Download Newly Approved Anticoagulants

Novel Oral Anticoagulants
(NOAC)
Dan Moellentin, PharmD, BCPS,
Associate Professor Husson
University
Strokes in Atrial Fibrillation
• 1/5 of strokes are caused by a. fib
• 1/3 cardiac arrhythmias hospitalizations
• 2 million Americans affected by a. fib
~50% are anti-coagulated?
What would be the best
anticoagulation
Fast onset
Antidote
Brief History of Anticoagulation in
Atrial Fibrillation (a. fib)
Warfarin was approved in 1954
• INR wasn’t created by the World Health
Organization until the 1980’s
Until 2009, warfarin was considered the gold
standard for anticoagulation in a. fib.
Now there are three new oral anticoagulants
FDA approved for anticoagulation in a. fib
Vitamin K antagonist
Drug
• Warfarin
– Blocks vitamin K dependent clotting factors creation,
by inhibiting the vitamin vitamin K epoxide
reductase complex 1 (VKORC1)
– Vitamin K epoxside is responsible for the
regeneration of vitamin K in the vitamin K cycle by
blocking VKORC1
– Inhibit vitamin K epoxide reducatase thus interfering
with levels of II, V, VII, and IX LOOK UP LEVELs##
Patient Case #1
• The majority of warfarin is elimination via
metabolism
– Clinical example---pt post bowel resection--
Genetic Variance in 2C9
• Patients with 2C9 gene variance require lower
doses for therapeutic INR and are at increased
risk of bleeding
• Activity of 2C19 and 2C9 are genetically
determined, 2C9 is more important as it
metabolizes the most potent enantiomer, Swarfarin.
– 20% of Caucasians, 5% Africa Americans (AA), 2%
Asians have a least 1 gene variant
Genetic variations in Vitamin K
epoxide reductase complex 1 (VKORC1)
Loss of function, results in increased sensitivity
to warfarin and increased potential for drug
interactions because VKORC1 does not
function normally to produce vitamin K
dependent clotting factors (II, VII, IX, X,
proteins C and S)
– 37% of Caucasians, 14% of AAs, 89% of
Asians have at least one variant of VKORC1
Clinical Significance of Genetic Testing
before Warfarin initiation
• Not all centers have on-site testing
• Genetic testing costs about $200
• Is it paid for by Medicare part D or private
insurance?
• Adding a few extra days to hospitalization is
expensive
• Is it only useful in guiding early dosing, ie. does it
just save one dose?
• “Drug interactions with warfarin may negate the
influence of genetic variations and must be
considered”.
Cytochrome P450 Interactions
• Drugs that inhibit 2C9
– Bactrim, fluconazole, amiodarone, fluvastatin,
lovastatin, voriconazole, metronidazole,
acetaminophen 2g daily for more than a week,
cimetidine 400mg daily or less, omeprazole at
higher doses,
• 3A4 Strong Inhibitors
– Erythromycin, diltiazem, nefazadone, verapamil
Drugs Affecting Absorption Case #1
Cholestyramine or Colestipol
• Get Dan to write case
Warfarin
MOA: Vitamin K Antagonist (VKA)
Initial dose: 10 mg PO x 2 days, then dose based on
INR
Half-life: 40 hours
Monitoring:
• If INR is ≤ 0.5 from the target range, keep the
same dose and check INR in 1-2 weeks.
• Once INR is stabilized, one INR reading up to
every 12 weeks is adequate.
Only One is Also Approved for DVT/PE
Treatment/Prophylaxis
Rivaroxaban
• “Treatment of deep vein thrombosis (DVT)
pulmonary embolism”
• “Reduction in the risk of recurrence of DVT”
• “PE for the prophylaxis of DVT, which may lead to
PE in patients undergoing knee or hip replacement
surgery”
Newly Approved PO anticoagulants
• All 3 are FDA indicated for
– “reducing the risk of stroke and systemic embolism
in patients with non-valvular atrial fibrillation”
• Direct Thrombin Inhibitor
– Pradaxa® (dabigatran)
• Approved in 2010
• Xa Inhibitors
– Xarelto® (rivaroxaban)
• Approved in 2011
– Eliquis® (Apixaban)
• Approved in 2013
Medication
Warfarin
Dabigatran
Rivaroxaban
Apixaban
Class
VKA
Direct Thrombin
Inhibitor
Xa Inhibitor
Xa Inhibitor
Half-life
40 hours
12 to 17 hours
5 to 9 hours
12 hours
Dosing for A. fib
10mg x 2 days, then 150 mg twice daily
based on INR
20 mg once daily
5mg twice
daily
Majority of
Elimination
Hepatic CYP
• 2C9
80% Renal
Renal 66%
25% Hepatic
• CYP 3A4
27% Renal
Plasma Protein
Binding
99%
35%
92 – 95%
87%
Dialyzable
No
60%
No
No Data
Medication
Warfarin
Dabigatran
Rivaroxaban
Apixaban
Renal Dose
Adjustments
Based on INR
CrCL 15-30
mL/min
• 75 mg twice
daily
CrCL 15-50
mL/min
• 15 mg once
daily
If ≥2 of the
following
• ≥ 80 yoa
• ≤ 60 kg
• ≥ 1.5 mg/dL
2.5 mg twice
daily
• CrCL < 15
mL/min
• Moderate to
Severe
hepatic
impairment
• Prosthetic
heart valves
Hepatic Dose
Adjustments
None
Avoid Use
• CrCL < 15
mL/min
• Mechanical
prosthetic
heart valves
• Bioprosthetic
heart valves
LAST DOSE
UFH IV
INFUSION
24h
Switching from UFH to PO
Anticoagulant
FIRST DOSE
DABIGATRAN
FIRST DOSE
RIVAROXABAN
FIRST DOSE
APIXABAN
Switching from
PO anticoagulant
to UFH
LAST DOSE
DABIGATRAN
(CrCl > 30mL/min)*
12h
LAST DOSE
APIXABAN
LAST DOSE
RIVAROXABAN
12h
24h
FIRST DOSE
UFH IV
INFUSION
*For patients with a CrCl <30mL/min, 24 hours before starting UFH infusion is recommended
Coagulation Cascade
®
Pradaxa
(dabigatran)
MOA: Direct Thrombin Inhibitor
Half-life: 12 to 17 hours
Dosing:
• 150mg PO twice daily
• CrCL 15-30 mL/min
– 75 mg twice daily
Adverse Effects:
• Dyspepsia
• GI bleeding
Prescribing Information Drug
Interactions for Dabigatran
• USA
– Amiodarone, dronedarone, quinidine, verapamil,
clarithromycin, and ketoconazole, rifampin.
• Canada
– Amiodarone, dronedarone, verapamil, quinidine,
rifampicin
– Contraindications: Ketoconazole
• EMA
– Strong P-gp inhibitors: Amiodarone,, verapamil,
quinidine, clarithromycin
– P-gp inducers: rifampicin
– Contraindications: Ketoconazole, itraconazole, tacrolimus,
dronedarone, cyclosporine
Xarelto® (rivaroxaban)
MOA: Xa Inhibitor
Half-life: 5 to 9 hours
Dosing:
• A.Fib:
– CrCL >50 mL/min
• 20 mg once daily
– CrCL 15-50 mL/min
• 15 mg once daily
Adverse Effects
Eliquis® (apixaban)
MOA: Xa Inhibitor
Half-life: 12 hours
Dosing:
5mg PO twice daily
• 2.5 mg twice daily
– If ≥2 of the following
• ≥ 80 yoa
• ≤ 60 kg
• ≥ 1.5 mg/dL
Adverse Effects:
Pt casen #1
dabigitran plus amiodarone
• Pgp- problem is fda lit
P-glycoproteins (P-gp)?
P-gps are efflux drug transporters
P-gp
P-gp function is to excrete or protect the tissues
from xenobiotic absorption.
• Also referred as PGY1, multidrug resistance
protein-1 (MDR1).
• Member of the adenosine triphosphate (ATP)
binding cassette (ABC) gene
• ABCB1 is the gene that encodes for P-gp
P-gp in the body
P-gp Substrates, Inhibitor, Inducer
P-gp Substrates
P-gp Inhibitors
P-gp Inducers
Amiodarone
Amiodarone
Prazosin
Atorvastatin
Atorvastatin
St. John’s Wort
Dabigatran
Carvedilol
Digoxin
Diltiazem
Diltiazem
Dipyridamole
Lidocaine
Dronedarone
Lovastatin
Lidocaine
Nadolol
Lovastatin
Nicardipine
Quinidine
Pravastatin
Propranolol
Propranolol
NIcardipine
Quinidine
NIfedipine
Rivaroxaban
Simvastatin
Simvastatin
Verapamil
Verapamil
Clinically
Significant
P-gp
Inhibitors
Captopril
Carvedilol (Males)
Ranolazine
Quinidine
Cmaxi ,ss/Cmax,ss Ratio
Quinidine
AUCi/AUC Ratio
Verapamil
Amiodarone (400 mg x 5 wks)
Amiodarone (800mg x 1 wk)
Ranolazine
0
0.5
1
1.25
1.5
2
2.5
3
Clinically Significant P-gp Inhibitor
• ≥ 1.25 ratio for AUCi/AUC Ratio and Cmaxi,ss/Cmax,ss
Ratio
Source
http://www.medscape.org/viewarticle/467503
P-gp Substrates
P-gp Inhibitors
P-gp Inducers
Digoxin
Amiodarone
Amiodarone
Diltiazem
Atorvastatin
Diltiazem
Quinidine
Diltiazem
Nicardipine
Verapamil
Felodipine
Nifedipine
Lidocaine
Verapamil
Nicardipine
Quinidine
Verapamil
Dabigatran P-gp interactions
P-gp Substrate
Dabigatran
P-gp Inhibitor
Dronedarone
Amiordarone
Quinidine
Verapamil
Dabigatran + P-gp inhibitor
• Results in increased dabigatran concentrations
and adverse events
Rivaroxaban P-gp Interactions
Removed from the intestines by P-gp
Don’t use with rivaroxaban
Greater risk with decreased renal function
Strong P-gp and 3A4
Inhibitors
Moderate P-gp and
3A4 Inhibitors
Ketoconazole
Itraconazole
Amiodarone
Dronedarone
Diltiazem
Verapamil
Felodipine
Quinidine
Ranolazine
Apixaban P-gp Interactions
Apixaban
• ↑Apixaban conc.
– Itraconazole, ketoconazole, ritonavir, and
clarithromycin
Case #3 rivaroxaban
Time in Therapeutic Range (TTR) for
Warfarin
• TTR
– % of days that the patients INR is from 2.0 to 3.0
• “TTR in all the other modern warfarin-controlled studies
of anticoagulatns ranged from 63% to 73%”
– Phase III Trials’ TTR %
» RELY (Dabigatran)
• 64%
» Rocket AF (Rivaroxaban)
• 55%
» Aristotle (Apixaban)
• 62.2%
Is Rivaroxaban Dosing Appropriate?
Half-life: 5 to 9 hours
Non-valvular A. Fib
• 20 mg PO once daily
Phase II trials suggested that 10 mg twice daily
could be safer than 20 mg once daily
FDA WORDING
• INADEQUATE ON DABIGITRAN
• DOSING LIKELY WRONG FOR DVT PROP ON
RIVAROX
APIXIBAN DOSING CORRECTNESS IS
UNKNOWN
• WHAT IS DIFFERENT ON LAST 2 DRUGS IS THAT
DECISION FOR DOSE ADJUSTMENT IS NOW A
PROVIDER JUDGEMENT BASED ON 3A4 AND
PGP
No NOAC Are Approved for ACS
Medications
Phase II
Trials
Clinically Significant
Bleeding
P < 0.001
Hazard Ratio
Dabigatran
RE-DEEM
75 mg: 4.3%, 150
mg: 7.8%,
150 mg
4.27 (95 % CI 1.86 -9.81)
Rivaroxaban
ATLAS ACSTIMI 46
Percentages were not listed, P
<0.0001
10 mg: 3.35
15 mg: 3.6
20 mg: 5.06
Apixaban
APPRAISE
2.5 mg BID: 3.2%
10 mg QD: 5.5%
10 mg BID and 20 mg QD were
stopped because of too many
bleeding episodes
2.5 mg BID: 1.78
10 mg QD: 2.45
Safety of Triple Antithrombotic Therapy in
ACS Patients
Single Antiplatelet + NOAC
• Aspirin
– ↓’d the occurrence of major adverse cardiovascular events
(MACE)
• HR 0.70, (95% CI 0.59- 0.84)
– BUT ↑’d clinically relevant bleeding
• HR 1.79 (95% CI 1.54-2.09)
Dual Antiplatelet +NOAC
• Aspirin + Clopidogrel
– ↓’d the occurrence of MACE
• HR 0.87 (95% CI 0.80-0.95)
– More than two fold ↑ in clinically relevant bleeding
• HR 2.34 (95% CI 2.06-2.66)
Risk Assessment
Physicians will need assess the patient’s risk for
• Thromboembolism
– CHADS2 Score ≥ 2 = probably require triple antithrombotic
therapy
• Hemorrhaging
“ Clinicians should strive to limit the use of dual
antiplatelet agents with concurrent antithrombotics in
patients who are at the highest risk for thromoembolic
events and ensure that these patients are instructed to
report any signs and sympotms of bleeding or recurrent
thrombosis” Dager W PharmD PCPS (AQ Cardiology)
Reversal and Monitoring of nOAC
Reversal of Dabigatran
Management
of Dabigatran Bleeding
Management Algorithm for Dabigatran Bleeding
Management
for bleeding
from Xa
Inhibitors
Management Algorithm for Rivaroxaban and Apixaban Bleeding
Reversal of Dabigatran
• Since dabigatran directly blocks thrombin and
does not decrease the coagulation factors,
using coagulation factors like, PCC, FFP is NOT
expected to be completely effective as a
reversal agent.
• The best method of reversing dabigatran is to
be excreted out by the kidneys.
What are PCCs?
Prothrombin Complex Concentrates (PCC)
Note: No PCC is FDA approved for reversing anticoagulants
Three Factor (II, IX, X) FDA approved
– Profilnine® SD
– Bebulin® VH
Four Factor (II, VII, IX, X)
• Unactivated (NOT FDA Approved)
– Beriplex P/N
– Octaplex
• Activated
– Feiba NF (Factor VII blocker bypassing function) Factor VII
Blockers)
• Only factor VII is activated
Antibody Antidote for Dabigatran?
Boehringer Ingelheim: manufacture dabigatran
(Pradaxa®)
• Currently developing and studying pre-clinically
a humanized antibody fragment (Fab) that
could be used as a reversal agent for
dabigatran.
– Rats were given dabigatran and “there was a rapid,
dose-dependent decrease in bleeding time after IV
injection of Fab”
– Additionally, the Fab reversed clotting ex vivo as
well.
Reversal of Rivaroxaban?
Phase I Trials
• Four Factor PCC (Factor II, VII, IX and X)
– After 3 days of rivaroxaban and one dose of PCC PT and
ETP was statistically significantly decreased
• PRT4445
– New recombinant protein that blocks Xa inhibitors by
serving as a decoy.
– The manufacters of PRT4445 has report its safe and
tolerable and claims it reverses Xa inhibitors in 5
minutes and last 3 hours, however, the study isn’t
available online yet.
So What is the “Right” Answer?
Pre-clinical studies
Studies showing PCC only improves labs not
bleeding in apixaban and rivaroxaban
Warfarin
Reversal
• Is warfarin really “reversed?”
• Example intracranial hemorrhage (ICH)….
Gastrointestinal Bleeding
• Higher risk for DVT/PE treatment vs. DVT/PE
prophylaxis after hip/knee replacement surgery
– Rivaroxaban 10 mg once daily
• Hip: 35 days
• Knee: 12 days
– Maybe a dose-dependent effect
• Dabigatran and rivaroxaban
– Higher risk than apixaban
Numbers of post-marketing cases of
ICH and retroperitoneal hemorrhages
Apixaban
Rivaroxaban
Dabigatran
Post Marketing
• Incidence of stroke, major bleeding, ICH
Post Marketing
• Bleeding Risk with Dabigatran in the Frail
Elderly NEJM
http://www.nejm.org/doi/full/10.1056/NEJMc
1112874
Surgery
Dabigatran
• CrCL ≥ 50mL/min stop 1-2 days prior to surgery
• CrCL < 50mL/min stop 3-5 days prior to surgery
Rivaroxaban
• Stop ≥ 48 hours prior to surgery for moderate to severe
bleeding risk
• Stop ≥ 24 hours prior to surgery for normal risk of
bleeding
Apixaban
• Stop ≥ 48 hours prior to surgery for moderate to severe
bleeding risk
• Stop ≥ 24 hours prior to surgery to low risk of bleeding
Monitoring
Dabigatran
• Useful in establishing if drug in present or not
– Normal aPTT: barely any dabigatran present
– TT (Thrombin Time): linear dose-response curve for
dabigatran, NOT after steady-state.
Rivaroxaban and Apixaban??
• aPTT
• PT/INR
• Anti-Xa Level
Monitoring for Dabigatran
Monitoring on Xa Inhibitors
(Rivaroxaban & Apixaban)
Why Not Just Use Anti-Xa Assays to
Monitor Xa Inhibitors
Dosing Adjustments
Hepatic Impairment
Apixaban
Mild
• No dose reduction is required
Moderate
• No data available
Severe
• Not recommended
Hepatic Impairment
Rivaroxban
• Don’t use
– Moderate and severe impairment
– Liver disease that involves bleeding disorders
Renal Impairment
Apixaban
• 2.5 mg twice daily if 2 or more of the following
exist
1. ≥ 80 years of age
2. Weight ≤ 60 kg
3. Scr ≥ 1.5 mg/dL
Currently per package insert there is “no date
inform use in patients with CrCl <15 min/ml or
on dialysis”
Renal Impairment
Rivaroxaban
• A. fib
– CrCl >50 ml/min
• 20 mg daily with dinner
– CrCl 15-50 ml/min
• 15 mg daily with dinner
– Don’t use if CrCl <15ml/min
• Treatment of DVT, PE and decreasing the risk of
another DVT and PE
– Don’t use if CrCl <30 ml/min
Renal Impairment
•
•
•
•
Dabigatran
80% excreted renally
~60% is removed by dialysis
Half-life > 24 hours during renal impairment
CrCL
– 15 to 30mL/min
• 75mg twice daily
– < 15mL/min or on dialysis :
• Don’t use
Institute for Safe Medication Practices
(ISMP)
ISMP
• Federally certified, nonprofit organization
dedicated to patient safety by
– Education on safe medication use
– Compile and examine medication errors, side
effects, and near misses.
– Distribute up to date medication safety news,
provide ways of preventing errors, and tools to
decrease risks
ISMP 1st Quarter Watch 2012
Rivaroxaban
• 356 Reports of severe, damaging, or
deadly adverse effects
– 44%: thrombotic events
• Majority: PE
• Appearing in prophylaxis for
DVT/PE post surgery and in
younger patents than dabigatran
adverse effects
» (average age 66)
• Dabigatran
– Bleeding was appearing in elderly
patients (average 80 years old)
ISMP 2012 2nd Quarter Watch
Dabigatran
– The odds of recorded death from dabigatran were
about five fold greater than warfarin.
Rivaroxaban
– The odds of recorded death from rivaroxaban were
about less than two times greater than warfarin.
– 10 mg once daily vs. 20 mg once daily
• 10 mg once daily
– 7 fold greater odds of a recoded emoblicthrombotic occurrence.
FDA Draft Briefing Document for the
Cardiovascular and Renal Drugs
Advisory committee (CRDAC) for
Rivaroxaban
• “Mean compliance rates ranged from a low of 95.2%
(North America, warfarin arm) to a high of 97.1%
(Eastern Europe, rivaroxaban arm)”
• Day 1-30: % of warfarin naïve patients with an INR in 23 range
– 30.68%
• It wasn’t until day 181-360 that over 50% warfarin
naïve patients
• By Day 181-360 50% of warfarin naïve patients had an
INR of 2-3.
Incidence of Myocardial Infarction (MI)
Dabiagatran
• Displays a significantly greater risk for MI/Acute
Coronary Syndromes (ACS).
Rivaroxaban
• Lower risk for MI/ACS
When to discontinue
Apixaban
Rivaroxaban
Dabigatran
Cardioversion
• Dabigatran has been shown to be an
acceptable alternative to warfarin
• No studies have evaluated rivaroxaban or
apixaban
Maybe a slide
• whaT PERCENTAGE OF NEW RX FOR A FIB ARE
NON WARFARIN DRUGS
Summary