The New An)coagulants: Prac)cal Applica)on Ma8hew Rondina, M.D. Department of Internal Medicine University of Utah Medical Center
Learning Objec)ves 1. Understand the prac)cal considera)ons and poten)al disadvantages of the new oral an)coagulants. 2. Understand how to switch to and from the new oral an)coagulants and other agents, including their use in the peri- procedural period. 3. Recognize the limita)ons, poten)al pinalls, and educa)onal needs for effec)ve administra)on of the new an)coagulants in the real world.
NEW OACs: UNCHARTED WATERS IN REAL WORLD? Physicians considering dabigatran or an oral factor Xa inhibitor for individual pa)ents should be extraordinarily conserva)ve in considering whether these medica)ons are appropriate replacements for warfarin. Annals Opinion, R.P. Radecki, M.D. Annals of Internal Medicine 2012; 157:66
NEW OACs: POTENTIAL DISADVANTAGES? Limited Clinician Experience Unselected, Real World PopulaGons PaGent Adherence? PaGent selecgon? Drug interacgons? CrCl FU? Subop)mal dosing with CKD Switch among ACs? Periprocedural Rx? Uncertain OAC intensity Bleeding Rx? No angdote Cost: $250/mo No monitoring pt educagon Not detect adherence PaGent vigilance/ adherence (17% DC at 4mo) Increased Major Bleeding and/or Stroke/SE? Circula)on 2011; 124: Abs 16675 Blood 2012; 119:3016 Sem Thromb Haemost 2012; 38:7 Thromb Haemost 2012; 107:838
HOW TO CHOOSE: WARFARIN vs NEW OAC? Warfarin mandatory if: Mitral stenosis no data Prosthe)c heart valve FDA 12/2012: new OAC contraindicated REALIGN stopped early warfarin be8er Crea)nine clearance < 30 ml/min no data/toxicity Non- adherence as cause of low TTR 36% miss 20% of warfarin doses TTR Can t assess adherence to new OACs BID dosing (dabi, apixaban), short dura)on of ac)on Cannot afford new OACs - $3,000/y CAD? ACCP- 2012 favors warfarin > dabi Blood 2012; 119:3016 Thromb Haemost 2012; 107:838 Arch Int Med 2007; 167:229
HOW TO CHOOSE: WARFARIN vs NEW OAC? Clinical consideragons favoring warfarin? TTR 70% (?) and pagent prefers warfarin S)ll, ICH with new OACs! Risk factors for new OAC accumulagon Bleeding Wt < 60 kg ± CrCl 30-49 ± age 75-80y ± interac)ng drugs FluctuaGng CrCl: CHF High GI bleeding risk (dabigatran, rivaroxaban) Prior bleed, IBD, angiodysplasia, other Wt <50 kg or > 120 kg no data Blood 2012; 119:3016 Thromb Haemost 2012; 107:838
HOW TO CHOOSE: WARFARIN vs NEW OAC? Cost- effecgveness modeling studies (<$50,000/QALY): CHADS 2 Score Cost- effecgve? 0 ASA or No Rx 1, 2 Warfarin 3 bid No, if high bleed risk No, if TTR < 57% Dabigatran, 150 mg No, if TTR 73% New OACs cost- effecgve (not cost- saving) in pagent subsets Circula)on 2011; 123:2519, 2562 BMJ 2011; 343:d6333 Heart 2012; 98:573 Thromb Haemost 2011; 105:908
NEW OACs: CAN WE AFFORD THEM? Hospital budget implicagons for angcoagulagon clinic: 1774 AF pa)ents: 94% eligible for dabigatran 150 mg bid Dabigatran 150 mg bid: $2464/y*; warfarin: $31/y* Labor $483/pt INR tes)ng $267/pt Warfarin Costs/y Dabigatran Costs/y MedicaGon 54,994 4,371,136 INR monitoring 473,658 - - - Labor 856,842 - - - (???) $1,385,494 $4,371,136 (??) *wholesale acquisi)on costs #Costs due to AE not considered Clin App Thromb Haemost 2012; 18:181
increase in medica)on cost far exceeds the budgetary savings from elimina)ng all costs for labor and laboratory coagula)on monitoring. Consequently, clinicians and pa)ents can expect imposi)on of external cost- control measures that may include a preferred formulary choice, prescrip)on preauthoriza)on, increasing pa)ent copayment, or an ini)al trial of generic warfarin. Clin App Thromb Haemost 2012; 18:181
Drug DRUG INTERACTIONS: NEW OACs Dabigatran r in Exposure Rivaroxaban/Apixaban r in Exposure *Dronedarone + 170-200%?? *Azole an)fungals (eg., ketoconazole) + 150% + 160% *Amiodarone + 60% - - - *Quinidine + 53% - - - *Verapamil + 50% - - - *Clarithromycin - - - + 50% *Ritonavir - - - + 50% *St. John s wort?? *Rifampicin, phenytoin, carbamazepine - 67% Cannot detect/monitor interacgon! - 50% *Contraindicated or therapy modificagon for CrCl = 30 49? Blood 2012; 119:3016
NEW OACs: A DARKER SIDE? Bleeding and patient selection in the community: FDA, 12/2012: 542 Dabigatran deaths in the U.S. unknown for warfarin >50% involved off-label use European Medicine Agency, 5/2012: Dabigatran deaths fewer than expected from RCTs No data presented FDA, 11/2012: Insurance/administrative data: ICH/GIB 1.6 2.2x in new warfarin vs new dabigatran users. Bloomberg News, 12/2012: >150 U.S. Lawsuits vs Boehringer-Ingeleheim
WHO BLEEDS ON NEW OACs? Australia/NZ Hematology Society: 78 dabigatran bleeds Age 80: 66% CrCl <50 ml/min: 58% Wt < 60 kg: 50% (mean wt = 83 kg in Phase III RCTs) Bleeding risk mulgple RFs for drug accumulagon Age 80y CrCl 30-49 ml/min Wt < 50-60 kg - 50% serum dabi levels CHF South Asians - 50% of AF pts 80y Medica)ons: amiodarone, dronedarone, verapamil, dil)azem, PPIs, others NEJM 2012; 366:864 J Thromb Haemost 2012; 9:2168 Circulation 2011; 124:824
NEW OACs: TESTING HEMOSTATIC FUNCTION If bleeding/thrombosing/urgent surgery/? Adherence: Dabigatran: Normal aptt No therapeu)c AC Normal thrombin )me No drug present Rivaroxaban: Normal PT (not INR) No therapeu)c AC Normal an)- factor Xa ac)vity No/minimal drug Apixaban: Normal an)- factor Xa ac)vity No/minimal drug No tests are useful for rougne monitoring Br J Haem 2012; 159:427
NEW OACs: RX OF LIFE- THREATENING BLEEDING Specific angdotes: unavailable but in development Monoclonal Ab to dabigatran, rivaroxaban Reversal of angcoagulant effect: minimal, conflicgng data Animal models Healthy subjects: measuring lab effects ex- vivo Case reports: nega)ve or conflic)ng as to benefit Siegal, Eur Heart J, on-line 12/7/2012 Am J Hem 2012; 87 (suppl1): S 141 Thromb Haemost 2012; 108:583
SUMMARY OF STUDIES EVALUATING Oral ac)vated charcoal* NOAC REVERSAL Apixaban Dabigatran Rivaroxaban No data In vitro No data Hemodialysis No data Human volunteers No data Hemoperfusion # with Oral charcoal No data In vitro No data FFP No data Mouse model No data Ac)vated factor VIIa No data Rat model Rat and baboon models 3- factor PCC No data No data No data 4- factor PCC** No data Human volunteers and rat model *If drug intake within several hours **Not available in U.S. #Extracorporeal passage of volume over adsorbant surface (e.g. charcoal) Human volunteers Adapted from Am J Hematol 2012; 87:S141-145
PRO- THROMBIN COMPLEX CONCENTRATES U.S. Availability Factors Present Trade Name Associated with Thrombosis? 3- Factor PCC Yes II, IX, X (low VII levels) Profilnine SD Bebulin VH Yes Ac)vated 4- Factor PCC Yes II, IX, X, VIIa FEIBA NF Yes Highest Risk? 4- Factor PCC No II, VII, IX, X Beriplex Octaplex Yes Dosed ~ 25-50 units/kg body weight No need to thaw prior to administra)on or match blood type Also usually contain small amounts of endogenous ACs (PC/PS) May more rapidly correct coagulopathy due to VKA (vs. FFP) 2012 ACCP: Preferred over FFP (Grade 2C) Am J Hematol 2012; 87:S141-145 Blood Transfusion 2011; 9:117-119 Chest 2012; 141:e152S-184S
BLEEDING ON NEW OAC Mild DC new OAC No AC effect a er 24-48h if CrCl normal Severe DC new OAC Verify Gme of last dose Oral Charcoal if < 4h since administragon Stabilize, support, monitor Rx bleeding site FFP not likely useful Reversal needed for life- threatening bleeding Am J Hem 2012; 87(Suppl 1):S141
*May precipitate thromboembolism use only if life- threatening bleeding Am J Hem 2012; 87(Suppl 1):S141 LIFE- THREATENING BLEEDING ON NEW OAC Reversal needed Dabi: aptt > 1.0 X control Riva, apixa: an)factor Xa Rx Dabigatran assay Rivaroxaban Apixaban Hemodialysis Yes No No Hemoperfusion Unclear Possible Possible 4- factor PCC* Possible Possible Possible FEIBA Possible Possible Possible 3- factor PCC* Unclear Unclear Unclear rfviia* Unclear Unclear Unclear Ac)vated charcoal Yes Yes Yes
HOW TO SWITCH TO/FROM DABIGATRAN OR RIVAROXABAN? Warfarin Dabi or Riva: start D/R when INR < 2.0 D or R Warfarin: calculate creagnine clearance (egfr) CrCl, ml/min Dabigatran: start W # days before stop D Rivaroxaban: start W # days before stop R >50-3 - 4 31-50 - 2-3 15-30 Stop D or - 1 R on day 0 above - 2 - Off dabi 1-2 days for lab INR to be useful Do not use point- of- care INR tesgng - OveresGmates INR on dabi (riva?) Blood 2012; 119:3016 van Ryn J, Am J Med epub 2/2012
HOW TO SWITCH TO/FROM DABIGATRAN OR RIVAROXABAN? Enoxaparin bid D or R: Start D or R 10-12 hours a er last dose enoxaparin Dalteparin qd D or R: Start D or R 20-24 hours a er last dose dalteparin IV UFH D or R: Start D or R within 2h of stopping IV UH Dabigatran LMWH or IV UFH: Start LMWH/IV UFH 12h a er last dose dabi if CrCl 30; wait longer if CrCl < 30 (?) Rivaroxaban LMWH or IV UFH: Start LMWH/IV UFH 24h a er last dose riva if CrCl 30; wait longer if CrCl < 30 (?) (PI: First dose of LMWH/UFH at )me next riva dose would be due) Circ J 2011; 75:1539 Xarelto PI
DRUG Dabigatran, 150 mg bid Rivaroxaban, 20 mg qd Apixaban, 5 mg bid PERIPROCEDURAL USE OF NEW OACs: PRE- OP CrCl Ml/min > 50 30 50 > 50 30 50 > 50 30 50 Last Dose Pre- op: Low Bleeding Risk Surgery 2d: Skip 2 doses 3d: Skip 4 doses 2d: Skip 1 dose 2d: Skip 1 dose 2d: Skip 2 doses 3d: Skip 4 doses *Dabigatran: ü a PTT 24h pre- op Rivaroxaban/Apixaban: ü an)- factor Xa 24h pre- op Last Dose Pre- op: High Bleeding Risk Surgery* 3d: Skip 4 doses 4-5 d: Skip 6-8 doses 3d: Skip 2 doses 3d: Skip 2 doses 3d: Skip 4 doses 4d: Skip 6 doses Blood 2012; 120:2954
DRUG PERIPROCEDURAL USE OF NEW OACs: POST- OP Resume Rx: Low Bleeding Risk Surgery Resume Rx: High Bleeding Risk Surgery Dabigatran 24 h post op 48 72 h post op* Rivaroxaban 24 h post op 48 72 h post op* Apixaban 24 h post op 48 72 h post op* *High TE risk: consider prophylac)c dose LMWH un)l restart new OAC Blood 2012; 120:2954
NEW OACs: INITIAL PATIENT ASSESSMENT ü Risk factors for drug accumulagon: Age 75y CrCl = 30 59 ml/min Wt <50 kg Concurrent interac)ng drugs ü Risk factors for low pagent adherence: 21-25% DC rate Ability to afford Ability to take dabi, apixa bid Pa)ent preference vs warfarin ü Risk factors for bleeding: reverse if possible HAS- BLED score Prior GI bleeding Need (?) for concurrent ASA Blood 2012; 119:3016 Int Soc Thromb Haemost, J Thromb Haemost 2012; on- line 10/22
NEW OACs: PATIENT EDUCATION! Benefits/risks vs warfarin: ICH ± Ischemic Stroke ± GI bleeding ± Major bleeding Cost Consequence of non- adherence: Response to missed doses Drug interacgons: New drug repor)ng Periprocedural management Brochures Face- to- Face AC Clinic opgmal!
NEW OACs: FOLLOW- UP/ MONITORING Follow- up interval of q 3-12 months determined by: Renal func)on: baseline instability likelihood Bleeding risk: eg., HAS- BLED score 3 Interac)ng medica)on risk: polypharmacy Low adherence risk: 21-25% DC rate in RCTs Int Soc Thromb Haemost, J Thromb Haemost 2012, online 10/22