Direct Oral Anticoagulants

Eliot Williams, MD PhD

Division of Hematology & Medical Oncology

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

Oral thrombin and Xa inhibitors

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

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

Ansell, 2011 HTRS meeting

Indirect inhibitors

Direct inhibitors

RivaroxabanApixabanEdoxaban

Edoxaban

Pharmacology of oral anticoagulant drugs

Warfarin DOACsBioavailability 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

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

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)

*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)

*Not FDA-approved indication

DOACS for ATRIAL FIBRILLATION

DIRECT 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

Trial 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 2.1 66%

ENGAGEAF-TIMI 48

Edoxaban(two doses)

21,105 2.8 68%

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

Ruff et al, Lancet 2013

Dabigatran 150 mg bid

Rivaroxaban 20 mg qd

Apixaban 5 mg bid

Edoxaban 60 mg qd

Combined

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 150D 110

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

JAMA Intern Med 2015;175:18

Favors warfarin→

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

Wallentin et al, Circulation 2013

Favors apixaban Favors warfarin

The benefit of switching from warfarin to a DOAC appears to be greatest in patients with relatively poor INR control

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 warfarinmeta-analysis of phase 3 trials

J Thromb Haemost 2014;12:320

Efficacy and safety of alternative treatments for acute VTE vs LMWH/VKA

JAMA 2014;312:1122-35

Unfractionated heparin + VKA inferior to LMWH + VKA

Single-agent rivaroxaban and apixaban appear safer than LMWH + VKA

Gómez-Outes et al, J Cardiovasc Pharmacol Ther, 2015

Safety and efficacy of DOACs for initial and extended treatment of VTE

A systematic review

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

J Thromb Haemost 2015;13:2012

DOACS for VTE PROPHYLAXIS

DOACs vs LMWH after total hip or knee arthroplastyA systematic review of the literature

Ann Intern Med 2013;159:275

Mortality

Symptomatic DVT

Nonfatal PE

Major bleeding

Dabigatran vs LMWH Xa inhibitors vs LMWH

Less thrombosis, more bleeding with NOACs

Extended-duration (30 day) prophylaxis with DOACs vs LMWH after total hip arthroplasty

A meta-analysis of RCT data

J Thromb Haemost 2014;12:107

Symptomatic VTE

Total VTE +All-cause mortality

Major bleeding

DOACS for ACUTE CORONARY SYNDROME

DOACs 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

Monitoring

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

“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?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

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

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 stoppedRemember that NOACs can prolong PT/INR

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)