Non$VitaminKOralan/coagulants (NOACs) · PDF fileObjecves • AdvancesinwarfarinmanagementiniCentra – An#coagula#onManagementSuite* • TheNon$VitaminKOralan/coagulants(NOACs)

Non-‐Vitamin K Oral an/coagulants (NOACs)

in clinical prac/ce

Sco$ C. Woller, MD Co-‐Director, Thrombosis Program

Intermountain Medical Center Associate Professor of Medicine

University of Utah School of Medicine

Central Region Primary Care Clinical Program Learning Day Intermountain Medical Center 20 February 2015

Disclosures

•  Poten/al Financial COI: –  Inves/gator ini/ated grant recipient: Bristol-‐Myers-‐Squibb (paid to Intermountain Healthcare)

•  Poten/al Intellectual COI: – Panelist American College of Chest Physicians (ACCP) Clinical Prac/ce Guideline: An/thrombo/c therapy for venous thromboembolic disease (AT10)

Objec/ves •  Advances in warfarin management in iCentra – An#coagula#on Management Suite

•  The Non-‐Vitamin K Oral an/coagulants (NOACs) – Atrial fibrilla/on –  Venous thromboembolism –  Choice of drug

•  Peri-‐procedural interrup/on of the NOACs •  Transi/on from: – NOAC → warfarin – Warfarin → NOAC

Transi/ons

HELP2 Cerner iCentra AnCcoagulaCon Management Suite

•  Ini/a/on •  Rou/ne warfarin dose adjustment •  Peri-‐procedural management •  Inpa/ent / outpa/ent transi/on of care •  Feedback on performance •  Iden/fica/on of candidates for alterna/ve therapy

Warfarin Ini/a/on

Warfarin Ini/a/on

Warfarin Ini/a/on

Warfarin Ini/a/on

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sciencecodex.com

NOACs

The Non-‐Vitamin K Oral An/coagulants Rivaroxaban Apixaban Edoxaban Dabigatran

BRAND NAME PHARMACEUTICAL

Xarleto™ Bayer

Eliquis™ BMS & Pfizer

Savaysa™ Daiichi Sankyo

Pradaxa™ Boehringer Ingelheim

TARGET Factor Xa Factor Xa Factor Xa Factor IIa

BIOAVAILABILITY (%) ~80 ~50 62 6–7

TIME TO PEAK (h) 2–3 1–2 1-‐2 1.5

HALF-‐LIFE (h) 9-‐13 8-‐15 9-‐10 12-‐14

RENAL EXCRETION (%) 33 25 35 >80

EFFECT ON aPTT/PT* 1.8/2.6 1.2/~2 yes 2.3/NR

EFFECT ON Xa 68% NR NR No Effect

DRUG INTERACTIONS CYP3A4 IND/INH CYP3A4 INH P-‐gp INH/CYP3A4 Verapamil/rifampin

Derived from: Crowther. Blood. 2008;111:4871-4879; Garcia, D. Blood. 2010;115:15-20; http://www.eliquis.com/PDF/ELIQUIS%20%C2%AE%20(apixaban)%20SmPC.pdf Schulman Thromb Haemost 2014; 111:

TRIAL RE-‐LY ROCKET-‐AF ENGAGE-‐AF-‐TIMI ARISTOTLE

Drug Dabigatran Rivaroxaban Edoxaban Apixaban

Dose 110mg or 150mg BID

20 mg daily (15 mg daily RI)

60 mg QD#

(30 mg QD)* 5 mg BID (2.5mg BID)*

Comparator/TTR Warfarin/ 67% Warfarin/ 55% Warfarin/ 68% Warfarin/ 62%

Condi/on AF 6 mo + ≥1RF AF 6 mo + ≥2RF AF 6 mo + ≥1RF AF + ≥1RF

Enrolled 18,113 14,000 21,105 18,201

Design R OL R DB DD R DB DD R BD DD

Age/ %♂ 72 yrs / 64% 73 yrs / 60% 72 yrs / 62% 70 yrs / 65%

Mean CHADS2 2.1 3.5 2.8 2.1

Prior Stroke/TIA 20% 55% 28% 19.2%

Primary Outcome Stroke/SE Stroke/SE Stroke/SE Stroke/SE

Median follow-‐up 2 yrs 1.9 yrs 2.8 yrs 1.8 yrs SE: acute vascular occlusion of an extremity or organ, documented by means of imaging, surgery, or autopsy.

The Non-‐Vitamin K Oral An/coagulants: Atrial Fibrilla/on

RE-‐LY: Summary Comparison of Dabigatran to Warfarin

•  Dabigatran 150 mg BID was superior to warfarin – Systemic Embolism or Stroke: RR 0.66 –  ICH: RR 0.4 – Major bleeding did not differ RR 0.93

•  NNT to prevent one stroke: 357 •  NNT to prevent one hemorrhagic stroke: 370 •  Dabigatran 75mg BID CrCl 15-‐30 mL/min

Connolly NEJM 2009;361:1139-‐51

Atrial Fibrilla/on TRIAL RE-‐LY ROCKET-‐AF ENGAGE-‐AF-‐TIMI ARISTOTLE




60 mg QD#

(30 mg QD)* 5 mg BID (2.5mg BID)*


Condi/on AF 6 mo AF 6 mo + ≥2RF AF 6 mo + ≥1RF AF + ≥1RF

Enrolled 18,113 14,000 21,105 18,201



Mean CHADS2 2.1 3.5 (87% ≥ “3”) 2.8 2.1



Median follow-‐up 2 yrs 1.9 yrs 2.8 yrs 1.8 yrs

SE: acute vascular occlusion of an extremity or organ, documented by means of imaging, surgery, or autopsy.

Comparison of Rivaroxaban to Warfarin �  Non-‐inferiority achieved in “per-‐protocol as treated”

  Superiority ITT (2.1% vs. 2.4% p=0.12) not achieved

�  No difference in Major and NMCR bleeding seen �  Significantly fewer ICH & fatal bleeds with rivaroxaban

�  CHADS2 mean 3.5—Higher risk popula/on

�  TTR for the comparator group was 55%

�  Once daily dosing is meritorious   Compliance of 88% vs. 74% in serng chronic therapy

Corda RS. South Med J 2000; 93:585-‐589 Patel NEJM Aug 10, 2011

ROCKET-‐AF: Summary

Atrial Fibrilla/on TRIAL RE-‐LY ROCKET-‐AF ENGAGE-‐AF-‐TIMI-‐48 ARISTOTLE




60 mg QD#

(30 mg QD)* 5 mg BID (2.5mg BID)^



Enrolled 18,113 14,000 21,105 18,201



Mean CHADS2 2.1 3.5 2.8 2.1




#verboten if CrCl > 95 mL/min *CrCl 15-‐30 mL/min

ENGAGE-‐AF-‐TIMI 48: Summary Comparison of Edoxaban to warfarin

•  Edoxaban was noninferior to warfarin 1.18% vs. 1.5% (95% CI 0.63-‐0.99; p<0.001) for 60mg QD (30mg QD HR=1.07)

•  Edoxaban was superior to warfarin for major bleeding 2.75% (LD 1.61%) vs. 3.43% (p< 0.001) (HR 0.8 & 0.47)

•  Edoxaban was superior to warfarin for Composite Endpoint: 3.85%* (LD 4.23%) vs. 4.43% (HR 0.87; p=0.005*)

•  Net Clinical Outcome Benefit favors Edoxaban –  7.26% (LD 6.79%) % vs. 8.11% (p ≤ 0.003)

Giugliano, NEJM 2013;369:2093-‐104

Atrial Fibrilla/on TRIAL RE-‐LY ROCKET-‐AF ENGAGE-‐AF-‐TIMI ARISTOTLE



20 mg daily (15 mg BID RI)

60 mg QD#

(30 mg QD)* 5 mg BID (2.5mg BID)^



Enrolled 18,113 14,000 21,105 18,201



Mean CHADS2 2.1 3.5 2.8 2.1




SE: acute vascular occlusion of an extremity or organ, documented by means of imaging, surgery, or autopsy.

^if 2 of: age>80, wt <60kg, Cr >1.5

ARISTOTLE: Summary Comparison of Apixaban to Warfarin

�  Apixaban reduced the risk of stroke or systemic embolism by 21%, major bleeding by 31%, and death by 11%.

�  For each 1000 pa/ents treated for 1.8 years, apixaban prevented 6 strokes 15 major bleedings and 8 deaths.

�  Net Clinical Outcome Benefit favors apixaban �  6.13% vs. 7.2% p < 0.001

Granger NEJM 2011;365:981-‐92

NOACs vs. warfarin in AF

Ruff CT et al. Lancet 2014; 383: 955–62 *TTR > 66%

*

Comparing NOACs in AF Rivaroxaban vs. warfarin

Apixaban vs. warfarin

Apixaban vs. Rivaroxaban

Stroke + SE 0.87 (0.74-‐1.03)

0.8 (0.66-‐0.95)

0.91 (0.71-‐1.16)

Ischemic stroke 0.99 (0.82-‐1.19)

0.96 (0.77-‐1.21)

0.98 (0.73-‐1.31)

Hemorrhagic stroke 0.58 (0.38-‐0.89)

0.51 (0.35-‐0.75)

0.87 (0.49-‐1.55)

Major bleeding 1.04 (0.91-‐1.20)

0.69 (0.60-‐0.79)

0.66 (0.54-‐0.81)

GI Bleeding 1.45 (1.19-‐1.79)

0.89 (0.68-‐1.16)

0.61 (0.43-‐0.85)

DisconCnuaCon 1.08 (1.01-‐1.15)

0.91 (0.86-‐0.96)

0.85 (0.78-‐0.92)

Mortality 0.92 (0.82-‐1.03)

0.89 (0.80-‐0.998)

0.97 (0.83-‐1.14)

Derived from Mitchell M et al. CLIN APPL THROMB HEMOST 2013 19: 619

DRUG RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN TRIAL EINSTEIN-‐PE AMPLIFY HOKUSAI RE-‐COVER

Dose 15mg BID x 21d; 20mg QD

10mg BDX x 7d; 5mg BID

LMMH then 60mg QD (30mg CrCl30-‐50;<60kg)

LMWH then 150mg BID x 6 mo.

Comparator/TTR% LWWH + Warf / 62.7% LWWH + Warf / 61% LMWH + Warf / 63.5% LWWH + Warf / 60%

CondiCon (%) PE 100% B 25% DVT 65 PE 25 B 10 DVT 60 PE 40 B24 DVT 70 PE 20 B 10

Enrolled 4832 5395 8240 2539

Design R OL NI R DB NI R DB NI R DB NI

Age/ %♂ 58 yrs / 54% 57 / 61% 55.8 / 57% 55 yrs / 58%

Cancer 4.6% 2.5% 9.2% 5%

1o Efficacy Recurrent VTE Recur. VTE + VTE death Recur. VTE + VTE death Recur. VTE + death

Primary Safety MB + CRNMB MB + CRNMB MB+CRNMB Bleeding/ACS/LFT

Efficacy Outcome

2.1 v. 1.8; RR 1.12 (0.75-‐1.68) p<0.003 NI

2.3 vs. 2.7 RR 0.84 (0.6-‐1.2) p<0.001 NI

3.2 vs. 3.5 RR 0.89 (0.7-‐1.1) p<0.001 NI

2.4 v. 2.1; RR 1.1 (0.65-‐1.84)

Major Bleeding 1.1 v. 2.2 RR 0.49 p=0.11(ns) [PE: 0.49]

0.6 vs. 1.8 RR 0.31 (0.17-‐0.55) p<0.001 sup

8.5 vs. 10.3 RR 0.81 (0.71-‐0.94) p=0.004 sup

1.6 v. 1.9 RR 0.82 (ns)

Any bleeding 10.3 vs. 11.4% CRB: 4.3 vs. 9.7% 21.7% vs. 25.6% HR 0.71 (0.59-‐0.85)

Summary Non-‐inferior; QD dose Non-‐inferior and safer Non-‐inferior, safer; QD Non-‐inferior

Schulman NEJM 2009;361:2342; EINSTEIN Inves/gators NEJM Dec 4, 2010; AMPLIFY NEJM 1 Jul 2013; HOKUSAI NEJM 1 Sept 2013

NOACs for VTE

Choosing between NOACs in VTE

Castellucci JAMA. 2014;312(11):1122-‐1135.

Choosing between NOACs: Summary

Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban

Cost +++ + + + + Compliance +++ + ++ + ++ Bleeding risk + ++ ++ +++ +++ Renal Dysfunction +++ + + ++ + QOL + ++ +++ ++ +++

Anderson M Clev. Clin J Med, 2014, 8; 629;

�  About 2.5M Americans require long-‐term an/coagula/on

�  About 10% require interrup/on annually

�  Generally, interrupt 4-‐5 half-‐lives before HBR procedure

�  OK to interrupt 2-‐3 half-‐lives before LBR procedure

�  Half-‐life increases as crea/nine clearance increases

Preopera/ve interrup/on of NOACs

CrCl Half-‐Life (hours) Low Bleeding Risk High Bleeding Risk

Dabigatran >50 13-‐15 1 day 2 days

30-‐50 18 2 days 4 days

15-‐30 27 2-‐5 days > 5 days

Rivaroxaban >50 8-‐9 1 day 2 days

30-‐50 9 1 day 2 days

15-‐30 9-‐10 2 days 3 days

Apixaban >50 12 1 day 2 days

30-‐50 17-‐18 2 days 3 days

15-‐30 17-‐18 2 days 3 days

Derived from Anderson M Clev. Clin J Med, 2014, 8; 629;

Douke/s J. Current Pharmaceu#cal Design, 2010, 16, 3436-‐3441

Transi/oning between an/coagulants

Warfarin → NOAC h|ps://kr.ihc.com/ext/Dcmnt?ncid=522592305

h|ps://kr.ihc.com/ext/Dcmnt?ncid=522592305

•  Package inserts of the NOACs vary •  Representa/ve of expert opinion

•  Recommenda/on: Stop warfarin. Start apixaban, dabigatran, edoxaban, or rivaroxaban as soon as INR is less than 2.5.

Transi/oning between an/coagulants

NOAC → Warfarin

Transi/oning from NOAC → warfarin

•  Post hoc analysis of the ROCKET-‐AF – Rivaroxaban→warfarin: Increased risk of stroke – HR 3.72 (95% CI 1.51–9.16); P = 0.004

•  Retrospec/ve analysis of ARISTOTLE – Apixaban→warfarin: Increased risk of stroke – HR 4.07 (95% CI 1.54–10.81)

•  Especially those with a high CHADS2 score Patel MR, etal. J Am Coll Cardiol 61(6):651 Granger CB etal. Eur Heart J 33(suppl 1):685

Summary •  iCentra – An#coagula#on Management Suite

•  The Non-‐Vitamin K Oral An/coagulants – Atrial fibrilla/on –  Venous thromboembolism –  Choice of drug

•  Peri-‐procedural interrup/on of the NOACs – Drug, procedure, renal func/on

•  Transi/on from: – NOAC → warfarin – Warfarin → NOAC

Thank you

Documents

Non$Vitamin*K*Oral*an/coagulants* (NOACs) · PDF fileObjecves • Advances*in*warfarin*managementin*iCentra – An#coagula#on*Management*Suite* • The*Non$Vitamin*K*Oral*an/coagulants*(NOACs)*

Non$VitaminKOralan/coagulants (NOACs) · PDF fileObjecves • AdvancesinwarfarinmanagementiniCentra – An#coagula#onManagementSuite* • TheNon$VitaminKOralan/coagulants(NOACs)