardiovasc Pharmacol Ther, 2015

DOACs for treatment of VTE Efficacy comparable to warfarin Fewer bleeding complications Practical advantages No monitoring No injections No transitioning – single agent treatment Shorter hospital stay

DOAC treatment of AF or VTE associated with lower overall mortality vs warfarin Meta-analysis of 13 phase III trials Four trials of R vs E in high risk ortho surgery all showed better efficacy for R. Note bleeding rates for R are somewhat higher across the board. J Thromb Haemost 2015;13:2012

DOACS for VTE PROPHYLAXIS

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

Extended-duration (30 day) prophylaxis with DOACs vs LMWH after total hip arthroplasty A meta-analysis of RCT data Symptomatic VTE Total VTE + All-cause mortality Major bleeding J Thromb Haemost 2014;12:107

DOACS for ACUTE CORONARY SYNDROME

DOACs plus antiplatelet therapy in ACS: meta-analysis Favors NOA Favors placebo Non-significant decrease in overall mortality, large increase in risk for major bleeding Four trials of R vs E in high risk ortho surgery all showed better efficacy for R. Note bleeding rates for R are somewhat higher across the board. Arch Intern Med 2012; 172:1537

Monitoring Lotsa luck

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

Measuring blood levels of DOACs Dabigatran: Modified thrombin time assay (Hemoclot®) Rivaroxaban, apixaban, edoxaban: 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 Dabigatran assays likely to be available only via send-out for most hospitals. More hospitals doing anti-Xa assays but still not routinely available most places. Compliance testing dicey due to rapid onset and short duration of drug effect. Probably better off counting pills.

“Analyses conducted by Boehringer Ingelheim showed that in August 2011 the company had calculated that there was an optimal plasma concentration of the drug. In June 2012 another analysis showed that measuring blood dabigatran concentrations and changing the dose as needed could reduce major bleeds by 30-40% in comparison to well-controlled warfarin” BMJ 2014;349:4756

Is a “one size fits all” approach to dosing best Is a “one size fits all” approach to dosing best? An alternative approach to dabigatran dosing Boehringer Ingleheim web site, 2015

REVERSAL OF DOAC ANTICOAGULANT EFFECT

IDARUCIZUMAB FOR DABIGATRAN REVERSAL Idarucizumab (Praxbind®) is a monoclonal antibody fragment that binds to dabigatran with high affinity (350x that of thrombin) 5 mg of idarucizumab (2 x 2.5 mg vials) completely reverses the anticoagulant effect of dabigatran when the drug is taken at usual recommended doses This effect occurs within minutes of drug administration and restores normal hemostasis (NEJM 2015; 373:511) Idarucizumab approved by FDA in October 2015

ANDEXANET ALFA FOR FACTOR Xa INHIBITOR REVERSAL Modified recombinant factor Xa lacking procoagulant activity Binds factor Xa inhibitors with high affinity and thus acts as a “decoy protein” Short half-life: given as bolus plus a 1-2 hour infusion In healthy volunteers taking either apixaban or rivaroxaban, the drug reduced anti-factor Xa activity by > 90% and restored normal hemostatic function in >95% of subjects (NEJM 2015;373:2413) Not yet FDA-approved

OTHER OPTIONS FOR FACTOR Xa INHIBITOR REVERSAL Activated charcoal reduces drug absorption if administered within a few hours of drug ingestion 4-factor prothrombin complex concentrate (PCC) reverses laboratory indices of drug effect (limited clinical data)

Transitioning Lotsa luck

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 Note that delay between stopping dabigatran and starting another anticoagulant should be longer if there is any degree of renal insufficiency. Note also that INR may be affected by dabigatran for a day or two after stopping the drug.

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 Note that delay between stopping dabigatran and starting another anticoagulant should be longer if there is any degree of renal insufficiency. Note also that INR may be affected by dabigatran for a day or two after stopping the drug.

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

Who are the best candidates for new oral anticoagulants? Patients who have unstable INR on warfarin not due to poor compliance Adequate renal & hepatic function No mechanical valve Not pregnant (drugs cross placenta) Not at extremes of weight (can’t adjust dose) Not at high risk of lower GI bleeding Not at high risk for ACS (dabigatran)