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Novel Oral Anticoagulants: What’s the Evidence?
Mike Boyd, PharmDOctober 21, 2017
Objectives
• Briefly review evidence from major clinical trials of direct oral anticoagulants (DOACs) in atrial fibrillation
• Understand the evidence for the use of DOACs in atrial fibrillation patients in special circumstances‒ Obesity‒ Renal insufficiency‒ Valvular heart disease‒ Periprocedural considerations
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Anticoagulation for Atrial Fibrillation
Warfarin
DOACs
Inhibits clotting factor production, does nothing to factors already produced
•Slow onset•Parenteral “bridging” may be needed•Dietary interactions (vit K)•Unpredictable dosing •Reversible: vit K/FFP/PCC
•Rapid onset•No “bridging”•No dependence on vit K= no dietary interactions•Predictable dosing•No specific antidote*
Directly blocks specific clotting factors
Mechanism of Action Result
*reversal agent available for dabigatran
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Major Trials of Novel AgentsDabigatran Rivaroxaban Apixaban Edoxaban
Study RE-LY ROCKET-AF ARISTOTLE ENGAGE-AF
Design Open-label warfarin
Double-dummy with sham INR
Double-dummy with sham INR
Double-dummy with sham INR
Dose 110/150 mg BID 20 mg daily 5 mg BID 30/60 mg daily
Enrollment (n) 18,113 14,264 18,201 21,105
Renal Adjustment None 15 mg daily for CrCl30-49 mL/min
2.5 mg BID if ≥2: ≥80 yr; ≤60 kg; SCr≥ 1.5mg/dL
Half dose if any: CrCl 30-50mL/min; ≤60 kg; quinidine, verapamil, or dronedarone
Avoid if >95mL/min
Exclusion CrCl <30 mL/min <30 mL/min <25 mL/min <30 mL/min
CHADS2 ≥ 2 68% 100% 66% 100%
Aspirin 40% 36% 30% 29%
Clopidogrel NR NR 1.9% 2.3%
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Stroke and Systemic Embolism
Lancet 2014;383:955‐62
Major Bleeding
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DOAC Trial Outcomes vs. Warfarin
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Dabigatran 150mg Rivaroxaban Apixaban Edoxaban 60mg
Stroke and systemic embolism
Major bleeding
GI bleeding
Intracranial bleeding
Mortality
: Non-inferior
DOAC Use in AF
8http://www.roirevolution.com/blog/2014/10/getting-a-slice-of-the-pie-why-the-top-ad-position-might-not-be-all-its-cracked-up-to-be/
RCT
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DOAC Use in Obesity
9 https://www.wellnessmonk.com/weight-fluctuations-explained
Prevalence¶ of Self-Reported Obesity Among U.S. Adults by State and Territory, BRFSS, 2016
¶ Prevalence estimates reflect BRFSS methodological changes started in 2011. These estimates should not be compared to prevalence estimates before 2011.
*Sample size <50 or the relative standard error (dividing the standard error by the prevalence) ≥ 30%.
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ISTH Recommendations
• Standard DOAC dosing in:‒ BMI ≤ 40 kg/m2 and‒ Weight ≤ 120 kg
• Avoid DOAC in:‒ BMI > 40 kg/m2 or‒ Weight > 120 kg
• If a DOAC must be used, drug-specific monitoring should be done
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Martin K et al. J Thromb Haemost 2016;14:1308-13
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P R E S C R I B E R
SUB-GROUP ANALYSIS
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DOAC in Obesity: Dabigatran (RE-LY)
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Connolly S et al. N Engl J Med 2009;361:1139-51Reilly P et al. J Am Coll Cardiol 2014;63:321-8
Effects of Body Weight on Rivaroxaban
14Kubitza D et al. J Clin Pharmacol 2007;47:218-26
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DOAC in Obesity: Rivaroxaban (ROCKET-AF)
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Stroke/SEE
Major Bleeding
Patel M et al. N Engl J Med 2011;365:883-91
Rivaroxaban Warfarin HR (95% CI) P-value
DOAC in Obesity: Apixaban
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Parameter Reference weight (65-85kg) n=16
High weight(120kg) n=19
Geometric mean ratio (90%CI)
Cmax (ng/mL) 207 (24) 144 (28) 0.692 (0.586, 0.818)
AUC(0,∞) (ng h/mL) 2024 (24) 1561 (31) 0.771 (0.652, 0.912)
Upreti V et al. Br J Clin Pharmacol 2013;76:908-916
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ARISTOTLE Trial: Post Hoc Weight Analysis
17Sandhu R et al. Eur Heart J 2016;37:2869-78
Summary of Evidence: Obesity
• PK/PD studies: obesity reduces exposure to DOAC
• RCT sub-group analyses:‒ Not powered for these comparisons‒ Similar results seen compared to overall study population‒ Morbid obesity (BMI>40) under represented
• No accurate means of monitoring available
• ISTH recommendations seem reasonable
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DOAC Use in Renal Insufficiency
19https://www.medicalnewstoday.com/articles/152902.php
DOAC Pharmacokinetic Comparison
Dabigatran Rivaroxaban Apixaban Edoxaban
tmax 1 hr 2-4 hrs 3-4 hrs 1-2 hrs
t1/2 12-17 hrs 5-9 hrs 12 hrs 10-14 hrs
Vd 50-70 L 50 L 21 L 107 L
Protein Binding 35% 92-95% 87% 55%
RenalClearance
80% 66% 27% 50%
Product Information: Eliquis® oral tablets, apixaban oral tablets. Bristol-Myers Squibb (per manufacturer), Princeton, NJ 2012.Product Information: Xarelto® oral tablets, rivaroxaban oral tablets. Janssen Pharmaceuticals, Inc, Titusville, NJ 2011.Product Information: Pradaxa® oral capsules, dabigatran etexilate oral capsules. Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 2011.Product Information: Savaysa ® oral tablets, edoxaban oral tablets. Daiichi Sankyo, Inc. (per FDA), Parsippany, NJ, 2015.
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DOAC Dosing in Renal Insufficiency
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Dabigatran Rivaroxaban Apixaban Edoxaban
Clinical trialexclusion CrCl
30mL/min 30mL/min 25mL/min 30mL/min
FDA-approved renal dosing for AF
CrCl=• 15-30mL/min:
75mg BID• <15mL/min:
no recs
HD: no recs
CrCl=• 15-50mL/min:
15mg• <15mL/min:
avoid
HD: no recs
• 2.5mg BID if SCr ≥1.5 and either:
• Age ≥80 or
• Wt ≤60kgHD: normal dose
CrCl=• 15-50mL/min:
30mg daily• <15mL/min:
avoid
HD: no recs
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Dabigatran and Rivaroxaban in dialysis
• Fresenius Medical Care ESRD database
• N=29,977 between 10/2010 and 10/2014
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Event rate per 100 pt-years Unadjusted rate ratio
WarfarinN=8064
DabigatranN=281
RivaroxabanN=244
Dabi vswarfarin
Riva vs warfarin
Total major bleeds*
47.1 83.1 68.4 1.76 (1.44-2.15)
1.45 (1.09-1.93)
*Major bleed: any bleed resulting in death or hospitalization
Chan K et al. Circulation 2015;131:972-979
Apixaban in ESRD/Dialysis
• 2014: FDA revised labeling to allow use in dialysis patients
• Wang et al.‒ Healthy vs. HD patients (8 each)‒ Single 5mg post-HD dose‒ 36% increase in AUC, no difference in Cmax
• Chang et al.‒ Various levels of renal function (n=32)‒ Single 10mg dose‒ 44% increase in AUC for CrCl=15 vs. CrCl=100
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Wang X et al. J Clin Pharmacol 2016;56:628-36Chang M et al. J Clin Pharmacol 2016;56:637-45
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Apixaban in dialysis
25Mavrakanas T et al. J Am Soc Nephrol 2017;28:2241-48
DAY 1 (Phase 1)
Starts apixaban2.5mg BID
DAY 8
DAY 22(last day of
Phase 3)
DAY 9 (Phase 2)Last dose of apix
2.5mg this amDIALYSIS for 4hr
DAYS 10-14Washout
period
DAY 15 (Phase 3)
Starts apix 5mg bid this am
Apixaban in dialysis
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AUCss (ng h/mL) with 2.5mg and 5mg bid
2.5mg bid 5mg bid
10000
8000
6000
4000
2000
0
Mavrakanas T et al. J Am Soc Nephrol 2017;28:2241-48
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Summary of Evidence: Renal Insufficiency
• Current DOAC product labeling only supports apixaban‒ Label recommends unadjusted dose (5mg twice daily)‒ PK data with steady state dosing suggests reduced dose
• ACC/AHA/HRS AF guidelines: warfarin recommended
• KDIGO: routine anticoagulation for 1º prevention of stroke is not indicated
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January C et al. J Am Coll Cardiol 2014;64:2246-80Herzog C et al. Kidney Int 2011;80:572-86
Anticoagulation: Valvular Heart Disease
Cardiol Res 2011;2:298-300 JAMA Cardiol 2016;1:1073-74
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RE-ALIGN Trial• Mechanical valves (AV, MV, or both)
• Dabigatran 150mg/220mg/300mg twice daily (n=168) vs. warfarin (n=84)
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Dabigatran Warfarin HR (95% CI) P-value
Death, stroke, SE, or MI 13 (8%) 2 (2%) 3.37 (0.76-14.95) 0.11
Asymptomatic valve thrombosis
5 (3%) 0
Any bleeding 45 (27%) 10 (12%) 2.45 (1.23-4.86) 0.01
Major bleeding 7 (4%) 2 (2%) 1.76 (0.37-8.46) 0.48
Eikelboom JW, et al. N Engl J Med 2013;369:1206-14
Guideline Recommendations: Native Valve Disease
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Recommendation COR LOE
2014 VKA indicated for patients with MS and • AF • Prior embolic event• LA thrombus
I B
2017 Update VKA indicated for patients with rheumatic MS and AF
I B-NR
Oral anticoagulant indicated in AF with CHA2DS2-VASc ≥2 and native AV or TV disease or MR
I C-LD
DOAC as alternative to VKA in AF with CHA2DS2-VASc ≥2 and native AV or TV disease or MR
IIa C-LD
Nishimura RA et al. J Am Coll Cardiol 2014;63:e57-185Nishimura RA et al. J Am Coll Cardiol 2017;70:252-89
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SUB-GROUP ANALYSIS
INTERPRET WITH CAUTION
VHD in DOAC Clinical Trials
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RE-LY (n=18,113)
ROCKET-AF (n=14,171)
ARISTOTLE (n=18,197)
ENGAGE-AF (n=21,105)
Any VHD 3950 (21.8%) 2003 (14.1%) 4808 (26.4%) 2824 (13.4%)
• MR 3101 (17.1%) 1756 (12.4%) 3526 (19.4%) 2250 (10.7%)
• MS 193 (1.1%) ** 131 (0.7%) **
• AR 817 (4.5%) 486 (3.4%) 887 (4.9%) 369 (1.7%)
• AS 471 (2.6%) 215 (1.5%) 384 (2.1%) 165 (0.8%)
• TR 1179 (6.5%) ** 2124 (11.7%) **
Valve surgery ** 106 (5.3%) 251 (1.4%) 325 (1.5%)
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• VHD vs. No VHD‒ Similar rates of stroke/systemic embolism‒ VHD: increased rates of bleeding
• DOAC vs. warfarin‒ Similar results to main trials
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VHD in DOAC Clinical Trials
Major Bleeding
DOACs in VHD• Rivaroxaban
‒ Bioprosthetic SAVR (ASA vs rivaroxaban for 6 mos)‒ RIVER: warfarin vs rivaroxaban in AF patients with bio MV‒ GALILEO: DAPT vs ASA/rivaroxaban after TAVR
• Apixaban‒ ATLANTIS: apixaban vs standard care after TAVR
• Edoxaban‒ ENVISAGE-TAVI AF: edoxaban vs VKA in AF patients after TAVR‒ ENAVLE: edoxaban vs VKA for 3 mos after MV repair or bioprosthetic MV
or AV replacement
• Dabigatran‒ DECISIVE: dabigatran vs standard care for silent CVA in mod-severe valve
disease
34 www.clinicaltrials.gov Accessed 9/12/17
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Summary of Evidence: Valvular Heart Disease
• DOACs may be considered in non-MS, native valve disease
• DOACs should be avoided in mechanical valves
• Trials underway to assess DOAC use in bioprostheticvalves
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Anticoagulation: Periprocedural Bridging
www.milanonera.com
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Risk Assessment
Bleeding Clotting
Lower Bleeding Risk:• Dental extraction• Diagnostic endoscopy• Thoracentesis, paracentesis
Lower Clotting Risk:• AV replacement• Atrial fib without prior stroke• DVT/PE >3 months
Higher Bleeding Risk:• Cardiac surgery• Neurosurgery• Vascular surgery
Higher Clotting Risk:• Mechanical MV• Multiple mechanical valves• Atrial fib with prior stroke• DVT/PE ≤ 3 months
Baron TH et al. New Engl J Med 2013;368:2113-24
Procedure-related Factors Patient-related Factors
Bleeding risk of procedure Recent (<3 mos) bleed
Consequences of bleeding Thrombocytopenia
Supratherapeutic INR
Bleeding with prior bridging
Bleeding with similar procedure
HAS-BLED score
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Is OAC Interruption Necessary?
Doherty JU et al. JACC 2017;69:871-98
HAS-BLED Score
Hypertension 1 Score Annual Bleeding Risk
Abnormal liver/renal function
1 each 0 1.13%
Stroke 1 1-2 1.02-1.88%
Bleeding history 1 ≥3 ≥ 3.74%
Labile INR 1
Elderly (>65y) 1
Drugs: NSAIDs/antiplatelet, EtOH
1 each
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Uninterrupted Anticoagulation
• Cardiac catheterization‒ Right heart procedures‒ Radial access‒ Diagnostic
• Electrophysiology procedures‒ CIEDs
• BRUISE-CONTROL: warfarin (3.5%) vs. bridge (16%)• BRUISE-CONTROL 2: uninterrupted DOAC
‒ Ablation
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Birnie DH et al. New Engl J Med 2013;368:2084-93Essebag V et at. Am Heart J 2016;173:102-7
Anticoagulation During Ablation
• Strategies include:‒ Interrupted warfarin with bridge‒ Uninterrupted warfarin‒ Minimally interrupted DOAC‒ DOAC transition to warfarin for RFA‒ Uninterrupted DOAC
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Calkins H et al. New Engl J Med 2017;376:1627-36
RE-CIRCUIT
4242 Doherty JU et al. JACC 2017;69:871-98
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DOAC Holding Times
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DOAC CrCl (mL/min) Procedure Bleed Risk
Low Non-Low
Dabigatran ≥ 80 ≥ 24 h ≥ 48 h
50-79 ≥ 36 h ≥ 72 h
30-49 ≥ 48 h ≥ 96 h
15-29 ≥ 72 h ≥ 120 h
<15 ≥ 96 h (no data) No data- check dTT?
Factor Xa Inhibitors
≥30 ≥ 24 h ≥ 48 h
15-30 ≥ 36 h ≥ 72 h (no data)-check anti-Xa level?<15 ≥ 48 h (no data)
Doherty JU et al. JACC 2017;69:871-98
Conclusions
• RCTs have proven the value of DOACs in AF
• RCTs include select individuals
• Caution should be used interpreting sub-groups from RCTs
• Therapy decisions should be individualized
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Novel Oral Anticoagulants: What’s the Evidence?
Mike Boyd, PharmDOctober 21, 2017
ARISTOTLE Analysis
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Characteristic BMI Category P-value
18.5 to <25 kg/m2
N=405225-30 kg/m2
N=6702≥ 30 kg/m2
N=7159
Age, mean 71.3 (10) 70.1 (9.3) 66.8 (9.23) <0.0001
Hx stroke, TIA, systemic embolism
1004 (24.8%) 1330 (19.8%) 1111 (15.5%) <0.0001
CHA2DS2VASc score
≥ 2 3772 (93.1%) 4631 (91.4%) 4923 (90.1%) <0.0001
HAS-BLED score
≥ 3 585 (14.4%) 885 (13.2%) 768 (10.7%) <0.0001
Sandhu RK et al. Eur Heart J 2016;37:2869-78
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Apixaban in dialysis
47Mavrakanas T et al. J Am Soc Nephrol 2017;28:2241-48
DAY 1 (Phase 1)Starts apixaban
2.5mg BID DAY 8
DAY 22(last day of
Phase 3)
DAY 9 (Phase 2)Last dose of apix
2.5mg this amDIALYSIS for 4hr
DAYS 10-14Washout
period
DAY 15 (Phase 3)
Starts apix 5mg bid this am
