09/09/2015

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Update on Oral Anticoagulants – focus on the Novels

Tammy J Bungard, BSP, PharmD

AMS Program Director

Associate Professor of Medicine

Division of Cardiology, University of Alberta

“AHHH, but I was so much older then, I’m much younger than that now.” Bob Dylan

Presenter Disclosure

• I have the Relationships with commercial interests: – Advisory Board/Speakers Bureau – BMS-Pfizer, Bayer, Boehringer Ingelheim

– Funding (Grants/Honoraria) : Pfizer (unrestricted grant for VTE Audit)

– Speaker/Consulting Fees: Bayer, BMS-Pfizer

• Speaking Fees for current program: – I have received no speaker’s fee for this learning activity

Commercial Support Disclosure (for the learning activity)

• This program has received no financial or in-kind support from any commercial or other organization

Objectives

• To identify some sources of information for this evolving area

• To highlight aspects of controversy, reflecting on new data – Valvular vs non-valvular AF – Dosing of NOACs for AF – INR targets with OnX valves (Mechanical Valve) – Guideline Recommendation vs Coverage (private coverage, what

would your gramma be on?)

• To cover “new” data for anticoagulant therapies – Tissue & Mechanical Valve Replacement – Antidote development – Differentiate phases of VTE Care (Initial, Long-term & Extended),

knowing the nuances of dosing

Timing of Health Canada Approval

• Fast pace of information …

Feb 2012 Rivaroxaban

DVT

Apr 2013 Rivaroxaban

PE

June 2014 Dabigatran

VTE

Nov 2014 Apixaban

VTE

↑ ↑ ↑ ↑

↑

Oct 2010 Dabigatran

AF ↑ ↑

Jan 2012 Rivaroxaban

AF

Dec 2012 Apixaban

AF

Thrombosis Canada – Clinical Guides thrombosiscanada.ca

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Thrombosis Canada – Clinical Guides thrombosiscanada.ca

Canadian Cardiovascular Pharmacists Network (CCPN)

• CCPN SPAF tool (Atrial Fibrillation “Pocketcard”) – Paper-based (ccpn.ca – tool bar

on left side)

– Download the app from i-Tunes (ccpn.ca)

• Coming Soon …. Acute Venous Thromboembolism (VTE) Treatment Pocketcard – Paper-based planned at this

time

Rx Files: CLOT Sheets www.rxfiles.ca

2014 Canadian AF Stroke Prevention Guidelines

Can J Cardiol 2014;30:1114-1130.

*suggest a NOAC in preference to warfarin for non-valvular AF †Might require lower dosing

OAC if > 65 years or CHADS2 > 1

What do you mean, Valvular AF?

• Not solely a result of a valve replacement …

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Atrial Fibrillation: Types Temporal Pattern & Stroke Risk Classification

Valvular AF

• AF in the presence of: – mitral stenosis

– Mechanical or bioprosthetic heart valve

– Mitral valve repair

• Risk of Stroke is very high – require anticoagulation therapy

Non-Valvular AF

• AF without features of “Valvular AF”

• Risk of stroke is variable (low to high), requires risk stratification to determine prophylactic agent of choice

• Atrial Fibrillation = Atrial Flutter for Stroke Risk

assessment/determination of antithrombotic therapy

AHA/ACC AF guidelines (2011): “the historical term nonvalvular AF is restricted to cases in which the rhythm disturbance occurs in the absence of rheumatic mitral valve disease

a prosthetic heart valve, or mitral valve repair.”

ACCP (Chest 2008): refer to “vavlular heart disease and AF, including mitral stenosis and prosthetic heart valves.”

ACCP (Chest 2012) – no specific definition provided

AF Exclusions Based on “Valvular” Heart Disease RE-LY, ROCKET AF, ARISTOTLE

Study RE-LY (Dabigatran) NEJM Aug 2009

ROCKET AF (Rivaroxaban) NEJM Sept 2011

ARISTOTLE (Apixaban) NEJM August 2011

Exclusion Critieria

History of heart valve disorder (i.e., prosthetic valve or hemodynamically relevant valve disease)

Hemodynamically significant mitral valve stenosis; prosthetic heart valve (annuloplasty with or without prosthetic ring, commissurotomy and/or valvuloplasty are permitted)

Clinically significant (moderate to severe) mitral stenosis; Prosthetic mechanical valve

RE-LY Supplementary Appendix NEJM 2009;361. DOI: 10.1056/NEJMoa0905561. ROCKET AF Supplementary Appendix NEJM 2011. DOI 10.1056/NEJMoa1009638.

ARISTOTLE: NEJM 2011;365:981-992.

Rivaroxaban – “Valvular” Heart Disease in ROCKET AF

• 2003/14,171 (14.1%) had VHD – MR: 1756 (89.6%)

– AR: 486 (24.8%)

– AS: 215 (11.0%)

– Valve procedures: 106 (5.3%)

• VHD pts older, > comorbidities

• Efficacy of Riva vs Warf is similar with or without VHD

• Bleeding higher with Riva with VHD

EurHearJ July 2014

Riva vs Warf VHD group: SSE: HR 0.83 (0.55-1.27) MB+CRNMB: HR 1.25 (1.05-1.49)

Apixaban – “Valvular” Heart Disease in ARISTOTLE

• 4808/18,197 (26.4%) had VHD – Moderate MR; N=3526 (73.3%) – MS; N=131 (2.7%) – AR; N=887 (18.4%) – AS; N=384 (8.0%) – TR; N=2124 (44.2%) – Valve surgery; N=251 (5.2%)

• VHD pts older, > comorbidities • Excluded significant MS (moderate to severe) • No evidence of a differential effect of apixaban

over warfarin in stroke/systemic embolism reduction or decreased major bleeding

Abstract Data Only; EurHeartJ Circulation 2015;132:624-32.

Dabigatran (Pradaxa™) Rivaroxaban (Xarelto™) Apixaban (Eliquis™)

“Safety and efficacy … have not been studied in patients with prosthetic heart valves or those with hemodynamically significant rheumatic heart disease, especially mitral stenosis, with or without atrial fibrillation.” CI: “patients with prosthetic heart valve(s) requiring anticoagulation due to valvular status itself”

“Safety and efficacy … have not been studied in patients with prosthetic heart valves or those with hemo-dynamically significant rheumatic heart disease, especially mitral stenosis.” “… no data support that XARELTO … provides adequate anticoagulation in patients with prosthetic heart valves, with /without atrial fibrillation. “… not recommended in this setting.”

Safety and efficacy … have not been studied in patients with prosthetic heart valves or those with hemodynamically significant rheumatic heart disease, especially mitral stenosis. “… no data support that ELIQUIS … provides adequate anticoagulation in patients with prosthetic heart valves, with/ without atrial fibrillation. “… not recommended in this setting.

Product Monographs …

Prosthetic Heart Valves …. Tissue and Mechanical or just Mechanical ….

Prosthesis is an artificial device used to replace a missing or defective body part, such as a limb or heart valve. (Dictonary.com)

DAWA (Dabigatran 110BID vs Warfarin after mitral and/or aortic

bioprosthesis replacement and atrial fibrillation Postoperatively)

• Phase II, randomized, open label pilot study (N~100)

• Main Variable: appearance of Intracardiac thrombus (TEE at 3 months)

• “No formal primary or secondary clinical efficacy / safety outcomes – exploratory evaluation of mortality and morbidity”

• Enrolment Aug 2013- Apr 2015 (Brazil)

• Final results Sept 2015

JMIR Res Protoc 2014;3(2):e21

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RIVER trial (Rivaroxaban for Valvular Heart Disease and Atrial Fibrillation)

• Phase 2, randomized, open label, non-inferiority trial • Rivaroxaban 20mg QD (15mg QD if CrCl 30-

49mL/min) vs Warfarin (INR 2.0 – 3.0) • Aged 18-80, bioprosthetic mitral valve with

persistent or paroxysmal AF • Primary Outcome: Major clinical events (out to 12

months) disabling stroke, major bleeding, all-cause death, valve thrombosis and non-CNS systemic embolism

• Start Aug 2015 – Complete Aug 2018 (not yet recruiting)

https://clinicaltrials.gov/ct2/show/NCT02303795?term=rivaroxaban+valvular +heart+disease&rank=1; accessed July 8, 2015. Accessed Sept 8, 2015

Mechanical Valves What’s new, what’s hot & what’s not!

• Dabigatran – REALIGN

• Rivaroxaban – CATHAR

• Apixaban – nothing found

• Warfarin - PROACT Trials

Dabigatran – REALIGN

Comparison of Antithrombotic Treatments After Aortic Valve Replacement - Rivaroxaban: A New Antithrombotic Treatment for

Patients With Mechanical Prosthetic Aortic Heart Valve CATHAR

• Prospective, open label, phase 2 trial (N=30) with historical control group (center’s registry database)

• 18-70 years of age, aortic valve replacement, pre-op LVEF >35% • Rivaroxaban 20mg daily vs Phenprocoumon x 6 months • Primary: To determine if rivaroxaban 20 daily is feasible and

safe for prevention of major complications in patients undergoing a mechanical aortic (bileaflet) heart valve replacement. – Composite outcome of prosthetic thrombus requiring

reoperation/intervention, major bleeding, visceral ischemia, stroke, pulmonary embolism, myocardial infarction or death from any cause 180 days after intervention

• Estimated completion in December 2015 (moved to Jan 2017)

https://www.clinicaltrials.gov/ct2/show/record/ NCT02128841?term=rivaroxaban+pulmonary+embolism&rank=30

Accessed July 9, 2015 (Accessed Sept 8, 2015)

Mechanical Valves ….

On-X valve (?“4th generation”), designed to function with less anticoagulation, or in some cases, antiplatelet alone …

PROACT Trials Prospective Randomized On-X Anticoagulation Clinical Trial

• 3 Cohorts:

*High risk if: chronic atrial fibrillation, left ventricular ejection fraction <30%, enlarged left atrium > 50 mm in diameter, spontaneous echographic contrast in left atrium, vascular pathologic features, neurologic events, hypercoagulability (factor V Leiden mutation, prothrombin mutation, antithrombin III activity, protein C activity, protein S activity, factor VIII activity, and low density lipoprotein), left or right ventricular aneurysm, women receiving estrogen replacement therapy, lack of antiplatelet response to ASA or clopidogrel (urine 11-dehydro-thromboxane B2 for ASA and P2Y12 for clopidogrel)

www.clinicaltrials.gov; Accessed Apr 17, 2015

Risk 3 Months Post-op Randomization Status

Low Risk AVR Warf INR 2-3 + ASA Standard vs ASA + Clopidogrel

Terminated Early - ↑ events in DAPT

High Risk* AVR

Warf INR 2-3 + ASA Standard vs Warf INR 1.5-2.0 + ASA

Interim Results Published

MVR Warf INR 2.5-3.5 + ASA

Standard vs Warf INR 2.0-2.5 + ASA

Ongoing

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PROACT: “High risk” Aortics – Interim Data

• N=375; N=185 Test & N=190 Control

• Follow-up of 3.85 years

• Mean age 55.2 + 12.5 years

• 79% men

• 93% in sinus rhythm

Class / Test AVR – Test

N=185

AVR Control

N=190

Valve Pathology:

Calcific

Bicuspid

121 (65%)

69 (37%)

130 (68%)

72 (38%)

Atrial fibrillation 3 (2%) 11 (6%)

Ejection fraction <30% 9 (5%) 7 (4%)

Abnormal Labs

P2Y12 inhibition

Urine thromboxane

42 (23%)

84 (45%)

52 (27%

69 (36%)

• Weekly INRs with point-of

care device (average interval

between tests was 9 days)

• Within Target:

• 63.6% test group

(mean INR 1.89 + 0.5)

• 69.8% control group

(mean INR 2.5 +0.64)

RR=0.86 (0.41-1.82; P=0.7)

TE: 0.11 v 0.52%/pt year ; P=0.2

Valve thrombosis: 0.23 v 0.26%/pt year; P=0.9

1.6 vs 3.9%/pt year; P=0.007

PROACT – Practice Implications

• 3 months standard care PRIOR to alteration of target

INR (endothelialization of sewing cuff of valve)

• “High-risk AVRs” – not the typical patient…

– Qualified with “hypercoagulability testing” not routinely

done in clinical practice

• Patient self-testing (POC) weekly

• Limitations:

– Await publication of full (vs interim) results

– On-X valve is FDA approved, ?Health Canada

– Non-inferior trial design for composite endpoint (encompassing

all types of bleeding, all types of stroke & thromboembolism) –

lacked power to discern differences in TE risk

Valvular Heart Disease – NOAC use Valvular AF & Valve Replacement

• Valvular Heart Disease – Many types – Valvular AF = mitral stenosis, not studied hence off label use of

NOAC, as per study inclusion criteria / patients recruited – Preliminary (sub-group) data from ROCKET-AF & ARITSTOLE

suggests similar efficacy (rivaroxaban & apixaban) vs warfarin for other forms of “valvular heart disease”

• Studies underway with bioprosthetic (tissue) valves • AVOID entirely with any type of mechanical valve

• PROACT – “High Risk AVRs” – careful with application of INR

target 1.5- 2.0 (plus ASA 81mg daily) to the studied population

Will Stroke Prevention Rates Improve with the NOACs?

• Warfarin use … challenges –

– Prescribing it

– Dosing it (targeting the INR)

Warfarin Use: “The error of omission vs commission” Are we diverging to some of the challenges faced with

Warfarin with the use of NOACs?

Bungard TJ et al. Arch Intern Med 2000.

Underuse of Anticoagulation Therapy (Warfarin) for Stroke Prevention in Atrial Fibrillation

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Supra-therapeutic 71 (18.9%); INR 4.71 + 1.77

Sub-therapeutic 167 (44.5%)

INR 1.49 + 0.29 Therapeutic 137 (36.5%) INR 2.41 + 0.31

Bungard TJ et al. Pharmacotherapy 2000;20:1060-1065.

Warfarin Use: “The error of omission vs commission” Are we diverging to some of the challenges faced with

Warfarin with the use of the NOACs?

• Consecutive pts presenting to UAH ER on warfarin with INR drawn – ER, hence sick, hence anticipate elevated INRs

• N=1085 presented with AF, N=375 (34.6%) prescribed warfarin

• Majority had INRs < 2.0

Will Stroke Prevention Rates Improve with the NOACs?

• Warfarin use … challenges – – Prescribing it – Dosing it (targeting the INR)

• One would postulate the implementation of

NOACs should surpass warfarin?

• Limited, if any, data at this point – usage rates (population AF stroke prevention) – dose selected

NOAC Trials … “Lower” dose Real World Use

Trial RE-LY ROCKET AF ARISTOTLE

N 18,113 14,264 18,201

Lower dose qualifiers

Randomized, no criteria

CrCl 30-49 mL/min >2: >80 years, <60 Kg, Serum creatinine >

133µmol/L

N Warfarin 6,022 (33%) 7,116 (50%) 9,081 (50%)

N Higher dose 6,075 (33%) 5637 (40%) 8692 (48%)

N Lower dose 6,015 (33%) 1474 (10%)* 428 (2%)

Efficacy / Safety of Low dose

Main Trial Results Moderate renal failure subgroup

NA

Real World Data

No Published Data Found Appears more are on the “lower dose” relative to that studied

*Renal sub-analysis efficacy and safety profile was consistent with overall trial results … “Dose adjustment in ROCKET-AF yielded results consistent with the overall trial in comparison with dose-adjusted warfarin” Fox et al. Eur Heart J, doi:10.1093/eurheartj/ehr342

How can guidelines and drug coverage be so very divergent?

• Canadian practice guidelines for non-valvular atrial fibrillation (NVAF) recommend “most patients receive a novel oral anticoagulant (NOAC) in preference to warfarin to prevent stroke”

• Senior population, fixed income / pension and may not have insurance that covers NOACs

Coverage for NOACs

https://www.ab.bluecross.ca/dbl/pdfs/60019.pdf

Current Drug Cost Comparisons … Agent 1 Month

Supply 3 Month Supply

Alberta Blue Cross Coverage

ASA 81mg daily $3.59 $6.77 Covered

Warfarin 5 mg daily $14.46 $18.77 Covered

Enox 60 mg SQ Q12H $288.25 x 10 days Covered

Fragmin 12,500 SQ Q24H $292.45 x 10 days Covered

Dabigatran 110 mg BID $116.46* $324.78 Special Authorization AF*

(May 1, 2012) Dabigatran 150 mg BID $116.46* $324.78

Rivaroxaban 15mg BID $141.72 x 3 weeks Special Authorization AF*

(Oct 1, 2012) Rivaroxaban 15 mg QD $104.75† $289.63

Rivaroxaban 20 mg QD $104.75† $289.63

Apixaban 2.5mg BID $116.46 $324.78 Special Authorization AF*

(Mar 20, 2013) Apixaban 5mg BID $116.46 $324.78

Pharmacy in close proximity to UAH, October 2014

*Special Authorization ONLY for AF indication: Inadequate anticoagulation following reasonable trial with warfarin OR Warfarin is CI / cannot monitor INRs

Government of Alberta, Updates to Drug Benefit List

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Patient Flow

AMS patients screened (n=677)

Venous thromboembolism* (n=285)

Valvular AF (n=464)

Other† (n=74)

Patients with NVAF (n=272)

*Venous thromboembolism included pulmonary embolisms (n=158) and deep vein thrombosis n=127

†Patients coded as ‘other’ include: arterial clots (n = 17), TIA/stoke (n = 9), VTE (n = 17), pulmonary hypertension (n = 4), sinus thrombosis (n = 3), congenital (n = 6), left ventricle dysfunction and LV aneurysm (n = 15) and database entry error (n = 3)

Dhillon, McMurtry & Bungard, Accepted Can J Cardiol Feb 2015.

The Disconnect between Novel Oral Anticoagulant Eligibility & Provincial Drug Coverage: An Albertan Anticoagulation Clinic Audit

Dabigatran Rivaroxaban Apixaban

Eligible for NVAF 240/269 (89.2%) 247/269 (91.8%) 258/269 (95.9%)

Reason for NVAF Ineligibility*

Low Creatinine Clearance

Drug Interaction

Hypersensitivity/Allergy

Significant Liver Disease

22/269 22/269 11/269

6/269 0/269 0/269

2/269 0/269 0/269

N/A 0/269 2/269

Blister-packaging 35/239 (14.5%) 35/247 (14.1%) 37/258 (14.3%)

Eligible for Coverage 95/242 (39.3%) 98/249 (39.4%) 106/259 (40.9%)

Reason for Coverage Eligibility*

CHADS2≥1

TTR<65% & minimum 2 month warfarin trial Warfarin Side Effect

Home Collections

218/239 224/247 234/258

63/218 66/224 72/234

0/218 0/224 0/234

42/218 44/224 48/234

NVAF: nonvalvular AF; TTR: time in therapeutic range *Values are not mutually exclusive

Dhillon, McMurtry & Bungard. Can J Cardiol August 2015.

~15% were actually transitioned

The Disconnect between NOAC Eligibility & Provincial Drug Coverage: An Albertan Anticoagulation Clinic Audit

“I don’t want to take a NOAC because there is no antidote.” Anonymous AMS Patient

Commonly heard by AMS team from patients based on education provided by prescribers

Trial ROCKET AF N=14,264

RE-LY N=18,113

ARISTOTLE N=18,201

Dosing Riva 20 QD

Warf Dabi 150 BID

Dabi 110 BID

Warf Apix 5 BID Warf

Stroke/SE 2.1%/y 2.4%/y 1.11%/y 1.54%/y 1.71%/y 1.27%/y 1.60%/y

NNT=167 NNT=303

Major Bleeding

3.6%/y 3.4%/y 3.32%/y 2.87%/y NNT=143

3.57%/y 2.13%/y NNT=104

3.09%/y

ICH 0.5%/y 0.7%/y 0.30%/y 0.23%/y 0.74%/y 0.33%/y 0.80%/y

NNT= 500

NNT=227 NNT=196 NNT=213

MI-original MI-update

0.9%/y 1.1%/y 0.74%/y 0.81%/y

0.72%/y 0.82%/y

0.53%/y 0.64%/y

0.53%/y 0.61%/y

Death

4.5%/y 4.9%/y 3.64%/y 3.75%/y 4.13%/y 3.52%/y NNT=238

3.94%/y

Recent Landmark Atrial Fibrillation Trials: Warfarin as standard care/comparison

Blue identifies statistical significance (superiority)

NEJM 2011;365(10):883-891 NEJM 2009;361:1129-51; NEJM 2011;365:981-92.

Event

Dabi 110 mg

(N=6015)

%/year

Dabi 150 mg

(N=6076)

%/year

Warfarin (N=6022)

%/year

Dabi 110 vs. Warfarin

RR (95% CI); P Value

Dabi 150 vs. Warfarin;

RR (95% CI); P Value

Major Bleeding

2.71

(322)

3.11

(375)

3.3

(397)

0.80 (0.69-0.93) p=0.003

0.93 (0.81-1.07) p=0.31

Life Threatening

1.22

(145)

1.45

(175)

1.80

(212)

0.68 (0.55-0.83) p<0.001

0.81 (0.66-0.99) p=0.04

Gastro- intestinal

1.12

(133)

1.51

(182)

1.02

(120)

1.10 (0.86-1.41) p=0.43

1.50 (1.19-1.89) p<0.001

Any bleeding

14.6

(1740)

16.4

(1977)

18.2

(2142)

0.78 (0.74-0.83) p<0.001

0.91 (0.86-0.97) p=0.002

Intra- cranial bleeding

0.23

(27)

0.30

(36)

0.74

(87)

0.31 (0.20-0.47) p<0.001

0.40 (0.27-0.60) p<0.001

RE-LY Safety Results – ICH Mortality

Connolly et al. N Engl J Med 2009 *DOI: 10.1161/STROKEAHA.112.0650614 P values are for superiority

Stroke 2012–ICH During RELY* Independent Predictors ICH:

ICH Mortality

41% (11/27)

35%

(13/37)

36%

(32/90)

Warfarin Assignment RR 2.9; P<0.001

ASA use RR 1.6; P=0.01

Age RR 1.1; P<0.001

Prior Stroke / TIA RR 1.8; P=0.001

Real World Reports of Bleeding

Southworth MR et al. NEJM March 14, 2013.

Unusually high rate of reported dabigatran-bleeding incidents, relative to warfarin

FDA Adverse Event Reporting System (FAERs)

Suggests bleeding with dabigatran is not higher

High rates of AE reporting

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THE GOLDEN QUESTION(S)

But what about an Antidote? Does having a reversal agent ultimately improve outcomes?

Are we chasing a laboratory value?

Does bleeding stop / size of hematoma lessen?

REVERSAL – “The Tincture of Time” • Limited data available (human bleeding) for novels

• “normalization” of laboratory parameters vs cessation of bleeding

• Does a reversal agent improve outcomes?

Vitamin K Prothrombin Complex Concentrate (Octaplex™)

Activated Prothrombin Complex Concentrate (FEIBA)

Prospective, multicentre registry with anticoagulant (warfarin) associated ICH receiving PCC (median time of onset to treatment time was 380 min, median dose 1000IU)

In hospital mortality rate of 42.3%, lower than 62% and 67% reported in studies not using PCC & closer to non aaICH rates

Significant hematoma expansion in 45.5%, 3 thrombotic complications

(Stroke 2012;43:1812-1817)

“Reversing” Warfarin & NOACS

Coagulation Testing

Procoagulant Agent(s)

Antidote(s) Other Options

Warfarin* INR PCC Vitamin K Tranexamic Acid 10mg/kg IV or 25mg/kg PO

Dabigatran† TT (aPTT) aPCC = FEIBA Idarucizumab

Rivaroxaban‡ Anti-Xa level (PT)

PCC or aFVIIa, if not then aPCC

Andexanet Alpha

Apixaban‡ Anti-Xa level

*PCC dose 25-50U/kg + administer with Vitamin K

†TT turn around time 1 hour (STAT); TT calibrated with [dabi] suggests negligible

amount with TT < 30ng/mL (reduced this to <20ng/mL for error margin); FEIBA

dose 25-50-100U/kg depending on level of bleeding and risk; PCC 25-50U/kg

‡Heparin Anti-Xa level qualitative only (<0.1U/mL suggests no residual effect); PCC

dose 25-50U/kg or aFVIIa 40-90mg/kg or FEIBA 25-50U/kg

Impact on Coagulation Factors vs Reversal of Bleeding/Minimizing Hematoma Expansion

Direct Oral Anticoagulant Agents, Practice Support Document – Guideline; April 23, 2015.

Antidotes: Current Status Antidote Idarucizumab Andexanet Alpha

Drug Reversed Dabigatran Rivaroxaban, Apixaban (& injectable indirect Xa inhibitors)

Engineered Antibody fragment (Frament antigen binding =Fab)

Human recombinant fXa – Catalytically inactive

Mechanism

Binds to dabigatran (with ~350 stronger affinity than for thrombin) – competitive displacement of dabigatran from thrombin

High affinity binding to direct fXa inhibitors and heparin-antithrombin III complexes

Half-life 4.5-9 hours “short”

Administration IV (bolus or rapid infusion) – 2 consecutive doses of 2.5g (50mL vial)

IV (bolus +/- infusion): Riva 800mg IV bolus, 8mg/min infusion x 2hours; Apixa 400mg IV bolus, 4mg/min x 2 hours

Storage Refrigeration Refrigeration

Data Available Phase 3 Interim Cohort Data* Phase 3 studies ongoing

Status Submitted for accelerated approval in Canada

FDA Orphan drug status

Rapid effect (minutes)

*http://clinicaltrials.gov/ct2/show/NCT01688830?term=dabigatran&rank=19 Schiele F et al. Blood 2013;121(18):3554-35562. CADTH June 2015

Aripazine – Synthetic molecule Broad reversal activity Single IV bolus No refrigeration Phase 2 data underway

Reversal Effects of Idarucizumab on Active Dabigatran (RE-VERSE AD)

• Interim Data, for the first 90 patients recruited (plan to recruit 300) • Prospective Cohorts: A) serious bleeding & B) require surgery/invasive

procedure in < 8 hours • Idarucizumab 5g (2 infusions of 2.5mg separated by no longer than

15mins) • Primary Endpoint: maximum percentage reversal of anticoagulant effect

of dabigatran within 4 hours of idarucizumab administration

N=51 N=39

NEJM, June 22, 2015.

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Andexanet Alpha: Clinical Trials Healthy Volunteers Bleeding

A Phase 3 Randomized, Double-Blind, Placebo-controlled Study in Older Subjects to Assess Safety and the Reversal of Apixaban* Anticoagulation With Intravenously Administered Andexanet Alfa

A Phase 3 cohort study to evaluate the hemostatic efficacy of Andexanet alfa in patients receiving a factor Xa inhibitor who are experiencing an acute major bleed. The safety of Andexanet will also be studied

Andexanet Alfa vs Placebo Open label Andexanet alfa

N=54 “Reasonably healthy men and women aged 50 to 75”

N=270

Primary Endpoint: Reversal of Apixaban* anticoagulation effect as measured by anti-factor Xa activity

Primary Endpoint: Proportion of patients with excellent or good hemostasis

Completed, not yet published Jan 2015 – Nov 2022

*same protocol for Rivaroxaban study, too (Aug 2014)

https://clinicaltrials.gov/ct2/results?term=andexanet+alpha&Search=Search

VTE: Phases of Care & Trials

Vitamin K antagonist (VKA) or other agent†

Time since starting treatment

Ris

k o

f R

ecu

rren

t V

TE

Treatment

Secondary prevention

Initial1

(0 to ~7 days) Long-term

(~7 days to ~3 months) Extended

(~3 months to indefinite)

Start of treatment and secondary prevention2 Completion of treatment

Parenteral*

Kearon C et al. Chest 2012;141:e419S-e494S

ACUTE LONG TERM EXTENDED

(Parenterals) Dabigatran (RE-COVER) Dabigatran (RE-COVER II) Edoxaban (HOKUSAI)

Dabigatran (RE-SONATE) Dabigatran (RE-MEDY)

Rivaroxaban (EINSTEIN-DVT)

Rivaroxaban (EINSTEIN-PE)

Apixaban (AMPLIFY)

Rivaroxaban (EINSTEIN-Extension) Apixaban (AMPLIFY-Extension)

Acute VTE Care

• All 3 NOACs have Notice of Compliance

• Only Rivaroxaban has coverage for up to 6 months post acute VTE

• Application of data as per design in trials: – Rivaroxaban 15mgBID x 3 weeks, then Rivaroxaban 20

mg daily

– Apixaban 10mg BID x 1 week, then Apixaban 5mg BID

– After 5-10 days of an injectable anticoagulant, Dabigatran 150mg BID

• Implementation in the real world

Summary

• Rapidly changing field – need for current resources / tools

– New data evolving

• Importance of application to the right patient populations (at the right dose)

– Valvular vs Non-valvular AF

– OnX Valve INR target (PROACT trial)

– Barriers in daily practice (drug coverage, fears)