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
