Jointly provided by Potomac Center for Medical Education and Rockpointe Supported by an educational grant from Daiichi Sankyo, Inc. A CME-CERTIFIED CLINICAL

Jointly provided by Potomac Center for Medical Education and Rockpointe

Supported by an educational grant from Daiichi Sankyo, Inc.

A CME-CERTIFIED CLINICAL TOPICS GRAND ROUNDS PROGRAM

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Off-label Discussion DisclosureThis educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors.

Learning Objectives

• Identify AFib patients who are at risk for developing ischemic stroke and comply with treatment guidelines for their management

• Evaluate options to overcome the limitations of vitamin K antagonists to reduce the risk of new and recurrent strokes

• Individualize antithrombotic treatments to find the right drug at the right dose for the right patient

Polling Question 1Activity Survey

How confident are you in your ability to adopt evidence-based treatment strategies to manage patients with atrial fibrillation?

A. Not at all confident

B. Slightly confident

C. Confident

D. Very confident

E. Expert

Lecture Overview

• Prevalence and Incidence of Atrial Fibrillation (AF)

• Risk Stratification for Stroke and Bleeding

• Clinical Properties of Warfarin

• Clinical Properties of Non-vitamin K Oral Anticoagulants

• Current Guidelines on Management of AF

• Preventing and Managing Bleeding (Reversal Agents)

• Considerations for Choosing an Anticoagulant

The ECG of Atrial Fibrillation

Normal sinus

rhythm

Atrial fibrillation

Stroke and Atrial Fibrillation Burden

Wolf PA et al. Stroke. 1991;22:983-988.

AF prevalence

Strokes attributable to AF

%

Age Range (years)

0

10

20

30

50–59 60–69 70–79 80–89

Framingham

More than 2.2 million individuals in the US have AF AF increases risk of stroke about 5-fold Strokes in patients with AF strokes lead to worse outcomes Costly health care ~$16 billion/year

Atrial Fibrillation: An Epidemic

Chugh SS et al. Circulation. 2014;129:837-847.

Age-adjusted Global Incidence

AF-related Mortality

Lecture Overview

• Prevalence and Incidence of AF







Efficacy and Safety of Warfarin

Fang MC et al. Ann Intern Med. 2004;141:745. Hylek EM et al. N Engl J Med. 1996;335:540.

5.0 6.0 8.01.0 2.0 3.0 4.0 7.0

5

15

10

Ischemic Stroke

1

20

Odd

s R

atio

International Normalized Ratio

Target Intracranial Hemorrhage

Nonvalvular Atrial Fibrillation

Hart RG et al. Neurology. 2007;69:546-554.

0

2.5

5

7.5

10

12.5

15

PriorStroke/TIA

Age>75 years

Hypertension FemaleDiabetesHeart Failure LVEF

Stro

ke R

ate

(%/ y

ear)

Stroke Rates Without AnticoagulationAccording to Isolated Risk Factors

C H A D S


A patient who has atrial fibrillation and a CHA2DS2-VASc risk score of 4.0 has an approximate annual risk of stroke of:

A. 1.3%

B. 2.2%

C. 4.0%

D. 6.7%

E. >7.0%

Redefining Risk: CHA2DS2-VASc

ESC Guidelines. Eur Heart J. 2010;31:2369-2429.

Risk Factor Points

CHF / LV Dysfunction 1

Hypertension 1

Age ≥75 2

Diabetes Mellitus 1

Stroke / TIA / Embolism 2

Vascular Disease 1

Age 64-74 1

Sex Category (female) 1

Maximum Score 9

CHA2DS2-VASc Score Stroke (% / yr)

1 0 %

2 1.3 %

3 2.2 %

4 4.0 %

5 6.7 %

6 9.8 %

7 9.6 %

8 6.7 %

9 15.2 %

CHA2DS2-VASc Refines Stroke Risk Stratification in CHADS2=0 vs CHA2DS2VASc

Olesen et al. Thromb Haemost. 2012;107:1172-1179.

A nationwide Danish cohort study in 47,576 non-warfarin treated non-valvular AF patients with a CHADS2 score = 0-1 at baseline (1997-2008)

100%

CHADS2 = 0: n=17,327 person-years

CHA2DS2VASc = 0: n=6,919 person-years



CHA2DS2VASc = 3: n=250 person-years

Stroke / thromboembolism rate (% person-years)

Prop

ortio

n of

pat

ient

s fr

ee

of s

trok

e / t

hrom

boem

bolis

m

0%

92%

94%

96%

98%

0.84%

Days from discharge0 100 200 300

1.59%1.75%2.69%3.20%

Initiation of OAC to Reduce Stroke Risk in Patients with AF

• The CHA2DS2-VASc scoring system helps clinicians determine stroke risk and to choose oral anticoagulation (OAC) therapy

• OAC therapy options: New direct oral anticoagulants (DOAC) or vitamin K antagonists (VKA); The most commonly used VKA is warfarin

• Drug interactions should also be considered when prescribing

Risk Factor Points

C Congestive heart failure (or left ventricular systolic dysfunction)1

H Hypertension (blood pressure consistently above 140/90 mmHg) 1A2 Age ≥75 years

2D Diabetes mellitus

1S2 Prior stroke or TIA or thromboembolism

2V Vascular disease (peripheral artery disease, MI, aortic plaque)

1A Age 65-74 years

1Sc Sex category (i.e. female sex) 1

Total Score Anticoagulation Stroke Option

0 Low stroke risk No antithrombotic therapy (or aspirin 75-325 daily) 1 Moderate Either DOAC or warfarin at an internationalized ratio (INR) of 2.0-3.0 ≥2 High Either DOAC or warfarin at INR 2.0-3.0

Kovacs RJ et al. J Am Coll Cardiol. 2015;65:1340-1360.

Bleeding Risk: HAS-BLED

ESC Guidelines. Eur Heart J . 2010;31:2369-2429.

Letter Clinical Characteristic Points

H Hypertension 1

A Abnormal Liver or Renal Function 1 or 2

S Stroke 1

B Bleeding 1

L Labile INR 1

E Elderly (age >65) 1

D Drugs or Alcohol 1 or 2

Maximum Score 90 1 2 3 4 5

0

2

4

6

8

10

12

14

16

HAS-BLED Score

Bleeds per

100 pt years

Low Risk

ModerateRisk

High Risk

Net Clinical Benefit of WarfarinAll-cause Mortality, Ischemic Stroke, and ICH

Friberg L et al. Circulation. 2012;125:2298-2307.

Lecture Overview








Stroke Prevention in AF Warfarin vs Placebo (pooled analysis of 2900 participants)

Hart RG et al. Ann Intern Med. 2007;146:857-867.

100% 50% 0% -50% -100%

AFASAK-1 (671)

SPAF (421)

BAATAF (420)

CAFA (378)

SPINAF (571)

EAFT (439)

All Trials (n=6)

Warfarin Better Warfarin Worse

64%

Limitations of Warfarin

• Delayed onset/offset

• Multiple food and drug interactions

• Genetic variability in metabolism (VKORC1 and CYP2C9)

• Requires frequent monitoring of INR due to limited therapeutic index; continual dose titration needed

• Increases risk of intracerebral hemorrhage and fatal bleeding


In a recent survey of patients with atrial fibrillation who were at high risk for stroke (CHA2DS2VASc ≥2) and are eligible for warfarin anticoagulation, what percentage actually received such treatment?

A. Greater than 80%

B. 70%-80%

C. 50%-70%

D. Less than 50%

Modest Use of Vitamin K Antagonists Even in High-risk Patients

OAC = oral anticoagulant

Nieuwlaat R et al. Eur Heart J. 2006;27:3018-3026.

Gage BF et al. JAMA. 2001;285:2864-2870.

CHADS2 score

OA

C th

erap

y (%

)

58 5964 61

0

20

40

60

80

100

1 2 3 4

5333 AF patients in 35 countries: 2003–2004

European Heart Survey

Lecture Overview








Properties of an Ideal Anticoagulant

Properties Benefit

Oral, once-daily dosing Ease of administration

Rapid onset of action No need for overlapping parenteral anticoagulant

Minimal food or drug interactions Simplified dosing

Predictable anticoagulant effect No coagulation monitoring

Extra renal clearance Safe in patients with renal disease

Rapid offset in action Simplifies management in case of bleeding or intervention

Antidote For emergencies

Non-Vitamin K Oral Anticoagulants

Adapted from: Weitz JI, Bates SM. J Thromb Haemost. 2005;3:1843-1853.

Dabigatran

Xa

IIa

TF/VIIa

X IX

IXaVIIIa

Va

II

FibrinFibrinogen

RivaroxabanApixabanEdoxaban


Which of the direct oral anticoagulant agents are approved for once-daily dosing?

A. apixaban and edoxaban

B. apixaban and rivaroxaban

C. dabigatran and edoxaban

D. edoxaban and rivaroxaban

Comparison Overview of Non-vitamin K Oral Anticoagulants (NOACs) with Warfarin

Features Warfarin NOACs

Onset Slow Rapid

Dosing Variable Fixed

Food effect Yes No

Drug interactions Many Few

Monitoring Yes No

Half-life Long Short

Antidote Yes No

Comparative PK/PDNovel Oral Anticoagulants

Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc. 2013.Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc. 2011.Weinz et al. Drug Dispos Metab. 2009;37:1056-1064. ELIQUIS Summary of Product Characteristics. Bristol-Myers Squibb/Pfizer EEIG, UK.

Matsushima et al. Am Assoc Pharm Sci. 2011; abstract.Ogata et al. J Clin Pharmacol. 2010;50:743-753.Mendell et al. Am J Cardiovasc Drugs. 2013;13:331-342.Bathala et al. Drug Metab Dispos. 2012;40:2250-2255.

Dabigatran Rivaroxaban Apixaban Edoxaban

Target IIa (thrombin) Xa Xa Xa

Hours to Cmax 1-3 2-4 3-4 1-2

Half-life, hours 12-17 5-13 12 10-14

Renal Clearance, % 80 33* 27 50

Transporters P-gp P-gp P-gp P-gp

CYP Metabolism, % None 32 ~25 <4

CYP = cytochrome P450; P-gp = P-glycoprotein *33% renally cleared; 33% excreted unchanged in urine

Stroke Prevention in Atrial Fibrillation TrialsNovel Oral Anticoagulants

a. Connolly SJ et al. N Engl J Med. 2009;361:1139-1151. b. Patel MR et al. N Engl J Med. 2011;365:883-891.

RE-LY[a] ROCKET-AF[b] ARISTOTLE[c] ENGAGE AF[d]

Drug Dabigatran Rivaroxaban Apixaban Edoxaban

# Randomized 18,113 14,266 18,201 21,105

Dose (mg) 150, 110 20 5 60, 30

Frequency Twice Daily Once Daily Twice Daily Once Daily

Dose Adjustment No 20 → 15 5 → 2.5 60 → 3030 → 15

At Baseline 0 21 5 25

After Randomization No No No 8%

Target INR (Warfarin) 2.0-3.0 2.0-3.0 2.0-3.0 2.0-3.0

Design PROBE* 2x blind 2x blind 2x blind

*PROBE = prospective, randomized, open-label, blinded, end-point evaluation

c. Granger CB et al. N Engl J Med. 2011;365:981-992. d. Giugliano RP et al. N Engl J Med. 2013;369:2093-2104.

Meta-analysis of All NOACs vs WarwfarinStroke or Systemic Embolic Events

Ruff CT et al. Lancet. 2014;383:955-962.

ENGAGE AF-TIMI 48

ARISTOTLE

ROCKET AF

RE-LY

Combined

Favors NOAC Favors Warfarin

0.88 (0.75 - 1.02)

0.80 (0.67 - 0.95)

0.88 (0.75 - 1.03)

0.66 (0.53 - 0.82)

0.81 (0.73 - 0.91)

Risk Ratio (95% CI)

P=<0.0001

0.5 1 2

[Random Effects Model]

n=58,541

Heterogeneity P=0.13

[60 mg]

[150 mg]


Results from meta-analyses of existing NOAC data reveal that NOACs offer greatest protection for prevention of:

A. All-cause mortality

B. Hemorrhagic stroke

C. Ischemic stroke

D. Myocardial infarction

E. All of the above

Meta-analysis of All NOACs vs WarfarinSecondary Efficacy Outcomes


All-cause Mortality

MI

Hemorrhagic Stroke

Ischemic Stroke

0.90 (0.85 - 0.95)

0.97 (0.78 - 1.20)

0.49 (0.38 - 0.64)

0.92 (0.83 - 1.02)

Risk Ratio (95% CI)

P=0.0003

P=0.77

P<0.0001

P=0.10

Favors NOAC Favors Warfarin

0.2 0.5 1 2

Heterogeneity P=NS for all outcomes


Meta-analyses of existing NOAC data reveal that risk of gastrointestinal or intracranial bleeding is:

A. Less with NOACs than with warfarin

B. Comparable with NOACs and warfarin

C. Less with warfarin than with NOACs

D. There are insufficient data to draw conclusions

How Frequent is Bleeding with NOACs?


% /

Yea

r

NOACs Warfarin0.00

1.00

2.00

3.00

4.00

5.00

2.392.80

1.170.92

0.320.66

Major Bleeding

GI Bleeding

ICH

P = 0.06

P = 0.04

P < 0.01

71,683 Patients: 4 Phase III AF NOAC Trials

AHA, ACC, and HRS Guidelines for the Management of Patients with AF

• Use CHA2DS2-VASc instead of CHADS2 for patients with non-valvular AF

• A CHA2DS2-VASc score of 1 in patients with non-valvular AF should be treated with either no anti-coagulation therapy, aspirin, or an oral anticoagulant

• A CHA2DS2-VASc score of ≥2 warrants use of an oral anticoagulant, if there are no contraindications

• A CHA2DS2-VASc score of ≥2 warrants use of an oral anticoagulant, either warfarin, dabigatran, rivaroxaban, apixaban, or edoxaban

Updated from January CT et al. Circulation. 2014;130:2071-2104.

Is Aspirin as Effective and Safe as NOACs?Data from Apixaban in the AVERROES Trial

Connolly SJ et al. N Engl J Med. 2011;364:806-817.

Stroke or Systemic Embolic Event Major Bleeding

HR 0.45 (0.32-0.62) HR 1.13 (0.74-1.75)

Aspirin

Apixaban

P<0.001

0 3 6 9 12 18

0.05

0.04

0.03

0.02

0.01

0.00

Aspirin

Apixaban

P<0.001

0 3 6 9 12 18

0.020

0.015

0.010

0.005

0.000

Aspirin is less efficacious and has similar bleeding to apixaban.

Lecture Overview








Choice of Anticoagulant in Patients with AF European Society of Cardiology Guidelines

Camm AJ et al. Eur Heart J. 2012;33:2719-2747.

Japanese Circulation Society 2014 Guidelines Antithrombotic Therapy in AF

JCS Joint Working Group. Circ J. 2014;78:1997-2021.

NVAF Mitral stenosisor

mechanical valve Other risk factors

Cardiomyopathy65 to 74 years old

Vessel disease

CHADS2 scoreHeart failureHypertensionAge ≥75DiabetesHistory of cerebral infarction/TIA

11112

≥2 points 1 point

*<70% TTR: INR 2.0–3.0, ≥70% TTR: INR 1.6–2.6

Recommended

DabigatranRivaroxaban

ApixabanEdoxaban

Warfarin*

RecommendedDabigatranApixaban

Considered

DabigatranRivaroxaban

ApixabanEdoxaban

Warfarin*

ConsideredRivaroxaban

Edoxaban

Warfarin*

Recommended

Warfarin*

When there is adaptation of an

equivalent level, an NOAC is more

desirable than warfarin

Lecture Overview








Are We Using Too Much Aspirin in Patients with AF? Bleeding According to Antiplatelet Treatment

Hans DL et al. Circulation. 2013;127:634-640.

• Series of no, single, and dual antiplatelet therapy• HRs adjusted for age, gender, warfarin experience, SBP, CAD, HF, hypertension,

diabetes, TIA, CrCl, and statin use

Concomitant antiplatelet drugs appeared to increase the risk for major bleeding in RE-LY without affecting the advantages of dabigatran over warfarin

Warfarin Dabigatran 150 Dabigatran 11001234567

2.8 2.62.2

4.6 4.33.8

6.35.5 5.4

None ASA ASA + clopidogrel

Maj

or B

leed

ASA = aspirin; CAD = coronary artery disease; HF = heart failure; SBP = systolic blood pressure

Renal Function and NOACs

• All 4 Phase III NOAC trials excluded patients with an eGFR <25-30 mL/min

• Renal impairment is an independent risk factor for stroke, bleeding, and death

• All NOACs require dose adjustment for renal failure:– Dabigatran 150 mg bid for CrCl >30 mL/min

• 75 mg bid if CrCl 15-30 mL/min– Rivaroxaban 20 mg once daily for CrCL >50 mL/min

• 15 mg once daily if CrCL 15-50 mL/min– Edoxaban 60 mg once daily if CrCL >50 to <95 mL/min

• 30 mg once daily if CrCL<15-50 mL/min; should not be used if CrCl >95 mL/min– Apixaban 5 mg bid

• 2.5 mg twice daily with 2 of 3: age ≥80 y, weight ≤ 60 kg, serum creatinine ≥1.5 mg/dL

CrCL = creatinine clearance Package inserts for dabigatran, rivaroxaban, edoxaban, and apixaban

Managing Bleeding with NOACs

Kovacs RJ et al. J Am Coll Cardiol. 2015;65:1340-1360.

Step 1 Review• Stop anticoagulation and antiplatelet therapy• Review time of last dose of anticoagulant• Review medications including aspirin, P2Y12 inhibitors,

NSAIDs, P-gp inhibitors, CYP3A4 inhibitors• Assess for comorbid conditions, check for evidence of

cardiac decompensation• Order baseline laboratory parameters including CBC

with platelets, renal function tests, PT, aPTT• Maintain organ perfusion• Volume resuscitation• Pressors• Identify source of bleeding• Evaluate for transfusion

Step 2 Remove• Gastric lavage for recent ingestion• Oral charcoal• Dialysis (dabigatran)

Step 3 RepairAssess need for Surgery

Step 4 Reverse

Vitamin K antagonists• Vitamin K• Consider FFP for poor hemodynamic condition• 4-factor prothrombin complex concentrate• Platelet transfusion (for thrombocytopenia or if

patients received antiplatelets)

Direct acting oral anticoagulants• Consider 4 factor prothrombin complex

concentrate• Platelet transfusion (for thrombocytopenia

or if patient received antiplatelets)

Non-specific Reversal Agents

Only after D/C drug and supportive care (fluids / transfusions)

Agent Clotting Factors Replaced Dose

4 Factor-PCC Factors II, VII, IX, X 25-50 units/kg

3 Factor-PCC Factors II, IX, X 25-50 units/kg

aPCC Factors II, VIIa, IX, X 80 units/kg

rFVIIa FVIIa 90 ug/kg

New and Emerging Antidotes

Idarucizumab (BI 655075)Target: DabigatranStructure: humanized antibody fragment (FAb) to dabigatranFDA approved: October 2015

Andexanet alfa (PRT064445)Target: FXa inhibitorsStructure: FXa lacking catalytic and binding activity

Aripazine (PER977; Ciraparantag)Target: Universal – all NOACs, heparin, LMWHStructure: synthetic small molecule (D-arginine)

Lecture Overview








Patients Not Well-Suited for an NOAC

• Mechanical heart valves

• Moderate-severe mitral stenosis and AF

• Pregnancy and nursing mother

• Stage V CKD

(apixaban OK in patients on stable hemodialysis per the US FDA)

• Moderate-severe hepatic failure

• Children

• Extremes of physiology (e.g. weight, age)

• Malabsorption

Optimal Candidates for NOACs

• Almost all patients with non-valvular AF should be considered as candidates for NOACs

• Patients with normal renal function

• European and Japanese guidelines recommend NOACs over VKA

• Ineligible patients include

– Those who are pregnant

– Those with mechanical heart valve or in early post-operative cardiac surgery

Renal Function and NOACs • All 4 Phase III NOAC trials excluded patients with an eGFR <25-30 mL/min• Dabigatran is 80% renally eliminated, greater than rivaroxaban (33% renally

metabolized and 33% excreted unchanged by kidneys), edoxaban (50%), and apixaban (27%)[a]

• Renal impairment is an independent risk factor for stroke, bleeding, and death• 150 mg twice daily of dabigatran: use cautiously in the elderly (>80 yr) and with

renal impairment (<40 mL/min)[b] • All NOACs require dose adjustment for renal failure:

– Dabigatran 75 twice daily if CrCl 15-30 mL/min (US FDA)

– Rivaroxaban 15 mg once daily if CrCL <15-49 mL/min

– Edoxaban 30 mg once daily if CrCl <15-50 mL/min[c]; should not be used if CrCl >95 mL/min

– Apixaban 2.5 mg twice daily with 2 of 3: age ≥80 y, weight ≤60 kg, SCr ≥1.5 mg/dL

a. Heidbuchel H et al. Europace. 2013;15:625-651. b. Dabigatran SMPC. www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/000829/WC500041059.pdf.c. Edoxaban Package Insert. www.accessdata.fda.gov/drugsatfda_docs/label/2015/206316lbl.pdf.

Important Factors when Considering an NOAC

• All patients with atrial fibrillation should be considered for an NOAC, except if mechanical valve, rheumatic MS, pregnant, children

• NOACs decrease intracerebral hemorrhage (50%) and major bleeding (14%) compared to warfarin

• NOACs decrease stroke/systemic embolism (18%) and death (10%) compared to warfarin

• NOACs are not all the same, so selection of which NOAC depends on patient characteristics


In choosing an NOAC, consideration should be given to:

A. Patient’s risk of bleeding

B. Patient’s risk of ischemic stroke

C. Patient history of coronary artery disease

D. Patient’s renal function status

E. All of the above

“Pointers” Regarding Which NOAC to Choose*

* All of these “pointers” are debatableSavelieva I et al. Clin Cardiol. 2014;37:32-47.Gonzelz-Quesada CJ, Giugliano RP. J Thromb Thrombolysis. 2015;39:129-138.

Spec

ific

Patie

nt C

hara

cter

istic

s

Patient preference Consider once daily formulation Riva; Edox

High risk of bleeding, e.g.HAS-BLED 3; very elderly

Consider agent/dose with the lowest incidence of bleeding

Dabi 110; Edox; Apix

Previous GI bleeding, or high-risk, or GI upset

Consider agents with the lowest reported incidence of GI bleed Apix; LD Edox

CAD, previous MI or high-risk for ACS/MI

Consider agent with a positive effect in ACS Riva; HD Edox

High risk of ischemic stroke; low bleeding risk

Consider agent/dose with the best reduction of ischemic stroke Dabi 150

Renal impairment Consider agent least dependent on renal function

Apix; Edox 30; Riva 15

Concomitant CYP inhibitor Consider agents with no/little metabolism via CYP system Dabi; Edox

Previous stroke (secondary prevention)

Consider best investigated agent or greatest reduction of 20 stroke

Riva; Apix; HD Edox

Conclusions

Properties of Ideal AnticoagulantDo NOACs Fit the Bill?

Proven efficacy Low bleeding risk Fixed dosing Good oral bioavailability No routine monitoring needed Reversibility: ?PCC, FEIBA, rVIIa Rapid onset of action Few drug or food interactions

Additional Issues Regarding Direct OACs

1. How do we compare the different drugs and studies in the absence of head-to-head studies?

2. Would more flexible dosing improve safety:efficacy (e.g. in patients who bleed or are at extremes of age, weight)?

3. Are NOACs “better” if patients are well controlled on warfarin?

4. How should we incorporate measures of drug concentration or anticoagulation levels in clinical practice, if at all?

5. Is the fast offset a problem if patients are not compliant?

6. Are there specific adverse drug reactions?

7. Which drug and what dose when dual antiplatelets are needed (e.g. ACS or post-stenting)

8. How do we best evaluate cost-effectiveness?

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Jointly provided by Potomac Center for Medical Education and Rockpointe Supported by an educational grant from Daiichi Sankyo, Inc. A CME-CERTIFIED CLINICAL