New Oral Anticoagulants When should they replace our ...

New Oral Anticoagulants When should they replace our ...

Common Pathway New Oral Agents Apixaban Rivaroxaban Xa Blocker Xa Dabigatran Prothrombin Thrombin Clot Fibrinogen Fibrin

Replacing Traditional Anticoagulants Treatment VTE UFH, LMWH Bridge to Warfarin RE-COVER Study Dabigatran 150 mg, BID for 6 months Double Blind, Double Dummy, Non-Inferiority Schulman S, et al NEJM 2009;361:2342-2352 RE-COVER Study VTE Major Bld Dabigatran 150 mg, BID 2.4%

1.6% Warfarin INR 2-3 2.1% 1.9% VTE Parenteral Anticoagulant Median 9 days 6 months Warfarin TTR= 60% Schulman S, et al NEJM 2009;361:2342-2352 RE-COVER Study

Index Events Dabi 1273 Warfarin 1266 Schulman S, et al NEJM 2009;361:2342-2352 RE-COVER Study Major Bleeding Dabi Warfarin Schulman S, et al NEJM 2009;361:2342-2352 RE-COVER A limitation of the study is that the first

dose of dabigatran, was given only after initial parenteral anticoagulation therapy had been administered for median of 9 days There is no data to support the use of dabigatran monotherapy for acute venous thromboembolism Schulman S, et al NEJM 2009;361:2342-2352 Rivaroxaban 15 mg, PO, BID x 3 weeks then 20mg, Qday Enoxaparin 1mg/kg/Q12hrs bridge to Warfarin INR 2-3 Open Label, Non-Inferiority trial Einstein Investigators NEJM 2010;363:2499-2510 Einstein DVT Rivaroxaban 15 mg, BID x 3 wks 20 mg, Qday DVT

Proximal DVT VTE Major Bld 2.1% 8.1% 3.0% 8.1% Enoxaparin Warfarin INR 2-3 3, 6, 12 months

Warfarin TTR = 57.7% Einstein Investigators NEJM 2010;363:2499-2510 Einstein Acute DVT Study Causes of VTE Riva Standard Einstein Investigators NEJM 2010;363:2499-2510 Einstein Acute DVT Study Safety Outcomes Riva Standard Einstein Investigators NEJM 2010;363:2499-2510

Rivaroxaban 15 mg, PO, BID x 3 weeks then 20mg, Qday Enoxaparin 1mg/kg/Q12hrs bridge to Warfarin INR 2-3 Open Label, Non-Inferiority Einstein Investigators NEJM 2012;366:1287-1297 Einstein PE Rivaroxaban 15 mg, BID x 3 wks 20 mg, Qday PE Enoxaparin Warfarin INR 2-3 VTE Major Bld 2.1%

1.1% Non-Inferior 1.8% 2.2% 3, 6, 12 months Warfarin TTR = 62.7% Einstein-PE Investigators NEJM 2012;366:1287-1297 Einstein PE Causes Riva Standard

Einstein Investigators NEJM 2012;366:1287-1297 Einstein PE Anatomical Extent Riva Standard Einstein Investigators NEJM 2012;366:1287-1297 ED - OBS History & Physical Laboratory Testing Diagnosis DVT Select Treatment Hospital Admission

Secure Rx OBS Discharge Plan Communication Follow Up Acquire Med Contact PCP Phone call 24 hrs Pt Education D/C Summary Appointment 3-5 days

Discharge OBS Your patient who has been on long term warfarin would like to convert to one of the new oral anticoagulant. Rivaroxaban 15 mg, PO, BID x 3 weeks then 20mg, Qday Enoxaparin 1mg/kg/Q12hrs bridge to Warfarin INR 2-3 Open Label, Non-Inferiority trial Einstein Investigators NEJM 2010;363:2499-2510 Einstein DVT-Extend Rivaroxaban 20 mg, Qday DVT VTE

Major Bld 1.3% 0.7% All Rxed Placebo 7.1% 3, 6, 12 mo 0% 6-12 mo Einstein Investigators NEJM 2010;363:2499-2510 Double Blind, Randomized Trial Schulman S, et al NEJM 2013;368:709-718

RE-MEDY Dabigatran 150 mg, BID VTE Major Bld 1.8% 0.9% 1.3% 1.8% VTE Warfarin INR 2-3 Patient Rx

3 to 12 months 6 months Schulman S, et al NEJM 2013;368:709-718 RE-SONATE Dabigatran 150 mg, BID VTE Major Bld 0.4% 0.3% DVT Placebo

Patient Rx 6 to 18 months 5.6% 0% 6-18 months Schulman S, et al NEJM 2013;368:709-718 RE-SONATE Study Schulman S, et al NEJM 2013;368:709-718 Agnelli G, et al NEJM 2012;1-10 AMPLIFY-EXT VTE

VTE Rx 6-12 mo Major Bld Apixaban 2.5 mg, BID 1.7% 0.2% Apixaban 5.0 mg, BID 1.7% 0.1% Placebo

8.8% 0.5% 12 months Agnelli G, et al NEJM 2013;368(8):699-708 AMPLIFY-EXT Apixaban 2.5 Apixaban 5 Placebo Agnelli G, et al NEJM 2013;368(8):699-708 Warfarin to NOAC Agent

Recommendation Rivaroxaban Start when INR < 3.0 (we recommend < 2.0) Apixaban Start when INR < 2.0 Dabigatran Start when INR < 2.0 NOAC= New Oral Anticoagulants Non-Valvular Atrial Fibrillation Atrial Fibrillation Studies

Trial RE-LY ARISTOTLE ROCKET-AF Design Randomized Open Label N=18,113 Randomized Double blind N=18,209 Randomized double blind &

dummy N=14,000 Treatment Dabigatran 150 mg, BID 110 mg, BID Apixaban 5 mg, BID Rivaroxaban 20 mg, Qday Comparator Warfarin 2-3 (67% TTR)

Warfarin 2-3 (66% TTR) Warfarin 2-3 (57.8% TTR) Mean CHADS2 2.1 2.1 3.5 Time Therapeutic Range = TTR Modified Ahrens I, et al Thromb Haemost 2011;105 Primary Endpoints Atrial Fibrillation Trials Study

NOAC VKA Outcome RE-LY Dabigatran 1.1% Warfarin 1.7% RR 0.66 95% CI 0.53-0.82 P < 0.001 superiority

ARISTOTLE Apixaban 1.3% Warfarin 1.6% HR 0.79 95% CI 0.66-0.95 P= < 0.001 Non- I P= 0.01 Superiority ROCKET-AF Rivaroxaban 1.7% Warfarin

2.2% HR 0.79 95% CI 0.66-0.96 P = <0.001 Non-Inferiority Major Bleeding Atrial Fibrillation Trials Study NOAC VKA Outcome RE-LY Dabigatran

3.3% Warfarin 3.6% RR 0.93 95% CI 0.81-1.07 P = 0.31 ARISTOTLE Apixaban 2.1% Warfarin 3.1% HR 0.69 95% CI 0.60-0.8 P = < 0.001

ROCKET-AF Rivaroxaban 5.6% Warfarin 5.4% HR 1.04 95% CI 0.90-1.20 P = 0.58 Intracranial Hemorrhage Atrial Fibrillation Trials Study NOAC VKA

Outcome RE-LY Dabigatran 0.3% Warfarin 0.7% RR 0.40 95% CI 0.27-0.60 P= <0.001 ARISTOTLE Apixaban 0.3%

Warfarin 0.8% HR 0.42 95% CI 0.30-0.58 P = <0.001 ROCKET-AF Rivaroxaban 0.5% Warfarin 0.7% HR 0.67 95% CI 0.47-0.93 P = 0.02 Dosing Schedules

Atrial Fibrillation Agent Dosing Recommendations Dabigatran 75mg, 150mg CrCl > 30 cc/min: 150 mg, BID CrCl 15 to 30 cc/min: 75 mg, BID Avoid < 15 cc/min Apixaban 2.5mg, 5mg CrCl > 15 cc/min: 5 mg, BID Any 2 ( > 80 yrs, < 60 kg, SCr > 1.5mg/dL: 2.5 mg, BID) Avoid < 15 cc/min

Rivaroxaban CrCl > 50 cc/min: 20 mg, Qday 10mg, 15mg, 20mg CrCl 15-50 cc/min: 15 mg, Qday Avoid CrCl < 15 cc/min Atrial Fibrillation Studies When should new orals be started? RE-LY (Dabigatran) Stroke within 14 days Severe stroke within last 6 months ARISTOTLE (Apixaban) Stroke within 7 days ROCKET-AF (Rivaroxaban) Stroke within 14 days Severe stroke within last 3 months Modified-Ahrens I, et al Thromb Haemost 2011;105 Medically ill Patient

EXCLAIM Extended VTE Px Medically-ill Endpoint Enoxaparin Placebo RRR VTE 28 +/- 4 d 2.5% 4.0% -1.53 95% CI -2.54 to -0.52 Major Bleed 0.8%

0.3% 0.51 95% CI 0.12 to 0.89 Hull R, et al, Ann Intern Med 2010;153:8-18 ADOPT Apixaban 2.5 mg BID Enoxaparin 40mg, Qday Goldhaber S, et al NEJM 2011;365(23):2167-2177 ADOPT Study Endpoint Apixaban 2.5 mg BID

Control RRR VTE during parenteral Rx 1.73% 1.61% Enox 1.06 95% CI 0.69-1.63 Non-Inferior P=NS VTE at 30 days 2.71%

3.06% Placebo 0.87 95% CI 0.62-1.23 Superior P=NS Major Bleed 35 days 0.47% 0.19% 2.58 P=0.04 CR Bleeding 35 days

2.67% 2.08% 1.28 P=0.12 Goldhaber S, et al, NEJM, 2011; 365: 2167-2177 Cohen A, et al NEJM 2013;368:513-523 MAGELLAN Study Endpoint Rivaroxaban 10 mg, Qday Control

RRR VTE at 10 days 2.7% 2.7% Enox 0.97 95% CI 0.713-1.334 Non-Inferior P=0.0025 VTE at 35 days 4.4% 5.7% placebo

0.77 95% CI 0.618-0.962 Superior P=0.021 Major Bleed 35 days 1.1% 0.4% 2.9 P=0.0004 CR Bleeding 35 days 4.1% 1.7%

2.5 P < 0.0001 Cohen A, et al NEJM 2013;368:513-523 Extended VTE Prophylaxis In Medical Patients Net Clinical Benefit of Factor Xa Inhibitors EXCLAIM Incidence (%) 6 ADOPT MAGELLAN * p < 0.05 * p < 0.05

* 3 * 0 0.3 0.8* 2.1 3 2.7 1.7 (Major Bleeding)

4.1* 6 (n = 5,963) (n = 6,528) (n = 8,101) Hull R, et al, Ann Intern Med 2010;153:8-18 Cohen A, et al NEJM 2013;368:513523 Key Points Black Box Warnings, Stroke, MI Risk, Drug Interactions, Major Bleeding Black Box Warning Rivaroxaban & Apixaban ROCKET AF

Patel M et al, NEJM 2011;365:883-891 Patel M, et al JACC 2013;61:651-658 Rocket AF Study Group Riva Warfarin HR P value Temporary Interruption

6.2 (9) 5.05 (8) 1.28 0.49-3.31 0.62 Permanent Discontinuation 25.6 (42) 23.28 (36) 1.10 0.71-1.72 0.66

After end of study 6.42 (22) 1.73 (6) 3.72 1.51-9.16 0.004 All 11.2 (73) Discontinuation + End of study 7.57 (50) 1.5 1.05-2.15

0.026 Patel M, et al JACC 2013;61:651-658 Interruption or Discontinuation Rivaroxaban Rivaroxaban Events per 100-pt years Warfarin Events per 100-pt years Hazard Ratio (CI) P Value All discontinuations and interruptions prior to the

end of the study 16.49 14.05 1.21 (0.81-1.81) 0.35 Temporary Interruptions 6.20 5.05 1.28 (0.49-3.31) 0.62

Permanent Discontinuations 25.60 23.28 1.10 (0.71-1.72) 0.66 End of Study Transition to Open-Label 6.42 1.73 3.72 (1.51-9.16)

0.0044 All discontinuations and interruptions prior and after study 11.20 7.57 1.50 (1.05-2.15) 0.026 1.Temporary Interruption (Events starting 3 days after interruption until 3 days after resumption) 2.Early Permanent Study Drug Discontinuation (Events evaluated from 3-30 days after d/c) 3.End of Study Transition to Open-Label (Events evaluated from 3-30 days after d/c) Cumulative Proportion with INR > 2

Rocket AF Study Warfarin Rivaroxaban 81% 49% Days after Last Dose at End of Study Patel M, et al JACC 2013;61:651-658 What happened in ROCKET AF ? Warfarin patients continued warfarin Rivaroxaban patients discontinued study drug and then began warfarin Not anticoagulated during warfarin titration No Bridging

Strokes during the 30 days post study Warfarin group 6 Rivaroxaban group - 22 Black Box Warning Rivaroxaban Epidural or Spinal Hematoma Use of epidural catheter Concomitant use of NSAID, Anti-platelet Traumatic or repeated spinal puncture History of spinal deformity Dosing Rivaroxaban Epidural Catheters Surgery 8AM Remove

Epidural > 18 hrs from Last dose Riva 10 AM Leave PACU Epidural Placed Half-Life 7 11 hrs Riva 10 mg 6-8 hrs postop 4 PM 6 PM Noon Next Day

Start Riva 6 hrs after Epidural Removed 7 Clinical Trials Evaluated 2 Stroke Prophylaxis in Atrial Fibrillation 1 Acute Venous Thromboembolism 1 Acute Coronary Syndrome 3 VTE Prophylaxis Joint Replacement Surgery Uchino K, et al Arch Intern Med 2012;172:397-402 Dabigatran compared to control (warfarin, enoxaparin, placebo) 1. Increased absolute risk of MI or ACS 0.27% 2. Increased relative risk of MI or ACS 33% Uchino K, et al Arch Intern Med 2012;172:397-402

Eriksson B, et al Thromb Res 2012;130:396-402 Dabigatran & ACS Events Orthopedic Surgery ACS Events Adjudicated Dabi 150 mg (2665) Dabi 220 mg (2611) Enoxaparin (2639) MI 1

1 5 Unstable Angina 1 0 0 Cardiac Death 0 0 3

Total Definite ACS 2 (0.8) 1 (0.04) 7 (0.27) Conclusion: No ACS signal identified Eriksson B, et al Thromb Res 2012;130:396-402 Major Bleeding Pharmacologic Characteristics Characteristics Dabigatran Rivaroxaban

Apixaban Target IIa Xa Xa Bioavailability 7% 60%-80% 80% Half-Life

12-17 hrs 7-11 hrs 12 hrs Clearance 80% renal 60% renal 33% biliary 25% renal 75% biliary Metabolism Conjugation to active

glucuronides CYP3A4 CYP2J2 CYP3A4 P-GP interaction Yes Yes Yes minimal Galanis T et al Thromb Thrombolysis 2011;31:310-320 Laboratory Testing New Oral Agents Lab Tests

Useful Dabigatran Rivaroxaban Lab Test Strong ECT Chromogenic Anti-Xa TT aPTT, PT Apixaban Chromogenic Anti -Xa aPTT Weak

PT / INR Palladino M et al A J Hem 2012;87 Suppl:S127-S132 Novel Anticoagulant Comparison Dabigatran Rivaroxaban Apixaban Dialyzable Yes Probably Not Probably Not Molecular Weight 628 Daltons

436 Daltons 460 Daltons Protein Binding 35% >90% 87% Catalytic Binding Site Reversible Reversible Reversible Reversing

Agent No Possibly Possibly Erikkson BI, et al. Clin Pharmacokinet 2009;48:1-22. COFACT (Prothrombin Complex Concentrate) 1. Non-activated PCC 2. Factor II, VII, IX, X 3. Protein C, S, ATIII 4. 50 IU PCC/kg dosing Eerenberg E, et al Circulation 2011;124:1573-1579 Prothrombin Time Placebo

PCC Rivaroxaban 20 mg BID PCC or Placebo Eerenberg E, et al Circulation 2011;124:1573-1579 aPTT PCC Placebo Dabigatran 150mg BID PCC or Placebo

Eerenberg E, et al Circulation 2011;124:1573-1579 Thrombin Time Placebo Dabigatran 150mg BID PCC PCC or Placebo Eerenberg E, et al Circulation 2011;124:1573-1579 ECT PCC Placebo Dabigatran

150mg BID PCC or Placebo Eerenberg E, et al Circulation 2011;124:1573-1579 Four Factor vs Three Factor PCC Rivaroxaban Reversal Agent Reduction PT (sec) Beriplex (50 IU/kg) 2.5 sec 3.5 sec Profilnine (50 IU/kg) 0.6 1.0 sec

Rivaroxaban 20mg, BID x 4 days 30 minute following infusion effect noted Levi M, et al Abstract ISTH July 2013 GI Bleed Rivaroxaban PTT PT/INR Abnormal Normal Hemodynamic Status Transfuse PCC 50 IU/kg over 5-10 minutes PCC

Recheck: CBC, PT/INR & PTT Re-Evaluate Impaired Hemodynamic Status Transfuse PCC PRBC Recheck: CBC, PT/INR & PTT Re-Evaluate CNS Bleed Dabigatran Dialysis removes 60% PTT Creatinine

Abnormal Presence of any of following: Neuro Deterioration Renal Dysfunction (CrCl < 50 ml/min) Recent Dabigatran Dose (< 6 hrs prior) Neuro Intact Monitor Neuro Status Neuro Intact Neuro Deterioration Reassess Need

for Anticoagulation Dialysis Recheck PTT Q6hrs x 24 hrs Dialysis as indicated by PTT/TT Neuro Stable Package Insert Recommendations Dabigatran FFP, Prothrombin Complex Concentrate Activated Factor VII Dialysis Rivaroxaban & Apixaban Prothrombin Complex Concentrate Four Factor Concentrate (KCentra) FFP

Recently Viewed Presentations

  • Small Group Instruction - amazingachievement.weebly.com

    Small Group Instruction - amazingachievement.weebly.com

    Small Group Instruction. ... Jump rope rhymes and tongue twisters. Songbooks. Paper, pencils, crayons. ... Children enthusiastically visit this station to read plays and retell stories. It is a "space where oral language related to books can flourish. The more...
  • CSC 2231: Parallel Computer ... - University of Toronto

    CSC 2231: Parallel Computer ... - University of Toronto

    + Programmer does not need to know the physical size of memory nor manage it A small physical memory can appear as a huge one to the programmer Life is easier for the programmer ... 8-bit address. tag. index. byte...
  • Titre du Poster

    Titre du Poster

    Matériel - Méthodes ou observation. Congrès National de Chirurgie 2019. Il s'agit d'un patient de 70ans opéré il y a 4 ans pour un syndrome occlusif et qui présente suite à un accident de la voie publique un traumatisme au...
  • Aim: How can we prepare for the plot and themes that will ...

    Aim: How can we prepare for the plot and themes that will ...

    Aim: How can we prepare for the plot and themes that will arise in the play Hamlet?. Read each of the 4 scenarios and answer the questions for each. GROUPS- You will be put into a group to work on...
  • Your Role - Boston Consortium

    Your Role - Boston Consortium

    Emergency Management Developments at Harvard Since 9/11 Joe Griffin EH&S Director October 30, 2003 Responsibilities and Relationships Anthrax scare strengthened ties among HUPD, EH&S, UHS, Facilities, News Office, University Operations Center, schools and city Established teams at Executive, Operational Mgt....
  • How Do Trees Grow? - | FRST 100

    How Do Trees Grow? - | FRST 100

    How Do Trees and Stands Grow? Blog Question for the Week of September 25: "Labels on UBC waste management trucks read 'powered by natural gas: a renewable resource'. Do you think natural gas is a renewable resource? Cite two references...
  • Decision-Making Processes Lina Hourani Neeraja Ganeshalingam Riley Truswell

    Decision-Making Processes Lina Hourani Neeraja Ganeshalingam Riley Truswell

    Types of Decisions. Organizational decisions can be categorized based on their complexity… Programmed Decisions . Repetitive and well defined, and procedures exist for resolving the problem. Non-Programmed Decisions . Novel, ill structured, and poorly defined, and no procedure exists for...
  • WIOA and Registered Appenticeship

    WIOA and Registered Appenticeship

    Inspiring future leaders and empowering each student with the 21st century skills and knowledge necessary for success drive "Team 259" toward greatness every day. ... Cash Handling with Money Kits. Allows for hands on learning. Includes instruction on how to...