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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