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1 A New Era of Blood Thinners: Target Specific Oral Anticoagulants No Relevant Financial Disclosures Kiran Lassi, MD Agenda Case Scenarios Types of new anticoagulants Mechanism Of Action FDA approval status of TSOAC Patient Selection Absorption, Dosing schedule Practical considerations Mild/moderate, Major Bleeding Measurement of anticoagulant effect Interruption for Procedures: Preoperative/Postoperative guidelines Should the lack of antidote be a major concern? New Antidotes in development Case scenarios Case 1 Mr Smith has a history of Acute Unprovoked VTE and needs to be on lifelong anticoagulation. His INR is erratic and he has been on warfarin for 4 months now. He is tired of dealing with his INR s being all over the map and inquires about Rivaroxaban. He also weighs 300 lbs. He is not on any other medications and his Cr is normal. He is a very complaint patient. What would you suggest? 1

2 Case 2 A 32 year old is on Warfarin due to HIT causing a DVT. Her INR is always therapeutic on warfarin and she comes in for an INR check once a month. She has one more month of anticoagulation to go. She inquires about the new anticoagulants as Warfarin is causing mild hair loss and she wants to switch to Pradaxa. What would you recommend? Case 3 72 year old with non Valvular Atrial Fibrillation on Dabigatran and a Cr Cl 50 presents with hematochezia and a Hgb of 5.0. He is hypotensive. PTT/PT are both elevated. His last Dabigatran dose was 8 hours ago? His platelet count is also noted to be at 30,000. You order other work up and note that his fibrinogen is 120, d dimer is How would you manage this patient? Case 4 78-year-old female presents to the emergency department with a traumatic hip fracture. Her past medical history significant for atrial fibrillation for which she receives Rivaroxaban 20 mg daily. Her last dose was taken 12 hours ago. Routine blood work conducted in the emergency department shows PT, INR and activated PTT within normal range and estimated GFR of 50 cc per minute (normal greater than 60). You are asked by the surgical team to confirm that it is safe for her to proceed with surgery at this time using neuraxial anesthesia. What would you recommend? Case 5 A 70-year-old male with a history of atrial fibrillation whose been anti coagulated with the Dabigatran presents to the emergency room with melena. He reports taking his most recent dose of dabigatran within 2 hours ago. On examination he is hypotensive and tachycardic. He continues to have melanotic stools. Laboratory testing reveals a calculated creatinine of 15 cc per minute, PT of 16.5 reference range , INR of 1.2, PTT of 50 seconds (reference range seconds). You are asked by the emergency medicine physician whether hemodialysis should be considered to decrease the patient s plasma Dabigatran level? 2

3 Types of New Anticoagulants Mechanism of Action Dabigatran (Pradaxa) Rivoraxaban (Xarelto) Apixaban (Eliquis) Edoxaban (Savaysa) FDA Approval Status of Non-vitamin K Oral Anticoagulants in the United States Selection of Patients for the New Anticoagulants For Warfarin -Renal Failure -Mechanical Heart Valve -Antiphospholipid Antibody Syndrome -Heparin Induced thrombocytopenia -GI Bleeding (hx. of GI diseases) -Elderly Patients >75 -Poor Compliance -Drug Cost -Body Weight Extremes 3

4 For TSOAC Selection of Patients for the New Anticoagulants Unexplained poor Warfarin control Poor level of control because of significant drug-drug interactions, food interactions Fluctuating INRs/Chromogenic Xa New patients on anticoagulation for Atrial Fibrillation Absorption and Metabolism of TSOAC Dabigatran Apixaban Edoxaban Rivaroxaban Bioavailability 3-7% 50% 62% 66% (w/o food) 100% with food Elimination 80% Renal 25% renal 35% renal 33% renal 67% liver Liver metabolism (CYP3A4) Intake with food No (P glcoprotein drug interaction) Yes (minor CYP3A4) minimal No No No official recommendation yet yes Mandatory Absorption and Metabolism of TSOAC Dabigatran: special note Absorption with H2B/PPI Dabigatran Apixaban Edoxaban Rivaroxaban Plasma level 12-30% No effect no effect No Effect GI tolerability Dyspepsia 5- No effect No effect No Effect 10% Elimination T1/ h 12h 9-11h 9-13h formulated as a hypromellose capsule shell containing pellets. pellets are composed of a tartaric acid starter core, encased with a seal coating - Opening the capsule and ingesting the pellets increases the exposure of dabigatran by 75% compared with the intact capsule - Do not crush or open capsule before adminstration - Can t use with feeding tubes 4

5 Dosing Schedule Practical Considerations Individual Factors that can Modify Bleeding Risk Advanced age Renal insufficiency Dual Agent Therapy APPRAISE-II ATLAS ACS-2 TIMI-51 Possible Measures to take in case of bleeding Non Life threatening bleeding Life threatening bleeding 5

6 Non-Life Threatening Bleeding Hemodynamically stable Serial Hemoglobins stable Minor bleeds Mild anemia without evidence of major bleed In absence of bleeding, wait & see approach Life threatening bleeding Acute Recent ingestion of Overdose, activated charcoal to reduce absorption dabigatran within 2 hours rivaroxaban: within eight hours apixaban: within six hours edoxaban: within two hours Consider Plasma Removal: Dabigatran only, Hemodialysis Laboratory monitoring of TSOAC Preferred Method In an Emergency Dabigatran Ecarin Clotting time Dilute Thrombin Time APTT (preferably with specific calibrated Reagents) Rivaroxaban Anti-Xa PT (preferably with specific calibrated Reagents) Apixaban Anti-Xa Dilute PT Edoxaban Anti-Xa Few Firm Data 6

7 Bleeding Risk with TSOAC: Bottom Line Direct comparison difficult as all compared to Warfarin Overall major bleeding risk slightly lower, but may carry slightly higher rate of GI bleeding with Dabigatran In a patient with serious life threatening bleeding, and a CrCl <30, Hemodialysis is suggested if emergent hemodialysis is available and if appropriate vascular access can be obtained Periprocedural Management Interruptions for Procedures Temporary Interruptions of TSOAC Estimate thromboembolic risk Estimate bleeding risk Determine the time of anticoagulant interruption Determine whether to use bridging anticoagulation Data from large clinical trials suggest that short term interruption of TSOACs can be done safely in most cases without a parental anticoagulant bridge 7

8 Interruptions for Procedures Dependent upon Anticoagulant s half-life 2-3 half-lives for surgical procedures with standard/low risk for bleeding 4-5 half-lives for high risk bleeding procedures Interventions Not Necessarily Requiring Discontinuation of Anticoagulant Perform procedures at trough levels of NOAC. Consider scheduling intervention h after last intake and then restart 6 h later (i.e. skipping 1 dose with BID NOAC) Dental interventions Extraction of 1 to 3 teeth Periodontal surgery Incision of abscess Implant positioning Interventions Not Necessarily Requiring Discontinuation of Anticoagulant Ophthalmology Cataract or glaucoma intervention Endoscopy without surgery Superficial surgery (e.g. abscess incision, small dermatological excision) Classification of surgical interventions according to bleeding risk Low Risk Endoscopy with Biopsy Prostate and Bladder biopsy EP study Angiography Pacemaker or ICD placement (unless complex anatomical setting ex. congential heart disease) High Risk VT Ablation, Complex L sided ablation, Pulm vein isolation Spinal or Epidural anesthesia; lumbar diagnostic puncture Thoracic surgery Abdominal Surgery Major orthopedic surgery Liver biopsy Transuretheral Prostate Resection Kidney biopsy 8

9 Preoperative Interruption of New Anticoagulant Drug CrCl Low Risk of Bleeding (2 to 3 half lives between last dose and surgery) Dabigatran T ½ h >50 2 days before surgery (skip 2 doses) T ½ h days before surgery (skip 4 doses) Rivaroxaban T ½ 5-9 hours >50 2 days before surgery(skip 1 dose) T ½ 9-10 hours days before surgery(skip 1 dose) High risk of Bleeding (4 to 5 half lives between last dose and surgery) 3 days before surgery (skip 4 doses) 4-5 days before surgery (skip 6-8 doses) 3 days before surgery (skip 2 doses) 3 days before surgery (skip 2 doses) Drug CrCl Low Risk of Bleeding (2 to 3 half lives between last dose and surgery) Edoxaban T ½ 5-11 hours days before surgery (skip 2 doses) Apixaban T ½ 8-15 hours >50 2 days before surgery (skip 2 doses) T ½ 18 hours days before surgery (skip 3 doses High risk of Bleeding (4 to 5 half lives between last dose and surgery) 3 days before surgery (skip 4 doses) 3 days before surgery (skip 4 doses) 4 days before surgery (skip 6 doses) Postoperative Resumption of New Anticoagulants Anticoagulant Low Bleeding Risk High Bleeding Risk Dabigatran Resume 24 hour post Resume 2 to 3 days after operative surgery Rivaroxaban Apixaban Resume 24 hours post operative Resume 24 hours post operative Resume 2 to 3 days after surgery Resume 2 to 3 days after surgery Edoxaban No published guidelines No published guidelines Patients Undergoing Urgent Surgical Intervention Discontinue NOAC Try to defer surgery at least 12 h; ideally 24 h after last dose Urgent surgery associated with much higher rates of bleeding than elective procedures Coagulation tests can be considered (classical test or specific tests); strategy based on these results has never been evaluated. Thus, such strategy cannot be recommended and should not be used routinely 9

10 Impact of Bleeding Complications in Patients Receiving Target- Specific Oral Anticoagulants: A Systematic Review and Meta- Analysis Data from 12 phase III randomized, controlled trials involving more than 100,000 patients, the authors compared the direct oral anticoagulants (DOACs) apixaban, dabigatran, edoxaban, and rivaroxaban with more traditional anticoagulation strategies such as warfarin message from these pooled data is that the ability to reverse warfarin did not translate into fewer bleeding-related deaths Lack of Antidote: A Major Concern? For many patients with TSOAC associated bleeding, an antidote would not be used even if available TSOAC treated patients had fewer bleeds than did warfarin treatment patients Evidence that the rapid reversal of VKA effect will affect patient important outcomes is weak Chatree et al. October Blood 124 (15) New antidotes in development for TSOAC Andexanet (PRT06645) recombinant modified Xa Idarucizumab (BI655075) Monoclonal Ab against dabigatran Aripzaine (PER977) (D arginine compound) broad activity against new anticoagulants More Studies Needed In Morbidly obese Cancer patients Very low body weight Pregnant women Nursing mothers Serious thrombophilic defects Those requiring concomitant antiplatelet therapy 10

11 Case 1 Mr Smith has a history of Acute Unprovoked VTE and needs to be on lifelong anticoagulation. His INR is erratic and he has been on warfarin for 4 months now. He is tired of dealing with his INR s being all over the map and inquires about Rivaroxaban. He also weighs 300 lbs. He is not on any other medications and his Cr is normal. He is a very complaint patient. He is not on any other medications. He wants to be on Rivaroxaban after watching the commercial. What would you suggest? Case 1 1. Start 20 mg daily of Rivaroxaban 2. Tell him there is no good data with respect to obese (>100 kg) patients so he cannot switch 3. Make him aware of the data and start him on 20 mg of Rivaroxaban with evening meal 4. Tell him to loose weight and come back a few months later to readdress this issue Case 2 A 32 year old is on Warfarin due to HIT causing a DVT. Her INR is always therapeutic on warfarin and she comes in for an INR check once a month. She has a total of 3 months of anticoagulation and she has one month left. She inquires about the new anticoagulants as Warfarin is causing mild hair loss and she wants to switch to Pradaxa. What would you recommend? Case 2 1. Continue warfarin and complete the course 2. Switch her to Pradaxa 3. Do both warfarin and Pradaxa 4. Tell her there is no Data in HIT patients with Pradaxa and switch her after educating 11

12 Case 3 72 year old with non Valvular Atrial Fibrillation on Dabigatran and a Cr Cl 50 presents with hematochezia and a Hgb of 5.0. He is hypotensive. PTT/PT are both elevated. His last Dabigatran dose was 8 hours ago? His platelet count is also noted to be at 30,000. You order other work up and note that his fibrinogen is 120, d dimer is How would you manage this patient? Case 3 1. Give him activated charcoal, IV in for hemodialysis and blood transfusion 2. Consult GI and let them take care of things 3. Give fluids, Blood, platelets, Consider giving cyroprecipitate, GI consult stat, monitor serial H/H 4. Consult Hematology and go back to bed. This looks like a blood issue! Case 4 78-year-old female presents to the emergency department with a traumatic hip fracture. Her past medical history significant for atrial fibrillation for which she receives Rivaroxaban 20 mg daily. Her last dose was taken 12 hours ago. Routine blood work conducted in the emergency department shows PT, INR and activated PTT within normal range and estimated GFR of 50 cc per minute (normal greater than 60). You are asked by the surgical team to confirm that it is safe for her to proceed with surgery at this time using neuraxial anesthesia. What would you recommend? Case 4 1. Tell them go ahead and proceed, you have my blessing! 2. Recommend against the use of neuraxial anesthesia 12 hours after a dose of rivaroxaban because significant amounts of drug are likely present given the predicted half live, patient s age and insensitivity of INR/PT assay 3. Recommend to hold for a couple of more hours and then proceed 4. Offer to do it yourself 5. Consult hematology 12

13 Case 5 A 70-year-old male with a history of atrial fibrillation whose been anticoagulated with the Dabigatran presents to the emergency room with melena. He reports taking his most recent dose of dabigatran within 2 hours ago. On examination he is hypotensive and tachycardic. He continues to have melanotic stools. Laboratory testing reveals a calculated creatinine of 15 cc per minute, PT of 16.5 reference range ( ), INR of 1.2, PTT of 50 seconds (reference range seconds). You are asked by the emergency medicine physician whether hemodialysis should be considered to decrease the patient s plasma Dabigatran level? Case 5 1. No 2. Yes 3. May be Suggestions for Choice of Anticoagulants in New Acute VTE Conversion between anticoagulants Current Anticoagulant Anticoagulant being converted to Procedure Warfarin Dabigatran or Apixaban Discontinue warfarin and start Dabigatran or Apixaban when INR <2.0 Warfarin Rivaroxaban Discontinue warfarin and start Rivaroxaban when INR <3.0 LMWH or Heparin Dabigatran Start Dabigatran 0-2 hours before administration of last LMWH or at the same time as discontinuation of IV infusional heparin LMWH or Heparin Rivaroxaban or Apixaban Discontinue LMWH or Heparin and initiate TSOAC 0-2 hours prior to next scheduled dose of heparin or LMWH 13

14 Conversion between anticoagulants Current Anticoagulant Anticoagulant being converted to Procedure Dabigatran LMWH or Heparin CrCl>30 Start 12 hours after the last dose of dabigatran CrCl<30 Start 24 hours afte rthe last dose of Dabigatran Rivaroxaban Warfarin Initiate warfarin and parental anticoagulation 24 hours after discontinuation of Rivaroxaban Aprixaban or Rivaroxaban LMWH or Heparin Initiate LMWH or Heparin 24 hours after discontinuation of Apixaban or Rivaroxaban Apixaban warfarin Discontinue Apixaban and start Warfarin 24 hours later. If overlap needed consider alternate anticoagulation Thank you 14