Transcript The Novel A nticoagulants

The New Oral Anticoagulants:
Bleeding, Periprocedureal Management,
Laboratory Evaluation, and Use for VTE
Prevention/Treatment
Seth Scott MD
Background
• There are 2 approved new oral anticoagulants (NOACs):
– Dabigatran, and Rivaroxaban
• Will need to be ready to treat people who have
bleeding complications
– use of these medications is increasing in the community.
• Will need to advise surgical specialists on how to stop
and start medications in preparation for procedures.
• Recently one of the new oral anticoagulants was
approved for treatment for PE/DVT
TREATMENT OF BLEEDING
Review of Relevant Pharmacology
Dabigatran
• Oral medication with less
food/drug and drug/drug
interactions than warfarin
• Direct thrombin inhibitor
• Renally cleared
• t ½ 12-17 hrs
• Approved for stroke prevention
in non valvular afib
• Less protein bound with lower
volume of distributiondialyzable
Rivaroxaban
• Oral medication with less
food/drug and drug/drug
interactions than warfarin
• Factor Xa inhibitor.
• Mixed excretion with 1/3 in
stool 2/3 in Urine
• t ½ 1. 8-9 hrs (younger patients)
or 11-13 hrs (elders)
• Approved for stroke prevention
in non-valvular afib for DVT
prophylaxis in TKA and THA and
DVT treatment
• Highly protein bound nondialyzable
Pharmacologic Data on the Approved
Novel Anticoagulants
Dabigatran
Rivaroxaban
Peak Action
1-3 hr
1-3 hr
Protein Binding
35%
92-95%
Elimination t ½ with cr
clearnance >80
13.8 hr
8.3 hr
Elimination t ½ with cr
clearnance>50-70
16.6 hr
8.7 hr
Elimination t ½ with cr
clearance >30-49
18.7 hr
9.0 hr
Elimination t ½ with cr
clearance <30
27.5 hr
9.5 hr
Renal Clearance
80%
33%
Kaatz, S et al
Available literature on bleeding
• Two recent summary articles on treatment of bleeding
events associated with these medications
– Guidance on the emergent reversal of oral thrombin and
factor Xa inhibitors. Katz et. al THNSA meeting
proceedings from American Journal of Hematology
– Emergency Management of bleeding Associated with old
and New Oral Anticoagulants. Peacock et. al from Clinical
Cardiology
• Most data in these articles come from laboratory
measures of activity or animal studies
• Most data appears to have been put out by the drug
companies or their surrogates.
Options to Reverse Anticoagulation in a
Bleeding on Dabigatran
• Holding medication is 1st
choice
– T ½ varies depends on renal
function 13- 27 hr
• lab improvement 4-6 hr
• Less protein bound 2-3
hours of dialysis decreases
activity 60%
• Activated charcoal if taken
within 2 hours of
presentation.
• For life threatening bleeding
consider:
– FFP (mouse model of ICH)
– Recombinant factor VIIa
(laboratory data)
– Charcoal filtration (lab data)
– 4 factor prothrombin complex
concentrate (human
volunteer study and rat
model) but has associated
thrombosis (not available in
US. Current products are 3
factor complex concentrates)
• Real risk of thrombosis with
reversal agents having
unknown benefit.
Bleeding on Rivaroxaban
• Holding medication is 1st
line therapy
– T ½ is 8.3-9.5 hours
• HD and charcoal hemoperfusion not an option
due to protein binding
• No studies supporting
charcoal PO
• For life threatening
bleeding consider :
– Prothrombin complex
concentrate (PCC)
– 3 factor PCC only
available no clear
evidence for its use as 4
factor PCC is the studied
– All evidence for this is
based on lab studies in
healthy volunteers
• Real risk of thrombosis
Current UNM protocols
Current UNM Protocols
PREOPERATIVE/POSTOPERATIVE
MANAGEMENT OF PATIENTS ON THESE
MEDICATIONS AND LAB MONITORING
Available summary articles on
Laboratory Monitoring
• Van Ryn et Al Dabigatran etexilate- a novel
reversible oral direct thrombin inhibitor:
interpretation of coagulation assays and
reversal of anticoagulant activity.
• Douxfils, J et Al Assessment of the impact of
rivaroxaban on coagulation assays: Laboratory
recommendations for the monitoring of
rivaroxaban and review of the literature
Qualitiative testing for Dabigatran Levels
ECT Not widely available
PT/INR: Poor dose-response ratio
TT: Multiple readings not
able to be read at all
aPTT
More quantitative Lab testing for
Dabigatran
Dilutional Assay
Currently Available Data For labs to
monitor Rivaroxaban
Useful for
monitoring
Reliable but requires
Not recommended
laboratory experience
dPT
TGA
(Peak IC
50)
aPTT
PiCT
ACT
TT
ECT
8
56 to
362
3 to 14
208 420
185
334
No
Influence
Slightly
Influenced
29 –
545
13 –
224
141 –
1090
N.D
164 –
1090
N.D
N.D
N.D
N.D
0.5 to
1.3
1.3
0.9
1.1 -1.9
1.0
0.9 4.4
0.4 to
5.6
17
N.D
N.D
Dependence
of reagent
Yes
No
No
Yes
Yes
Yes
No
Yes
No
No
Linearity of
response
Yes
Yes
Yes
Yes
Yes
No
No
No
Not
Influenced
Yes
PT
Biophen
DiXaI
LAX
Sensitivity
(ng/mL)†
66 to
258
9
Dynamic
range of
quantitation
(ng/mL) ‡
80 –
1090
Reproducibili
ty (%) ††
Laboratory Evaluation of Patients on
Dabigatran and Rivaroxaban
Dabigatran
• Usual Coagulation studies
not as useful including aPTT
• Preferred study is TT
(thrombin time) with
dilution/calibration
Rivaroxaban
• Usual coagulation stuides
not as useful but PT may
have some utility in
determining if
anticoagulation is ongoing.
Suggestions for timing of surgery in
patients on Dabigatran
Renal Function (calculated
Cr clerance)
Ok for surgery if standard
risk of bleeding
Ok for surgery if surgery
has high risk for bleeding
complications
>80
24 hr (last dose 2 days
prior)
2-4 days (last dose 3-5 days
prior)
50-80
24 hr (last dose 2 days
prior)
2-4 days (last dose 3-5 days
prior)
30-50
2 Days (last dose 3 days
prior)
4 days (last dose 5 days
prior)
<30
2-5 days (last dose 3-5 days >5 days
prior)
• High risk surgery: cardiac surgery, neurosurgery abdominal
surgery or those involving a major organ
• In these patients: Use normal TT (Thrombin Time) as an
indication that dabigatran has been cleared.
• Restart time: 24-72 hrs and when no longer bleeding
Suggestions for timing of surgery for
patients on Rivaroxaban
Renal Funtion
T½
Any procedure requiring
interruption of
anticoagulation
Pre-op Cr Clearance >50
5-9 hrs
Stop 1 day before ( last
dose 2 dose before
procedure)
Pre-op Cr Clearance 3050
11-13 hrs
Stop at least 2 days
before procedure (last
dose days before)
Post op
n/a
Restart 24-72 post
procedure if hemostasis
achieved
Mounting evidence for use of NOACs
ACCESS TO NOACS
Current Pharmacy Recommendations for who
may get these medications as inpatient
• Rivaroxaban
– For DVT prophylaxis in THR and TKR in patients
who are suitable
– Patients on Rivaroxaban for non-valvular afib as
outpatients who remain suitable for treatment
inpatient
• Dabigatran
– Patients on Dabigatran for non-valvular afib as an
outpatient who remain suitable as an inpatient
Outpatient recommendations
• Can consider either Rivaroxaban/Dabigatran if any of
the following apply:
– Poor INR control on Warfarin despite good complaince
– Significant barriers to monitoring due to transport or
physical problems
– Verified Warfarin Allergy
– Non-hemorrohagic adverse events of Warfarin
– Stroke on Warfarin
• Must be clearly documented why NOAC is needed in
the Chart
• Must be approved by Molina Medical Director (SCI) or
Director of Clinical Pharmacy (UNM care)
The Question of Cost
• Rivaroxaban (based on 30
day supply) inpatient
• ~$6.59 per dose
– Based on recommended
course for hip replacement
=$230 and $79 for a knee
replacement
– Cost less to outpatient
pharmacy ($~160/30 tabs)
– Out of pocket cost for 30 tab
(Wallgreens):
• 10 mg 294.99
• 15 mg 301.99
• 20mg 301.99
• Some Availability for patient
assistance programs
• Dabigatran cost to
pharmacy
– $5.76 per dose as an
inpatient
– $4.80 per dose as an
outpatient
– Out of pocket cost
(Wallgreens):
• 75 mg $138.99
• 150 mg 142.49
• Some availability for patient
assistance programs
• Enoxaparin for bridging
costs $163.50 per day out of
pocket at Wallgreens.
USES AND DVT/PE TREATMENT
Multiple Studies on Efficacy and Safety
Drug
DVT
prophylaxis
VTE treatment
Stroke
prevention in
Afib
ACS
Dabigatran
BISTRO
REMODEL
RENOVATE
REMOBILIZE
RECOVER
REMEDY
RESONAT
RELY
RE-DEEM
Rivaroxaban
RECORD 1
RECORD 2
RECORD 3
RECORD 4
EINSTEIN PE
EINSTEIN DVT
EINSTEIN EXT
ROCKET AF
ATLAS
Apixaban
ADVANCE 1
ADVANCE 2
ADVANCE 3
Rivaroxaban Approved for DVT and PE
Reason to consider using NOACs for
DVT treatment or AFIB
Patel et. Al Rivaroxaban versus warfarin in Non-Valvular Afib NEJM 9/8/2011
(ROCKET-AF)
Similar data exists for Dabigatran
Einstein Study for Acute DVT
• The Einstein Investigators. Oral Rivaroxaban
for symptomatic venous thrombo-embolism.
NEJM 12/23/2010
• Open Label, randomized, event driven, noninferiority study
• Primary efficacy outcome = recurrent VTE.
• Primary Safety Outcome- major
bleeding/clinically relevant non-major
bleeding.
Rivaroxaban for DVT
The Einstein Investigators. Oral Rivaroxaban for symptomatic venous
thromboembolism. NEJM 12/23/2010.
Population Characteristics
Characteristics of treatment
Efficacy Data
Safety Data from EINSTEIN
Conclusions
• Treatment for bleeding on NOACs is mostly supportive.
–
–
–
–
Short T½ relative to warfarin
Minimal evidence for reversal agents
Can consider HD for dabigatran.
Power plan is available in power chart
• Best easily available lab test for rivaroxaban activity is PT
and/or aPTT
• Best easily available lab test for Dabigatran is aPTT or TT
• These agents can be used in house for DVT prophlyaxis in
LE joint repairs
• May want to consider use of NOACs for DVT/PE treatment
in selected patients based on decreased incidence of the
most morbid types of bleeding.
Questions
Acknowledgments
• Thanks to Peggy Beeley
• Thanks to Allison Burnett
References
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Guidance on the emergent revesal of oral thrombin and factor Xa inhibitors. Katz et. al THNSA meeting
proceedings American Journal of Hematology 7 March 2012.
Emergency Management of bleeding Associated with old and New Oral Anticoagulants. Peacock et. Al
Clinical Cardiology May 9 2012.
Eckert, Evan. Xalreto. UNM Pharmacy and Theraputics
Van Ryn et Al Dabigatran etexilate- a novel reversible oral direct thrombin inhibitor: interpretation of
coagulation assays and reversal of anticoagulant activity. Thrombosis and Haemostasis 103.6.2012
Douxfils, J et Al Assessment of the impact of rivaroxaban on coagulation assays: Laboratory
recommendations for the monitoring of rivaroxaban and review of the literature
The Einstein Investigators. Oral Rivaroxaban for symptomatic venous thromboembolism. NEJM
12/23/2010.
Patel et. Al Rivaroxaban versus warfarin in Non-Valvular Afib NEJM 9/8/2011
Minichiello, T. The new anticoagulants and other updates.
Burnet, A. New Oral Anticoagulants: Have we found the Holy Grail? Powerpoint presentation