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