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 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 hrs (younger patients) or 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 DabigatranRivaroxaban Peak Action1-3 hr Protein Binding35%92-95% Elimination t ½ with cr clearnance > hr8.3 hr Elimination t ½ with cr clearnance> hr8.7 hr Elimination t ½ with cr clearance > hr9.0 hr Elimination t ½ with cr clearance < hr9.5 hr Renal Clearance80%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 1 st choice – T ½ varies depends on renal function 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 1 st line therapy – T ½ is 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 LAXdPT TGA (Peak IC 50) aPTTPiCTACTTTECT Sensitivity (ng/mL) † † 66 to to to No Influence Slightly Influenced Dynamic range of quantitation (ng/mL) ‡ ‡ 80 – – – – 1090 N.D 164 – 1090 N.D Reproducibili ty (%) †† †† 0.5 to to N.D Dependence of reagent YesNo Yes NoYesNo Linearity of response Yes 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 >8024 hr (last dose 2 days prior) 2-4 days (last dose 3-5 days prior) hr (last dose 2 days prior) 2-4 days (last dose 3-5 days prior) Days (last dose 3 days prior) 4 days (last dose 5 days prior) <302-5 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: hrs and when no longer bleeding

Suggestions for timing of surgery for patients on Rivaroxaban Renal FuntionT ½Any procedure requiring interruption of anticoagulation Pre-op Cr Clearance >505-9 hrsStop 1 day before ( last dose 2 dose before procedure) Pre-op Cr Clearance hrsStop at least 2 days before procedure (last dose days before) Post opn/aRestart 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 mg mg 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 $ mg Some availability for patient assistance programs Enoxaparin for bridging costs $ per day out of pocket at Wallgreens.

USES AND DVT/PE TREATMENT

Multiple Studies on Efficacy and Safety DrugDVT prophylaxis VTE treatmentStroke prevention in Afib ACS DabigatranBISTRO REMODEL RENOVATE REMOBILIZE RECOVER REMEDY RESONAT RELYRE-DEEM RivaroxabanRECORD 1 RECORD 2 RECORD 3 RECORD 4 EINSTEIN PE EINSTEIN DVT EINSTEIN EXT ROCKET AFATLAS ApixabanADVANCE 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, 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 Emergency Management of bleeding Associated with old and New Oral Anticoagulants. Peacock et. Al Clinical Cardiology May 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 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