Transcript History of anticoagulant therapy

Direct Oral Anticoagulants
Eliot Williams, MD PhD
Division of Hematology &
Medical Oncology
History of anticoagulant therapy
Anticoagulant in
spoiled sweet
clover (K.P. Link)
1910
1920
1930
First clinical use of
4-hydroxycoumarin
(O. Meyer et al)
1940
1950
Heparin
Clinical use of
discovered heparin
by medical
Requirement
student
for plasma
(McLean)
cofactor
discovered
(K. Brinkhous)
1960
Warfarin
Warfarin
clinical trials
mechanism
elucidated Warfarin
(J. Suttie) dosing/INR
1970
Cont infusion of
heparin; aPTT
monitoring
1980
1990
2000
Oral thrombin
and Xa
2010
LMWH trials
LMWH
(J. Hirsch)
Fondaparinux
trials
Direct oral anticoagulants
• Dabigatran (Pradaxa®) – thrombin inhibitor
– FDA approval 2010: stroke prevention in nonvalvular 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
Rivaroxaban
Apixaban
Edoxaban
Direct inhibitors
Ansell, 2011 HTRS meeting
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
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
Trial
RE-LY
Drug being
compared
Dabigatran
# subjects
CHADS2
(mean)
TTR
(median)
18,113
2.1
67%
(two doses)
ROCKET-AF
Rivaroxaban
14,264
3.5
58%
ARISTOTLE
Apixaban
18,201
2.1
66%
ENGAGE
AF-TIMI 48
Edoxaban
(two doses)
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
D 110
D 150
Warfarin
Warfarin
D 150
D 110
• 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
The benefit of switching
from warfarin to a DOAC
appears to be greatest in
patients with relatively
poor INR control
Favors apixaban
Favors warfarin
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
DO NOT USE
DOACs IN PATIENTS
WITH
thrombotic
complications
(5% vs 0) and
more
MECHANICAL
bleeding (4%
vs 2%) with VALVES
dabigatran (Eikelboom
et al, NEJM 2013; 369:1206)
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
J Thromb Haemost 2015;13:2012
DOACS for
VTE PROPHYLAXIS
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, Symptomatic
more bleeding
with NOACs
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: metaanalysis
Favors NOA
Favors placebo
Non-significant decrease in overall mortality,
large increase in risk for major bleeding
Arch Intern Med 2012; 172:1537
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 wellcontrolled 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 stopped
 Remember 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)