09/09/2015 1 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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09/09/2015
1
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),
• 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
“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
09/09/2015
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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)
*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
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*
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
09/09/2015
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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
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
09/09/2015
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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
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)