Pharmacy Practice Webinar Series - DOAC Semchuk Fall 2017

01/11/2017

1

DOACS: What’s New and Important and What’s Old and Still Important!

WelcomeWe will begin shortly.

Wm. Semchuk, MSc,Pharm.D,FCSHP

Manager, Pharmacy Practice

Regina Qu’Appelle Health Region

Assistant Clinical Professor,

College of Pharmacy and Nutrition

College of Medicine

University of Saskatchewan

Member – Thrombosis Canada

01/11/2017

2

DOACS: What’s New and Important and What’s Old and

Still Important!

4

Session Objectives

• After participating in this session, participants will be better able to:

• Describe current and emerging indications for DOACs

• Discuss evidence pertaining to DOAC use in AF and VTE

• Describe current challenges in DOAC use

• Discuss opportunities for pharmacist involvement to ensure best outcomes with DOAC use

5

Conflict of interest/disclosure:

Company Involvement

Bayer Advisory Board, Honoraria

Sanofi Aventis Advisory Board, Honoraria and Research Grants

BMS Advisory Board, Honoraria and Research Grant

Pfizer Advisory Board, Honoraria and Research Grant

Servier Advisory Board, Honoraria

Astra Zeneca Advisory Board, Honoraria

Boehringer Ingelheim Advisory Board, Honoraria and Research Grants

6

01/11/2017

3

Parenteral

Oral

1910 201019601950194019301920 1970 1980 1990 2000

Heparin

Warfarin

LMWH’s

Direct Thrombin

Inhibitors

Indirect FXaInhibitors

Direct Thrombin Inhibitors Direct FXaInhibitors

Adapted from: Weitz J, Hirsh J. Chest. 2001;119:95S; Alban. Eur J Clin Invest 2005; Link. Circulation 1959; Maraganore et al. Biochemistry 1990

Timeline of Anticoagulation Options

2008 201120102009 20132012

2014

Health Canada Approvals of DOACs

DabigatranVTE prophylaxis following THR/TKRCDR Approved

RivaroxabanVTE prophylaxis following THR/TKRCDR Approved

ApixabanVTE prophylaxis following THR/TKRCDR Approved

DabigatranStroke prevention in AFCDR Approved

bApixabanStroke prevention in AFCDR Approved

RivaroxabanTreatment of DVTCDR Approved

RivaroxabanStroke prevention in AFCDR Approved

ApixabanTreatment of DVTCDR Approved

DabigatranTreatment of DVT

8VTE, venous thromboembolism; THR, total hip replacement; TKR, total knee replacement; CDR, common drug review; AF, atrial fibrillation, DVT, deep vein thrombosis

20152016 2017 REDUAL

COMPASSIdarucizamab

REVERSE‐AD

EINSTEINChoice

PIONEER

b

pp

EdoxabanStroke prevention in AF Treatment of DVT

CDR Approved

Health Canada Drug Product Database http://www.hc-sc.gc.ca/dhp-mps/prodpharma/databasdon/index-eng.php

2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028

Maybe not so new? Patent Expirations ‐ Canada

Pradaxa

Pradaxa

Pradaxa

Xarelto

Xarelto

Eliquis

Eliquis

Lixiana Lixian

a

Xarelto

x2

01/11/2017

4

Trends in Oral Anticoagulant Utilization – Coverage is Important in Uptake

10

Share of O

ral Anticoagulants Total

Prescription

apixabanrivaroxabandabigatran etexilatewarfarin

Weitz J, Semchuk W, Turpie G. Clin Ther 2015;37(11):2506‐2514.

Major Indications for Oral Anticoagulation

• Atrial Fibrillation

• Treatment of VTE and prevention of recurrent events

• Prevention of thrombosis in patients with valvular heart disease

• Prevention of thrombosis post orthopedic procedures

Atrial Fibrillation (AF) and Stroke

1. Heart and Stroke Foundation of Canada web site2. AFib Invest Group Arch Intern Med 1994 3. Singer DE et al. Chest 2008

4. Sanna T et al NEJM 2014;370:24785. Sally Lee et al. BMJ Open 2011;1:e0002696. 2014 CCS AF Guidelines. Can J Cardiol. 2014; 30: 113‐1130.

AFAGE

STROKE

• AF affects 1‐2% of Canadians and prevalence increases with age1

• About 6% of Canadians over age 65 years live with AF

• AF is an independent predictor of stroke (RR = 5)2

• AF accounts for 15% ‐ 20% of all strokes3

• Individuals with paroxysmal, persistent or permanent AF are all at increased risk of stroke

• AF is the leading preventable cause of stroke• AF is not diagnosed un l a er CVA in ⅓ of AF

strokes4

• Subclinical (asymptomatic) AF accounts for about 10% of cryptogenic strokes

• AF related embolic strokes are often severe: 25% mortality, 60% disabled5

• AF patients with an absolute risk of embolic stroke of > 1.5% per year require long‐term anticoagulation –represents over 95% of Canadians with AF6

01/11/2017

5

Warfarin (N=2900)

Relative RR vs. placebo 64% (CI 49–74%)Absolute RR primary 2.7%/yrAbsolute RR secondary 8.4%/yrNNT primary prevention 37NNT secondary prevention 12

100% 50% 0 -50% -100%Favours Warfarin Favours Placebo

or Control

Adjusted-dose warfarin compared with placebo or control

AFASAK I, 1989; 1990

SPAF I, 1991

BAATAF, 1990

CAFA, 1991

SPINAF, 1992

EAFT, 1993

All trials (n=6)

A Study, Year Relative Risk Reduction(95% CI)

Antiplatelet (ASA) (N=4876)

Relative RR vs. placebo 19% (CI -1–35%)Absolute RR primary 0.8%/yrAbsolute RR secondary 2.5%/yrNNT primary prevention 125NNT secondary prevention 40

100% 50% 0 -50% -100%Favours Antiplatelet Favours Placebo

or Control

Antiplatelet agents compared with placebo or control

B Study, Year Relative Risk Reduction(95% CI)

AFASAK I, 1989; 1990SPAF I, 1991EAFT, 1993ESPS II, 1997LASAF, 1997

DailyAlternate day

UK-TIA, 1999300 mg daily1200 mg daily

JAST, 2006

Aspirin trials (n=7)

SAFT, 2003ESPS II, 1997

DipyridamoleCombination

All antiplatelet trials (n=8)

Hart et al. Ann Intern Med 2007

Warfarin vs Antiplatelet (N=12,963)

Relative RR 37% (CI 23–48%)Absolute RR primary 0.9%/yrNNT primary prevention 111

Heterogeneity for secondary prevention trials precluded meta-analytic estimates.

100% 50% 0 -50% -100%Favours Warfarin Favours Antiplatelet

Adjusted-dose warfarin compared with antiplatelet agents

AFASAK I, 1989; 1990

C Study, Year Relative Risk Reduction(95% CI)

AFASAK II, 1998Chinese ATAFS, 2006EAFT, 1993PATAF, 1999SPAF II, 1994

Age ≤75 yAge >75 y

SIFA, 1997

Aspirin trials (n=8)*

ACTIVE-W, 2006NASPEAF, 2004

All antiplatelet trials (n=11)

Relative Effects of Antithrombotic Therapies on All Stroke From Randomised Trials in AF

13

Trials supports DOAC Efficacy vs Warfarin

14

Ruff CT, et al. The Lancet, Published online Dec 4, 2013 http://dx.doi.org/10.1016/S0140-6736(13)62343-0*dabigatran, rivaroxaban, apixaban, edoxaban (current not available in Canada)

Meta‐analyses – Stroke or Systemic Embolic Events

Stroke or systemic embolic events 19% 0.81 [0.73‐0.91, p<0.0001]

. . . DOAC Benefits on Mortality and ICH

15Ruff CT, et al. The Lancet, Published online Dec 4, 2013 http://dx.doi.org/10.1016/S0140-6736(13)62343-0*dabigatran, rivaroxaban, apixaban, edoxaban (current not available in Canada)

Meta‐analyses – Secondary Efficacy and Safety Outcomes

All‐cause Mortality 10% 0.90[0.85‐0.95, p=0.0003]

Intracranial Hemorrhage (ICH) 52% 0.48 [0.39‐0.50, p<0.0001]

01/11/2017

6

. . . Lack of difference in Major Bleeding

16Ruff CT, et al. The Lancet, Published online Dec 4, 2013 http://dx.doi.org/10.1016/S0140-6736(13)62343-0*dabigatran, rivaroxaban, apixaban, edoxaban (current not available in Canada)

Meta‐analyses – Major Bleeding

Major bleeding 0.86[0.73‐1.00, p=0.0]

Risks and Benefits of NOACs Compared with Warfarin (NNT/NNH)

Clinical Outcome Apixaban (5mg bid), HR, NNT per 2 years

Dabigatran (150 mg bid), RR, NNT or NNH per 2 years

Edoxaban (60 mg daily) HR,NNT or NNH per 3 years

Rivaroxaban (20mg daily), HR or RR, NNT or NNH per 3 years

Stroke or SE Superiority vs WHR = 0.79 (0.66‐0.95)

NNT=168

Superiority vs WRR = 0.66 (0.53‐ 0.82)

NNT=91

Non‐inferiority vs WHR =0.79 (0.63‐0.99),

NNT=141*

Non‐inferiority vs W

HR = 0.79 (0.65 – 0.95), NNT = 134*

Intracranial bleed Superiority vs WHR = 0.51 (0.35 to 0.75)

NNT=238

Superiority vs WRR=0.26 (0.14‐0.49),

NNT=182

Superiority vs WHR=0.54 (0.38 – 0.77),

NNT = 172

Superiority vs WHR = 0.67 (0.47 – 0.93),

NNT=247

Major bleed Superiority vs WHR 0.69 (0.60‐0.80)

NNT = 79

RR = 0.93 (0.81 – 1.07),

NSSuperiority vs WHR = 0.80 (0.71 – 0.91),

NNT 66

HR = 1.04 (0.90 – 1.20),

NS

GI bleed HR =0.89 (0.70‐1.15),

NSInferior vs WRR = 1.50 (1.19 – 1.89),

NNH = 100

Inferior vs WHR = 1.23 (1.02 – 1.50),

NNH 167

Inferior vs WRR = 1.45,

NNH 101

Any cause of death Superiority vs WHR =0.89 (0.80‐0.99),

NNT=132

RR = 0.88 (0.77 – 1.00),

NSHR = 0.92 (0.83 – 1.01),

NSHR = 0.85 (0.70‐1.02),

NS

1. Hijazi Z, et.al. Circulation 2014;129(9):961‐70.2. Fox KA, et.al. Eur Heart J 2011;32:2387‐94.3. Hohnloser SH, et al. Eur Heart J 2012; 22:2821‐30. 4. Bohula EA, et.al. Circulation 2016;134:24‐36.

* Indicates on treatment analysis used to calculate NNT as superiority was not demonstrated in ITT analysis

1. Hijazi Z, et.al. Circulation 2014;129(9):961‐70.

2. Fox KA, et.al. Eur Heart J 2011;32:2387‐94.

3. Hohnloser SH, et al. Eur Heart J 2012; 22:2821‐30.

4. Bohula EA, et.al. Circulation 2016;134:24‐36.

Age and Ageing 2015: 0:1-7 doi: 10.1093/ageing/afv156

Apixaban vs ASA: Stroke prevention above and below 75 years of age in AVERROES

P-value for interaction = 0.04Cumulative hazard rates of stroke in ASA and apixaban treatment groups, in patients <75 years or ≥ 75 years old.

0 3 6 9 12 15 18

0.00

0.01

0.02

0.03

0.04

0.05

0.06

0.07

0.08

Months

Cumulative hazard

ASA

Apixaban

No. at risk

ASA

Apixaban

1799

1901

1766

1869

1643

1745

1384

1455

1009

1037

675

722

402

419

0 3 6 9 12 15 18

0.00

0.01

0.02

0.03

0.04

0.05

0.06

0.07

Months

Cumulative hazard

ASA

Apixaban

No. at risk

ASA

Apixaban

992

906

951

887

885

820730651

536

479

375

327

229

196

0.08

Age <75 yearsHR with apixaban, 0.68

(95% Cl, 0.42–1.08)

Age ≥75 yearsHR with apixaban, 0.33

(95% Cl, 0.19–0.54)


01/11/2017

7


Apixaban vs ASA: Bleeding above & below 75 years of age in AVERROES

P-value not availableCumulative hazard rates of major bleeding in ASA and apixaban treatment groups, in patients <75 years or ≥ 75 years old.

0 3 6 9 12 15 18

0.00

0.01

0.02

0.03

0.04

0.05

0.06

0.07

0.08

Months

Cumulative hazard

Apixaban

ASA

No. at risk

ASA

Apixaban

1799

1901

1776

1872

1654

174813971455

1019

1040

682

724

407

424

0 3 6 9 12 15 18

0.00

0.01

0.02

0.03

0.04

0.05

0.06

0.07

Months

Cumulative hazard

Apixaban

ASA

No. at risk

ASA

Apixaban

992

906

960

885

896

816

740

645

548

474

382

321

233

195

0.08

Age <75 yearsHR with apixaban, 1.14

(95% Cl, 0.58–2.30)

Age ≥75 yearsHR with apixaban, 1.21

(95% Cl, 0.69–2.12)


Opportunities and Challenges in AF

• Continue to ensure that patients with AF are identified and treated to minimize stroke risk

• Frail populations:• Elderly

• Renal function : Need to ensure that patients are on the right dose• CCS guidelines suggest reduced dose for patients with CrCl < 50 mL/min – however remember that apixaban requires 2 out 3 criteria based on ABC rule

• Periodic renal function assessment for patients on AF

• Mitigate bleeding risk

• Adherence is important!

• Periprocedural management• Thrombosis Canada Guidelines

• ASRA guidelines

20

Epidemiology of VTE: Deep Vein Thrombosis and Pulmonary Embolism

Deep Vein Thrombosis

45,000 Canadians are affected by DVT each year

• 1/3 will suffer from post‐thrombotic syndrome*

• 1/3 will have a recurrent event within 10 years

• 1/3 of untreated DVT will result in potentially fatal pulmonary embolism

Pulmonary Emblism

Although Canadian data is lacking, est. 15,000 Canadians present with PE in the emergency department each year

Mortality rate for undiagnosed and untreated PE est. 5‐30%

PE causes more deaths annually in North America than

• breast cancer

• AIDS

• highway fatalities

01/11/2017

8

22

The Risk of Recurrent VTE

• Overall incidence of recurrent VTE at 6 months is 7%, despite anticoagulant therapy

• After an initial DVT, ~80% of the recurrences are DVTs2

• After an initial PE, ~60% of the recurrences are PEs2

1. Line B. Semin Nucl Med. 2001;31:90–101 2. Kearon C. Circulation 2003;107:I22–I30

Events occurring subsequent to an acute episode are termed recurrent VTE, and their prevention is termed secondary

prevention

Chance of recurrent VTE in first 3 months

47%If proximal DVT inadequately treated1

<2%If adequate anticoagulant response is achieved1 (2-4% in

subsequent 3 months)

Therapeutic Options for VTE

“Bridging” (5-10 d) to provide immediate ACLMWH SC or UFH IV or SCor fondaparinux SC

Warfarin INR 2-3, oral

Warfarin

Special cases - UFH

LMWH LMWH monotherapy, SC

UFH, SC - if CrCl <30 mL/min, increased risk for bleeding, if patient might need rapid reversibility, or thrombolytic therapy being considered

DOAC

Apixaban 10 mg BID for 7 days, then 5 mg BID

LMWH for 5-10 days, then dabigatran 150 mg bid or edoxaban 60 mg qd

Rivaroxaban 15 mg BID for 21 days, then 20 mg OD

Summary of Recent Trial Results in Acute VTE Treatment

• 1. Agnelli G et al. N Engl J Med 2013; 369: 799‐808. / 2. The EINSTEIN Investigators. New Engl J Med 2010; 363: 2499‐510 / 3. The EINSTEIN‐PE Investigators. New Engl J Med 2012; 366: 1287‐97. / 4. Schulman S et al. N Engl J Med. 2009;361:2342–2352. / 5. Schulman S et al. Blood (ASH Annual Meeting Abstracts) 2011;118: Abstract 205.

RECURRENT VTE + VTE DEATH

MAJOR BLEEDINGMAJOR + CRNM BLEEDING

Trial Study Drug Comparator NOAC vs Comparator (%), P‐value

AMPLIFY1Apixa 10 mg BID for 7d, then 5 mg BID

Enoxa/WarfarinNon‐inferiority

2.3 vs 2.7P<0.001 (NI)

SuperiorityRRR 69%

0.6 vs 1.8 P<0.001

SuperiorityRRR 56%

4.3 vs 9.7 P<0.001

EINSTEIN‐ DVT2Riva 15 mg BID for 21d, then 20 mg QD

Enoxa/VKANon‐inferiority

2.1 vs 3.0 P<0.001 (NI)

Not signif.0.8 vs 1.2P=0.21


EINSTEIN‐PE3Riva 15 mg BID for 21d, then 20 mg QD

Enoxa/VKANon‐inferiority

2.1 vs 1.8P=0.003 (NI)

SuperiorityRRR 51%1.1 vs 2.2P=0.003

Not signif.10.3 vs 11.4

P=0.23

RE‐COVER4 LMWH or UFH/Dabi 150 mg BID

LMWH or UFH/Warfarin

Non‐inferiority2.4 vs 2.1

P<0.001 (NI)


SuperiorityRRR 37%5.6 vs 8.8P=0.002

RE‐COVER II5,6LMWH or UFH/Dabi 150 mg BID



P<0.0001 (NI)

Not signif.1.2 vs 1.7

NR*Not reported

HOKUSAI‐VTE7LMWH or UFH/Edoxa 60 mg QD (30 mg QD in selected pts)



(1.6 vs 1.9 on‐Tx)P<0.001 (NI)**

Not signif.1.4 vs 1.6 P=0.35

SuperiorityRRR 19%

8.5 vs 10.3 P=0.004

24

01/11/2017

9

Treat VTE for Three Months and Reassess

Isolated distal DVT

Reversible provoking factor

Stop at 3 MonthsIndefinite therapy or until cancer

inactiveStop at 3 Months

Unprovoked proximal DVT or PE

High Bleeding RiskOR

Prefers to stop even if D‐dimer was positive1

Stop at 3 Months

Stay off therapy(Stop at 3 Months)

Cancer

Others

Stop and measureD‐dimer after

1 month

Not High Bleeding Risk

AND

Prefers to stay

on even if D‐dimer

was negative2

Indefinite therapy Indefinite therapy

Second VTE

Negative D‐dimerRestart therapy

(Indefinite therapy)

Positive D‐dimer

25

How Can We Prevent Recurrent VTE?

1. Goldhabber SZ. Circulation 2004;110:IV‐20‐IV‐24; 2. Kakkos SK. Eur J Vasc Endo Surgery 2014;48(5):565‐75.

9-12%Approx. 0%

During anticoagulation After anticoagulation is stopped

Rate of recurrence at 3 years1

Extension trials ‐ NOAC vs placebo83% relative risk reduction in recurrent VTE

Similar rates of major bleedingStatistically significant net clinical benefit favoring NOACs226

NOAC Trials for Extended VTE Treatment ≥ 6 months

1. Agnelli G et al. N Engl J Med 2013; 368: 699-708 2. The EINSTEIN Investigators. N Engl J Med. 2010;363:2499-25103. Schulman S et al. N Engl J Med. 2013; 368:709-718

Apixaban1 Dabigatran3 Rivaroxaban2Einstein Extension

RivaroxabanEinstein Choice4

Comparator and size Placebo, 2482 Placebo, 1353 Placebo, 1196 ASA, 3396

Duration of treatment 12 months 6 months 6 or 12 months 12 months

Dosing BID BID QD QD

Dose/s of NOAC studied/approved 2.5mg & 5mg150mg or 110mg*

20mg 10mg and 20mg

Superior efficacy (recurrent or fatal VTE) vs comparator

Yes Yes Yes Yes

Major bleeding vs comparator NS NS NS NS

Major or clinically-relevant non-major bleeding vs comparator

NS NS

Significant increase p<0.05To date there are no head-to-head trials between dabigatran, apixaban and rivaroxaban, therefore comparative efficacy and safety have not been established

NS = no significant difference

*not studied1. Agnelli G et al. N Engl J Med 2013; 368: 699-708 2. The EINSTEIN Investigators. N Engl J Med. 2010;363:2499-25103. Schulman S et al. N Engl J Med. 2013; 368:709-7184. Weitz J et al. N Engl J Med 2017;376(13):1211

01/11/2017

10

Co‐morbidity considerations in Atrial Fibrillation

Pfizer Canada Inc./BMS Canada. Eliquis (apixaban) Product Monograph, June 16, 2016.Boehringer Ingelheim Canada Ltd. Pradaxa (dagbatran) Product Monograph. August 11, 2016.Bayer Inc. Xarelto (rivaroxaban) Product Monograph. July 20, 2015.

Cairns Which OAC for which AF Patient Can J Cardiol 2013; :1‐8

2

Co‐Morbidity Expert Recommendation

Mechanical (metal) heart valve /Rheumatic mitral stenosis

warfarin absolutely indicated

Chronic kidney disease (CrCl<30mL/min) warfarin (NOACs contraindicated)

Chronic kidney disease (CrCl 30‐49mL/min) apixaban and rivaroxaban 15 mg preferred

Age ≥ 80 apixaban, rivaroxaban or dabigatran110 mg (recommended dose adjustment as per as per monograph)

Stable coronary artery disease ASA (Low Risk – CHADS2= 0 and age < 65 yrs) apixaban or rivaroxaban (if CHADS2 ≥ 1)

Recent ACS ASA + ticagrelor* x 12 mos (if age < 65 and CHADS2= 0)clopidogrel@ + NOAC x 12 mos (age ≥ 65 or CHADS2≥ 1)

Previous gastrointestinal bleeding apixaban preferred (as per results of 3 pivotal trials)

Dyspepsia Consider avoiding dabigatran

* or prasugrel if PCI performed@ and ASA x 3‐6 months if PCI performed

Granger et al., NEJM 2011; 365: 981‐992Connolly et al., NEJM 2009; 361: 1139‐1151Patel et al., NEJM 2011; 365: 883‐891Macle L et al. 2016 Focused Update of the CCS Management of AF. CJC 32;1170

Risk of Bleeding with Combination Antithrombotic Therapy

ASA alone

Clopidogrel Alone

Warfarin Alone

ASA + Clopidogrel

ASA + VKA

Clopidogrel + VKA

ASA + Clopidogrel + VKA

0.1 0.3 2.0 3.0 10.0

Hazard Ratio (95% CI)

1.00 Reference

HR 95% CI

1.33 1.11-1.59

1.23 0.94-1.61

1.47 1.28-1.69

1.84 1.51-2.23

3.52 2.42-5.11

4.05 3.08-5.33

Lancet 2009; 374: 1967-74.

P value not reported

CI = Confidence Interval

New data/new uses:

• A number of areas are actively being explored, data is being presented and as clinicians we may be challenged as these indications do not yet have indications and in some instances the dosage forms are not yet available

• ROUGH timeline is about a year to indication from submission if all goes well and then about another year from indication to CDR and then PCPA….

• PCI in the face of AF (PIONEER Trial, REDUAL Trial)

• Patients with established vascular disease (COMPASS Trial)

01/11/2017

11

PCI – in the face of AF • PIONEER: Gibson CM et al. N Engl J Med 2016; 375(25):2423.

• Patients with AF who require PCI randomized to: Riva 15 mg daily + Clopidogrel 75mg daily; or Riva 2.5 mg bid + Clopidogrel 75 mg daily + ASA 75‐100 mg daily for 1,6 or 12 months and then Riva 15 mg qd + ASA 75‐100 mg daily; or VKA + Clopidogrel 75 mg qd + ASA 75‐100 mg qd for 1, 6 or 12 months then VKA and ASA

• Result: Safety Riva and DAPT and Riva and P2Y12 had significantly lower bleeding rates than traditional triple therapy (18.0%, 16.8% vs 26.7%) with no difference in efficacy

• REDUAL: Cannon C et al. N Engl J Med 2017;377(16):1513.

• Patients with AF who require PCI randomized to Dabi 150 bid + P2Y12 or Dabi 110 bid + P2Y12 or traditional Tribple therapy with 6 month minimum treatment duration

• Result: both dabi arms significantly less bleeding than triple therapy; efficacy similar though trend to more MI and stent thrombosis in lower dose dabi arms

• Take home:• Data is still emerging (AUGUSTUS to come)

• In the face of AF and PCI – individualized decision making is occurring

Practice Questions Around Oral Anticoagulant Use….

• Indication?

• Dosing regimen and factors that affect it?

• Clot risk/bleed risk?

• Drug interactions?

• Follow Up?

• Reversal?

• Switching?

• Periop interruption?

Indications and Options:Need to know why we are using the drug….• AF:

• warfarin, apixaban, dabigatran, edoxaban, rivaroxaban

• ASA suboptimal choice, especially in the elderly

• PCI in face of AF: • ASA + P2Y12 inhibitor + VKA

• Clopidogrel 75 mg daily + Riva 15 mg daily

• ASA + Clopidogrel + Riva 2.5 mg bid

• P2Y12 + Dabi 150 bid

• P2Y 12 + Dabi 110 bid

• ASA + P2Y12 + VKA

• VTE• Treatment: Injectable and then oral; injectable than dabigatran or edoxaban; or apixaban or rivaroxaban

01/11/2017

12

DOAC Usual Starting Dose Dosing adjustmentCriteria

Apixaban (Eliquis) 5 mg BID 2.5 mg BID if any 2 of the following criteria: ‐ Age ≥80 years‐ Body weight ≤60 kg‐ Creatinine ≥133 μmol/L

Dabigatran (Pradaxa) 150 mg BID 110 mg BID if ‐ Age >80 or‐ >75 + ≥ one hemorrhagic risk factors* or‐ CrCl 30‐50 ml/min

Edoxaban(Lixiana)

60 mg OD

30 mg once daily if:‐ CrCl 30‐50 ml/min‐ body weight ≤60 kg‐ Concomitant use of P‐gp inhibitors except

amiodarone and verapamil

rivaroxaban (Xarelto)20 mg OD taken with food 15 mg OD taken with food

if CrCl 30‐49 mL/min

Dosing of DOACs is Important (AF):

Antithrombotic Dosing in VTE

Drug Initial Treatment Long Term (additional 3 months)

Extended >6 months if indicated

Apixaban 10 mg bid x 7 days 5 mg bid 2.5 mg bid

ASA Not indicated Not indicated 81-100 mg daily if OAC not possible

Dabigatran LMWH for 5-10 days 150 mg bid * 150 mg bid *

Edoxaban LMWH for 5-10 days 60 mg daily 60 mg daily

Rivaroxaban 15 mg bid x 21 days 20 mg daily 20 mg daily

Warfarin LMWH for 5 days min & INR > 2for 2 days

Variable (INR 2-3) Variable (INR 2-3)

Pfizer Canada Inc./BMS Canada. Eliquis (apixaban) Product Monograph, June 16, 2016. Bayer Inc. Xarelto (rivaroxaban) Product Monograph. July 20, 2015.Boehringer Ingelheim Canada Ltd. Pradaxa (dagbatran) Product Monograph. August 11, 2016.Daiichi Sankyp Inc. Lixiana (edoxaban) Product Monograph. November 2, 2016.Thrombosis Canada Clinical Guide. Deep Vein Thrombosis (DVT): Tretament. www.thrombosiscanada.ca

*(110 mg bid if age≥80, or age≥75 + higher risk of bleeding, including CrCl 30-50 mL/min)

Use determination to minimize Bleeding

Calculator available onlineThrombosisCanada.ca

Co‐prescribe PPI (if recurrent GI bleeding) Anticoagulation

should not be withheld based on bleeding risk, unless bleeding is active

or risk is extreme

Measure and monitor renal function

Ensure blood pressure controlled to target

Encourage alcohol abstinence

Correct anemia and determine cause

Provide mobility aids Discontinue ASA and NSAIDs if possible

36

01/11/2017

13

Drug Interactions

Dabigatran Rivaroxaban/Apixaban/Edoxaban

Contraindicated – clinically significant increased plasma levels

Potent P‐gp Inhibitors:Systemic azole antifungals (except fluconazole), cyclosporine, dronedarone, tacrolimus, simultaneous initiation with verapamil

Potent P‐gp and /or CYP 3A4 inhibitors:Systemic azole antifungals (except fluconazole), HIV‐protease inhibitors

Caution – avoid use or seek advice, dose change may be warranted

Less potent P‐gp inhibitors:Amiodarone, clarithromycin, erythromycin,fluconazole, HIV protease inhibitors, quinidine, ticagrelor

Less potent P‐gp and/or CYP3A4 inhibitors: amiodarone, cyclosporine, clarithromycin, erythromycin, diltiazem, fluconazole, quinidine, tacrolimus, verapamil

Potent P‐gp/CYP3A4 inducers: carbamazepine, phenobarbitone, phyenytoin, rifampin, St. John’s wort

Antiplatelet agents/anticoagulants: e.g.. warfarin, clopidogrel, prasugrel, ticagrelor, heparins

Some antidepressants: SSRI or SNRI

37

How to take

• Apixaban – take with or without food; can be crushed, suspended in water and administered by NG

• Rivaroxaban – take with food, alteration of AUC for doses greater than 10mg/day; can be crushed and administered by NG

• Dabigatran may be taken with food, or on an empty stomach. It should be taken with a glass of water to facilitate delivery to the stomach; do not chew, break or open capsules. Swallow capsules whole

• Edoxaban – take with or without food

• VTE missed doses• Rivaroxaban (15mg bid phase): if you miss a dose, take the dose as soon as remembered. If you forget to take a dose

you can take two 15mg tablets at the same time to get to a total dose of 30mg on one day• Apixaban: if you miss a dose, take as soon as remembered, and then continue with the remaining daily dose that day.

Do not take a double dose• Dabigatran: if a dose is missed, take the dose as soon as you remember, but if it is almost time for your next dose (less

than 6 h before next dose) take your next dose when you are supposed to• Edoxaban: if you miss a dose, take as soon as remembered. Do not double the dose for a missed dose

• Apixaban, Dabigatran, Ribaroxaban Edoxaban PM 38

Thrombosis Canada App

Search “Thrombosis” for the free app in the iTunes store, Google Play and BlackBerry App World or visit www.thrombosiscanada.ca

39

01/11/2017

14

Bungard et al. Can Pharm J (Ott.) 2015;148:241–245.

Pharmacist Follow Up: Repeat Visit/Refills

Gladstone et al. Ann Int Med 2015;163:382–385.

Patient Education

• Rationale for therapy

• Potential for minor, major or life‐threatening bleeding

• Dosing instructions, adherence, risk of non‐adherence, handling missed doses

• Avoiding OTC ASA and NSAIDs and minimizing EtOH to reduce bleeding risks

• Dosing around upcoming procedure/surgery if applicable

42

01/11/2017

15

Summary

• Evolution of management of both arterial and venous thrombosis

• New agents will continue to account for more and more patient management

• Best use of agents will result in optimization of outcomes.

43

Questions

Please type your questions in the “Questions” window in the control panel and click Send

Thank you!

This presentation and any resources will be available online to CPhA members at

http://www.pharmacists.ca/index.cfm/education‐practice‐resources/professional‐

development/pharmacy‐practice‐webinars/

Pharmacy Practice Webinar Series - DOAC Semchuk Fall 2017

Documents

Transcript of Pharmacy Practice Webinar Series - DOAC Semchuk Fall 2017