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Anticoagulation Update: DOACs, VTE Guidelines, “Bridging ... Anticoagulation... Anticoagulation Update: DOACs, VTE Guidelines, “Bridging” and iCentra (whew!) Scott C. Woller,

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  • Anticoagulation Update: DOACs, VTE Guidelines, “Bridging”

    and iCentra (whew!)

    Scott C. Woller, MD Co-Director, Thrombosis Program Intermountain Medical Center Professor of Medicine University of Utah School of Medicine

    Clinical Learning Day 2016

  • Disclosures

    • Investigator initiated grant recipient: Bristol-

    Myers-Squibb (paid to Intermountain Healthcare)

    • Panelist American College of Chest Physicians (ACCP) Clinical Practice Guideline: Antithrombotic therapy for venous thromboembolic disease (AT10)

  • Objectives • DOAC limitations & use in routine clinical care

    – Special populations • AT10 Updates: Venous Thromboembolism • Anticoagulation procedural interruption (“bridging”)

    – Warfarin – DOACs

    • Why & how to manage anticoagulation in iCentra

  • The Direct Oral Anticoagulants

  • The Direct Oral Anticoagulants 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:

    http://www.eliquis.com/PDF/ELIQUIS%20%C2%AE%20(apixaban)%20SmPC.pdf

  • Choosing a DOAC vs. warfarin in AF

    Ruff CT et al. Lancet 2014; 383: 955–62

  • Choosing a DOAC vs. warfarin in AF

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

    *

  • AT10 Summary of evidence: Recurrent VTE

    QUESTION: Should a DOAC or warfarin be used for acute and long-term treatment of VTE ? Quality assessment Summary of Findings

    NOAC n (studies)

    Risk of bias Overall quality of evidence

    Study event rates (%) Relative effect

    (95% CI)

    Anticipated absolute effects With LMWH

    and VKA With NOAC Risk w/

    LMWH &VKA

    Risk difference with NOACs

    (95% CI)

    Recurrent VTE RIVAROXABAN 8281 (2 studies)

    no serious risk of bias

    ⊕⊕⊕⊝ MODERATE

    due to imprecision

    95/4131 (2.3%)

    86/4150 (2.1%)

    RR 0.90 (0.68 to 1.2)

    23 per 1000 2 fewer per 1000 (from 7 fewer

    to 5 more)

    DABIGATRAN 5107 (2 studies)

    no serious risk of bias

    ⊕⊕⊕⊝ MODERATE

    due to imprecision

    55/2554 (2.2%)2

    60/2553 (2.4%)

    RR 1.12 (0.77 to

    1.62)

    22 per 1000 3 more per 1000 (from 5 fewer to 13 more)

    APIXABAN 5244 (1 study)

    no serious risk of bias

    ⊕⊕⊕⊝ MODERATE

    due to imprecision

    71/2635 (2.7%)

    59/2609 (2.3%)

    RR 0.84 (0.6 to 1.18)

    27 per 1000 4 fewer per 1000 (from 11 fewer

    to 5 more)

    EDOXABAN 8240 (1 study)

    no serious risk of bias

    ⊕⊕⊕⊝ MODERATE

    due to imprecision

    146/4122 (3.5%)3

    130/4118 (3.2%)

    RR 0.83 (0.57 to

    1.21)

    35 per 1000 6 fewer per 1000 (from 15 fewer

    to 7 more)

  • From the clinical trials:

    • Need for thrombolytic therapy • An indication for anticoagulation for which no DOAC approval exists • High risk of bleeding • Significant liver disease (hepatitis, cirrhosis, or AST/ALT ≥ 3x ULN) • Creatinine clearance 30 mL/min (apixaban threshold was 25 mL/min) • Aspirin use (100 mg/day) • Concomitant use of interacting medications • Uncontrolled hypertension

    Who is not?

    Who is a candidate for a DOAC therapy to treat VTE?

    Schulman S (2013) N Engl J Med 368:709–718. EINSTEIN Investigators (2010) N Engl J Med 363:2499–2510. Agnelli G (2013) N Engl J Med 368:699–708. Schulman S (2009) N Engl J Med 361:2342–2352. Schulman S (2014) Circulation 129:764–772 EINSTEIN–PE Investigators (2012). N Engl J Med 366:1287–1297. Agnelli G (2013) N Engl J Med 369:799–808. Hokusai-VTE Investigators (2013) N Engl J Med 369:1406–1415.

  • From the school of hard knocks:

    • Patients who struggle with compliance (unless related to transportation for INRs) • Warfarin is likely favorable to allow ascertainment of and

    anticoagulant effect

    • Financial barriers to longitudinal compliance • After 1.1 year f/u

  • DOAC therapy: Special populations

  • Pregnancy

    Candidates for a DOAC therapy: Special populations

    XARELTO-PM-ENG-10JUL2014-172618.pdf. http://www.bayer Boehringer Ingelheim Canada Ltd (2014) Pradaxa product monograph. http://www.boehringeringelheim.ca; images from: colorbox.com; dailykos.com; Bapat P et al.. J Thromb Haemost 2016; 14: 1436–41.; Bapat P etal. Obstet Gynecol 2014; 123: 1256; 15 Bapat P etal. Am J Obstet Gynecol 2015; 213: 710.e1–6.

    + Dabigatran or rivaroxaban =

    • Apixaban has no human data in pregnancy, but showed no maternal or fetal harm in animal studies • Ex vivo drug concentration across placenta F:M ratio 0.9

    • Edoxaban animal studies demonstrated no fetal harm

    • DOAC excretion in breast milk is not known.

    http://www.boehringeringelheim.ca/

  • Pregnancy

    Candidates for a DOAC therapy: Special populations

    dailykos.com

  • Extremes of weight

    Candidates for a DOAC therapy: Special populations

    • Evidence is limited • Patients 100 kg • 1 meta-analysis showed that for patients >100kg recurrent VTE

    risk was 0.9 (95% CI 0.77-1.06) • Dabigatran does not appear to be affected by extremes of weight • Weight may affect kinetics of anti-Xa’s but the clinical significance

    is unknown. • ISTH and AC Forum suggest against use based on PK/PD in obese

    Schulman NEJM 2009; EINSTEIN Investigators NEJM 2010; AMPLIFY NEJM 2013; HOKUSAI NEJM 2013; Stangier DJ Clin Pharmacokinet 2008; Frost J. thromb Haemost 2009; Upreti VV 2013 Br J Clin Pharmacol; Kubitza D 2007 J Clin Pharmacol; clipartbest.com; van Es Blood. 2014; Martin K etal. J Thromb Haemost 2016; 14: 1308–13.; Burnett etal. J Thromb Thrombolysis (2016) 41:206–232

  • Extremes of weight

    Candidates for a DOAC therapy: Special populations

    dailykos.com

  • Elderly

    Candidates for a DOAC therapy: Special populations

    • Evidence from a meta-analysis of the Phase 3 trials studying VTE

    • Pooled DOAC vs. VKA for age ≥ 75 years for recurrent VTE or VTE-related death: HR 0.56 (95% CI 0.38-0.82) p=0.003

    • Pooled DOAC vs. VKA for age ≥ 75 years for Major bleeding: HR 0.49 (95% CI 0.25-0.96) p=0.04

    van Es N. Blood. 2014; pintrest.com

  • Elderly

    Candidates for a DOAC therapy: Special populations

    van Es N. Blood. 2014; pintrest.com

  • Thrombophilias

    Candidates for a DOAC therapy: Special populations

    • Evidence is limited • Patients with thrombophilias comprised 2-18% of those

    enrolled in DOAC trials

    • Post-hoc dabigatran data shows no difference in recurrent VTE

    • Exception: APS--3 ongoing studies • RAPS (Canada), TRAPS (Italy), ASTRO-APS (USA)

    Schulman S (2013) N Engl J Med 368:709–718. EINSTEIN Investigators (2010) N Engl J Med 363:2499–2510. Agnelli G (2013) N Engl J Med 368:699–708. Schulman S (2009) N Engl J Med 361:2342–2352. Schulman S (2014) Circulation 129:764–772 EINSTEIN–PE Investigators (2012). N Engl J Med 366:1287–1297. Agnelli G (2013) N Engl J Med 369:799–808. Hokusai-VTE Investigators (2013) N Engl J Med 369:1406–1415; Schulman S et al (2014) ASH 56th annual meeting Dec 2014, session 332 abstract 1544

  • Thrombophilias

    Candidates for a DOAC therapy: Special populations

    dailykos.com

  • Thrombophilias

    Candidates for a DOAC therapy: Special populations

    APS =

    dailykos.com

  • Cancer

    Candidates for a DOAC therapy: Special populations

    • No dedicated RCT evidence for cancer patients exists • Systematic reviews of the cancer subgroup from the clinical

    trials suggest DOACs are similar to VKA for VTE recurrence risk reduction and no difference in MB/CRNMB

    • 1 meta-analysis suggested for VTE recurrence RR 0.57 (95% CI

    0.36-0.91; p=0.02)

    Schulman S 2013 NEJM EINSTEIN Investigators 2010 NEJM ; Agnelli G 2013 NEJM; Schulman S 2009 NEJM; Schulman S 2014 Circulation; EINSTEIN–PE Investigators 2012 NEJM; Agnelli G 2013 NEJM; Hokusai-VTE Investigators 2013 NEJM; Castellucci LA. 2014 JAMA; Carrier M. 2014 Thromb Res; Vedovati MC. 2015 Chest; Di Minno MN. 2014 J Thromb Haemost; Franchini M.2015 Thromb Res

  • Cancer

    Candidates for a DOAC therapy

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