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 distribution- dialyzable
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 non- dialyzable
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 hemo-perfusion 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
PT/INR: Poor dose-response ratio
TT: Multiple readings not able to be read at all
ECT Not widely available
aPTT
More quantitative Lab testing for Dabigatran
Dilutional Assay
Currently Available Data For labs to monitor Rivaroxaban
Useful for monitoring
Reliable but requires laboratory experience Not recommended
PT Biophen DiXaI LAX dPT
TGA(Peak IC 50)
aPTT PiCT ACT TT ECT
Sensitivity (ng/mL)†
66 to 258 9 8 56 to
362 3 to 14 208 -420 185 334 No
InfluenceSlightly Influenced
Dynamic range of quantitation (ng/mL) ‡
80 – 1090
29 – 545
13 – 224
141 – 1090 N.D 164 –
1090 N.D N.D N.D N.D
Reproducibility (%) ††
0.5 to 1.3 1.3 0.9 1.1 -1.9 1.0 0.9 -
4.40.4 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
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 prior)
>5 days
• 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 T ½ 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 30-50
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
ACCESS TO NOACS
Mounting evidence for use of 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 SafetyDrug DVT
prophylaxisVTE treatment Stroke
prevention in Afib
ACS
Dabigatran BISTROREMODELRENOVATEREMOBILIZE
RECOVERREMEDYRESONAT
RELY RE-DEEM
Rivaroxaban RECORD 1RECORD 2RECORD 3RECORD 4
EINSTEIN PEEINSTEIN DVTEINSTEIN EXT
ROCKET AF ATLAS
Apixaban ADVANCE 1ADVANCE 2ADVANCE 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, non- inferiority 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• 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
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