University of Chicago Medical CenterChicago, IL

Janet Friant, MSN, APN-BC, AACC

What are all of these blood thinners? A review of oral anticoagulation options.

• Provide an overview of coagulation and highlight

potential targets for pharmacotherapy in thrombosis

• Detail the MOA of warfarin and the novel oral

anticoagulants (NOACs) with a focus on practical

considerations related to anticoagulation

• Review the data for use of NOACs in approved clinical

indications

• Outline initiation and transition strategies

Objectives

3

• Provide an overview of coagulation and highlight

potential targets for pharmacotherapy in thrombosis

• Detail the MOA of warfarin and the novel oral

anticoagulants (NOACs) with a focus on practical

considerations related to anticoagulation

• Review the data for use of NOACs in approved clinical

indications

• Outline initiation and transition strategies

Objectives

4

Definitions

• Coagulation - The physiologic process by which blood clots

• Hemostasis - Physiologic clotting of blood in response to injury or vascular leakage (“Keeping blood where it belongs”)

• Thrombosis - Pathologic clotting of blood (“Hemostasis in the wrong place”)

5

Coagulation in perspective:Thrombosis vs. hemostasis

“GOOD CLOT”

“BAD CLOT”

Issues of thrombosis and hemostasis often coexist in

the very same patient

6

Coagulation and platelet cascades

Nathan S, Swamy R. U.S. Cardiology 2008.7

Oral anticoagulationClinical indications

• Venous thromboembolism• Treatment• Prophylaxis

• Arterial thrombosis (including PE)• LV thrombus / post-myocardial infarction• Atrial fibrillation (valvular, nonvalvular)• Prosthetic heart valves• CVA (stroke)

8

Nonvalvular atrial fibrillation

• NVAF is the most common sustained cardiac arrhythmia in the U.S. affecting an estimated 2.7 million to 6.1 million adults in the United States and over 15 million patients worldwide.

• It is widely believed that the incidence and prevalence of atrial fibrillation will continue to rise, perhaps doubling over the next 25 years.

• The lifetime risk of developing atrial fibrillation after the age of 40 is as high as 25%, and is influenced by a variety of factors such as the development or coexistence of thyroid disease, diabetes, hypertension, obesity, sleep apnea, heart failure, myocardial ischemia and structural heart disease.

Nathan S, Shah AP. The Journal of Cardiothoracic and Vascular Anesthesia 2014. In press. 9

Miyasaka Y, et al. Circulation 2006; 114: 119.

Projected incidence of NVAF in the U.S.

10

Nonvalvular atrial fibrillation

• Thromboembolic disease, in particular stroke, remains the most significant and feared complication of atrial fibrillation.

• Atrial fibrillation is associated with 15% of strokes in people of all ages and 30% of strokes in people > 80 y.o.

• There are an estimated 500,000 hospitalizations primarily for atrial fibrillation annually in the U.S.

• It is estimated that atrial fibrillation contributes to at least 100,000 deaths per year, many as a consequence of stroke.

Nathan S, Shah AP. The Journal of Cardiothoracic and Vascular Anesthesia 2014. IDEM. Atrial fibrillation” a major contributor to stroke in the elderly; the Framingham Study. Arch Intern Med 1987; 147; 1561-4. 11

Clinical Calculation Tools

Clinical Calculation Tools: Qx Calculate

• Provide an overview of coagulation and highlight

potential targets for pharmacotherapy in thrombosis

• Detail the MOA of warfarin and the novel oral

anticoagulants (NOACs) with a focus on practical

considerations related to anticoagulation

• Review the data for use of NOACs in approved clinical

indications

• Outline initiation and transition strategies

• Briefly highlight pipeline agents and combination

therapies

Objectives

14

Oral anticoagulants

Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban

15

Warfarin

Wisconsin Alumni Research Foundation

16

Warfarin

Kinetics Absorption Oral: Rapid, complete

Metabolism Hepatic, primarily via CYP2C9; minor pathways include CYP2C8, 2C18, 2C19, 1A2, and 3A4

Excretion Urine (92%, primarily as metabolites)

Half-life 20-60 hoursDosing Variable

17

Warfarin

Key considerationsOnset of therapeutic effect

5-7 days May requiring bridging with indirect antithrombins

Antidote Vitamin K, FFP, PRBC

Factors influencing warfarin response

Vitamin K balance, drug interactions, genetic variations, impaired hepatic function, hypermetabolic states, co-morbid medical conditions

Adverse drug reactions Bleeding/Hemorrhage/HematuriaVasculitisDermatitis, pruritus, urticariaAbdominal pain, N/V/D AnemiaSkin necrosis, gangrene, “purple toes” syndrome

18

Indications for warfarin and recommended therapeutic range

19

Limitations of warfarin

Mean TTR is low in patients receiving warfarin

Only 55% of nonvalvular AF patients without contraindications receive

warfarin*1

51%

29%

67%

55%

58%

0 20 40 60 80 100

McCormick et al

Sarawate et al

Rose et al

Baker et al

Rose et al

Mean TTR (%)Age (y)

2

3

5

6

4

Pat

ien

ts (

%)

55%overall

use1

(N=22,237)

(N=124,551)

(N=3104)

(N=470)

(N=174)(n=1064) (n=1596) (n=3707) (n=3752) (n=963)

1. Go AS et al. Ann Intern Med. 1999;131(12):927-934. 2. Rose AJ et al. Circ Cardiovasc Qual Outcomes. 2011;4(1):22-29.3. Baker WL et al. J Manag Care Pharm. 2009;15(3):244-252. 4. Rose AJ et al. J Thromb Haemost. 2008;6(10):1647-1654. 5. Sarawate C et al. J Thromb Thrombolysis. 2006;21(2):191-198. 6. McCormick D et al. Arch Intern Med. 2001;161(20):2458-24637. Bungard et al. Arch Intern Med. 2000; 160; 41-46. 20

Warfarin vs. placebo in stroke prevention in patients with NVAF

50%100% 0 -50% -100%

Relative Risk Reduction (95% CI)

FavorsWarfarin

FavorsPlacebo

AFASAK

SPAF

BAATAF

CAFA

SPINAF

EAFT

All Trials

AFASAK = Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study; BAATAF = Boston Area Anticoagulation Trial for Atrial Fibrillation CAFA = Canadian Atrial Fibrillation Anticoagulation Study; EAFT = European Atrial Fibrillation Trial; SPAF = Stroke Prevention in Atrial Fibrillation Study; SPINAF = Stroke Prevention in Nonrheumatic Atrial Fibrillation.

Hart RG et al. Ann Intern Med. 1999;131(7):492-501.21

NOACs: “Are we there yet?”

22

• Provide an overview of coagulation and highlight

potential targets for pharmacotherapy in thrombosis

• Detail the MOA of warfarin and the novel oral

anticoagulants (NOACs) with a focus on practical

considerations related to anticoagulation

• Review the data for use of NOACs in approved clinical

indications

• Outline initiation and transition strategies

• Briefly highlight pipeline agents and combination

therapies

Objectives

23

Pros and cons of NOACs

Advantages DisadvantagesRapid onset/offset of action Use is contraindicated or dose reduction is

required in patients with severe CKD

Absence of food interactions Limited availability of assays for measuring drug levels

Limited hepatic metabolism/few strong DDIs Higher drug acquisition costsWide therapeutic window Rapid decline in effect if doses are missedLower risk of intracranial hemorrhage No specific antidoteLower potential risk of bleeding complications Increased risk for GI bleeding

Fixed dosing Contraindicated in patients with mechanical heart valves

24

Direct oral thrombin inhibition

VIIa

Xa

IXa

XIa

XIIa Tissue factor

Factor IIa(thrombin)

Dabigatran

II

×25

Dabigatran

Kinetics Absorption Rapid; initially slow postoperatively

Metabolism Hepatic; rapidly and completely hydrolyzed to active form by plasma and hepatic esterase

Excretion Renal (80%)

Half-life 12-17 hoursDosing 150mg twice daily if CrCl >30 ml/min

75mg twice daily is CrCl 15-30 ml/min

26

Dabigatran

• Onset: 1 hour, delayed by food • Antidote: None• Contraindications

– Hypersensitivity to dabigatran or any component– Active bleeding

• Warnings/Precautions – Bleeding– Renal impairment– Anticoagulants – Invasive/surgical invasions– P-gp inducers/inhibitors

• ADRs– Bleeding (8% to 33%; major ≤ 6%)– Dyspepsia (11%)

27

Dabigatran vs. warfarin in the RELY trial

Connolly SJ, et al. N Engl J Med 2009;361:1139-51.28

RELY: Cumulative hazard rates for the primary outcome of stroke or systemic embolism, according to treatment group

Connolly SJ, et al. N Engl J Med 2009;361:1139-51.29

RELY: Safety outcomes according to treatment group

Connolly SJ, et al. N Engl J Med 2009;361:1139-51.30

RELY: Conclusions

• In patients with atrial fibrillation, dabigatran given at a dose of 110 mg BID was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major haemorrhage

• Dabigatran administered at a dose of 150 mg BID, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major haemorrhage

31

Recommended use of dabigatran

32

Direct oral Xa inhibition

VIIa

Xa

IXa

XIa

XIIaTissue factor

Fibrinogen Fibrin clot

Factor II(prothrombin)

RivaroxabanApixabanEdoxaban

×

33

Rivaroxaban

Kinetics Absorption Intestines, rapid

Recommended to take with food

Metabolism HepaticCYP3A4/5 and CYP2J2

Excretion Renal (65%)

Half-life 5-9 hoursDosing 20 mg once daily if CrCl > 50 ml/min

15mg once daily if CrCl 15-50 ml/min

34

ROCKET-AF: Rivaroxaban vs. warfarin in NVAF at mod-high risk of stroke

Enrollment of subjects without prior stroke, TIA, or systemic embolism and only 2 factors capped at 10%

CHADS2 Risk Factors• Prior stroke, TIA, or non–CNS

systemic embolus – OR –

• CHF or LVEF ≤35% • Hypertension • Age ≥75 years • Diabetes

At least 2 required

Rivaroxaban 20 mg/d

(15 mg/d for CrCl 30 to <50 mL/min)

WarfarinINR target:

2.0 to 3.0 inclusive

Nonvalvular AF

Monthly assessments*Warfarin management was determined by clinician

Randomizeddouble-blind/

double-dummy(N=14,264)

CHADS2 = congestive heart failure, hypertension, age, diabetes, prior stroke or TIA; CHF = congestive heart failure; CNS = central nervous system; INR = international normalized ratio; TIA = transient ischemic attack.*Patients seen at weeks 1, 2, and 4, then as clinically indicated but at least monthly thereafter.1. Patel MR et al. N Engl J Med. 2011;365(10):883-891. 2. Online supplement to: Patel MR et al. N Engl J Med. 2011;365(10):883-891. http://www.nejm.org/doi/suppl/10.1056/NEJMoa1009638/suppl_file/nejmoa1009638_appendix.pdf. Accessed February 28, 2012.3. ROCKET AF Study Investigators. Am Heart J. 2010;159(3):340-347.35

ROCKET AF: Primary endpoint (per protocol)

Patel MR et al. N Engl J Med 2011;365:883-891.36

ROCKET AF: Primary endpoint (intention to treat)

Patel MR et al. N Engl J Med 2011;365:883-891.37

Rivaroxaban vs. warfarin in NVAF: ROCKET AF trial

XARELTO®

(n=7081)*Warfarin

(n=7090)*

HR (95% CI)No. (%)Rate/

100 PTY No. (%)Rate/

100 PTYPrimary composite

endpoint† 269 (3.8) 2.1 306 (4.3) 2.4 0.88 (0.74-1.03)

Stroke 253 (3.6) 2.0 281 (4.0) 2.2 –

Hemorrhagic stroke 33 (0.5) 0.3 57 (0.8) 0.4 –

Ischemic stroke 206 (2.9) 1.6 208 (2.9) 1.6 –

Unknown stroke type 19 (0.3) 0.2 18 (0.3) 0.1 –

Non–CNS systemicembolism 20 (0.3) 0.2 27 (0.4) 0.2 –

The overall results for the primary composite endpoint (time to first occurrence of stroke (any type) or non–CNS systemic embolism) were noninferior between rivaroxaban and warfarin

*Data are shown for all randomized patients followed to site notification.†The primary endpoint was the time to first occurrence of stroke (any type) or non–CNS systemic embolism.

1. Online supplement to: Patel MR et al. N Engl J Med. 2011;365(10):883-891. http://www.nejm.org/doi/suppl/10.1056/NEJMoa1009638/suppl_file/nejmoa1009638_appendix.pdf.

38

ROCKET AF: Secondary endpoints

Rivaroxaban(n=7081)*

Warfarin (n=7090)*

HR (95% CI)No. (%)Rate/

100 PTY No. (%)Rate/

100 PTYStroke, systemic embolism, and vascular death

572 (8.1) 4.5 609 (8.6) 4.8 0.94 (0.84-1.05)

Stroke, systemic embolism, MI, and vascular death

659 (9.3) 5.2 709 (10.0) 5.7 0.93 (0.83-1.03)

Stroke type Hemorrhagic Ischemic Unknown

33 (0.5)

206 (2.9)

19 (0.3)

0.3

1.6

0.2

57 (0.8)

208 (2.9)

18 (0.3)

0.41.60.1

0.58 (0.38-0.89)0.99 (0.82-1.20)1.05 (0.55-2.01)

Systemic embolism 20 (0.3) 0.2 27 (0.4) 0.2 0.74 (0.42-1.32)

MI 130 (1.8) 1.0 142 (2.0) 1.1 0.91 (0.72-1.16)

All-cause mortality 582 (8.2) 4.5 632 (8.9) 4.9 0.92 (0.82-1.03)

39

Comparable major and nonmajor bleeding in ROCKET AF for rivaroxaban and warfarin

Bleeding

Rivaroxaban(n=7111)*

Warfarin(n=7125)*

HR(95% CI)No. (%)

Rate/100 PTY No. (%)

Rate/100 PTY

Major and nonmajorclinically relevant 1475 (20.7) 14.9 1449 (20.3) 14.5 1.03 (0.96-1.11)

Major 395 (5.6) 3.6 386 (5.4) 3.5 1.04 (0.90-1.20)

Nonmajorclinically relevant 1185 (16.7) 11.8 1151 (16.2) 11.4 1.04 (0.96-1.13)

*Safety population on-treatment.

Patel MR et al. N Engl J Med. 2011;365(10):883-891.40

ROCKET-AF: Conclusions

• Rivaroxaban was noninferior to warfarin for prevention of stroke or systemic embolism.

• Rivaroxaban group had less intracranial and fatal bleeding that the warfarin group.

41

Apixaban

Kinetics Absorption Rapid; Intestines

Metabolism 15% liver metabolismCYP3A4

Excretion Primarily Biliary/Fecal (73%)Renal (27%) unchanged

Half-life 8 to 15 hours

Dosing Dose: 5mg twice dailyDose reduction to 2.5mg twice daily if 2+ of the following: ≥80 years;, weight ≤60kg, Cr ≥1.5mg/dl

42

Apixaban vs. warfarin in NVAF

Granger CB et al. N Engl J Med 2011;365:981-992.43

Granger CB et al. N Engl J Med 2011;365:981-992.

Apixaban vs. warfarin in NVAF

44

Granger CB et al. N Engl J Med 2011;365:981-992.

Apixaban vs. warfarin in NVAF

45

Granger CB et al. N Engl J Med 2011;365:981-992.

Apixaban vs. warfarin in NVAF

46

Granger CB et al. N Engl J Med 2011;365:981-992.

Apixaban vs. warfarin in NVAF

47

Granger CB et al. N Engl J Med 2011;365:981-992.

Apixaban vs. warfarin in NVAF

Treatment with apixaban as compared to warfarin in patients with AF and at least one additional risk factor for stroke:• Reduces stroke and systemic embolism by 21%

(p=0.01)• Reduces major bleeding by 31% (p<0.001)• Reduces mortality by 11% (p=0.047)with consistent effects across all major subgroups and with fewer study drug discontinuations on apixaban than on warfarin, consistent with good tolerability.

48

Granger CB et al. N Engl J Med 2011;365:981-992.

Apixaban vs. warfarin in NVAF

In patients with atrial fibrillation, apixaban is

superior to warfarin at preventing stroke or

systemic embolism, causes less bleeding, and

results in lower mortality.

49

Edoxaban

Kinetics Absorption Rapid; Intestines

Peak in 1-2 hours

Metabolism Predominant metabolite is active Hepatic clearance- 50%, 50% renalMinimal via hydrolysis

Excretion Urine (primarily unchanged)

Half-life 10-14 hours

Dosing Dose: 30 mg dailyDose increased if CrCl >50 to 95ml/min to 60mg

-AVOID in CrCl >95 ml/min or < 15ml/min

50

Edoxaban vs. Wafarin in NVAF

Giugliano PR et al. N Engl J Med 2013;369:2093-104..

Edoxaban Stroke or Embolic Event

Giugliano PR et al. N Engl J Med 2013;369:2093-104..

Giugliano PR et al. N Engl J Med 2013;369:2093-104..

Edoxaban Major Bleeding Event

ENGAGE AF TIMI 48: Conclusions

• Both once-daily regimens of edoxaban were noninferior to warfarin for stroke and systemic embolic protection in patients with non valvular atrial fibrillation.

• Both does were associated with significantly lower rate of bleeding and death from CV causes.

54

Trials of NOACs (vs. warfarin) in NVAF

Subjects, %

ROCKET AF(N=14,264)1

RE-LY(N=18,113)2

ARISTOTLE(N=18,201)3

ENGAGE AF –TIMI 48 (N=21,105)

CHADS2 score (mean) 3.5 2.1 2.1 2.8

0 or 1 <0.1* 31.9 34.0 <0.1

2 13.0 35.6 35.8 46

3-6 86.9 32.5 30.2 53.9

Prior VKA use 62.4 49.6 57.1 58.8

CHF 62.5 32.0 35.4 58.2

Hypertension 90.5 78.9 87.4 93.7

Diabetes mellitus 40.0 23.3 25.0 36.4

Prior stroke/TIA/embolism 54.8 20.0 19.4 28.1

Prior MI 17.3 16.6 14.2

*Three subjects with a CHADS2 score of 0 or 1 were enrolled in ROCKET AF in violation of the study protocol.

1. Patel MR et al. N Engl J Med. 2011;365(10):883-891. 2. Connolly SJ et al. N Engl J Med. 2009;361(12):1139-1151. 3. Granger CB et al. N Engl J Med. 2011;365(11):981-992 4. Giugliano RP et al. N Engl J Med. 2013; 369: 2093-104.

NOTE: Because these clinical trials were conducted with different designs and evaluated different populations, direct comparisons of their results cannot be made.

55

NOACs in NVAF:Comparison of trials

Comparative pharmacology of oral anticoagulants

57

Study NOAC VKA Outcome

RE-LY Dabigatran1.1%

Warfarin1.7%

RR 0.6695% CI 0.53-0.82

P < 0.001 superiority

ARISTOTLE Apixaban1.3%

Warfarin1.6%

HR 0.7995% CI 0.66-0.95P= < 0.001 Non- I

P= 0.01 Superiority

ROCKET-AF Rivaroxaban1.7%

Warfarin2.2%

HR 0.7995% CI 0.66-0.96

P = <0.001Non-Inferiority

ENGAGE AF-TIMI 48 HD Edoxaban1.18%LD Edoxaban1.61%

Warfarin1.5%

HR HD 0.7995%CI 0.63-0.99

HR LD 1.0795% CI 0.87-1.31

Non-Inferiority

NOACs in NVAF:Primary endpoints

Study NOAC VKA Outcome

RE-LY Dabigatran3.3%

Warfarin3.6%

RR 0.9395% CI 0.81-1.07

P = 0.31

ARISTOTLE Apixaban2.1%

Warfarin3.1%

HR 0.6995% CI 0.60-0.8

P = < 0.001

ROCKET-AF Rivaroxaban5.6%

Warfarin5.4%

HR 1.0495% CI 0.90-1.20

P = 0.58

ENGAGE AF-TIMI 48

HD Edoxaban2.75%LD Edoxaban1.61%

Warfarin3.4%

HD HR 0.8095 % CI 0.71-0.91

LD HR 0.4795% CI 0.41-0.55

NOACs in NVAF:Bleeding

59

Study NOAC VKA Outcome

RE-LY Dabigatran0.3%

Warfarin0.7%

RR 0.4095% CI 0.27-0.60

P= <0.001

ARISTOTLE Apixaban0.3%

Warfarin0.8%

HR 0.4295% CI 0.30-0.58

P = <0.001

ROCKET-AF Rivaroxaban0.5%

Warfarin0.7%

HR 0.6795% CI 0.47-0.93

P = 0.02

ENGAGE EF-TIMI 48

HD Edoxaban0.39%LD Edoxaban0.26%

Warfarin 0.85%

HD HR 0.4795 % CI 0.64-0.63

LD HR 0.3095% CI 0.21-0.43

NOACs in NVAF:Intracranial hemorrhage

60

Agent Dosing Recommendations

Dabigatran75mg, 150mg

CrCl > 30 cc/min: 150 mg, BIDCrCl 15 to 30 cc/min: 75 mg, BIDAvoid < 15 cc/min

Apixaban2.5mg, 5mg

CrCl > 15 cc/min: 5 mg, BIDAny 2 ( > 80 yrs, < 60 kg, SCr > 1.5mg/dL: 2.5 mg, BID)Avoid < 15 cc/min

Rivaroxaban10mg, 15mg, 20mg

CrCl > 50 cc/min: 20 mg, QdayCrCl 15-50 cc/min: 15 mg, QdayAvoid CrCl < 15 cc/min

Edoxaban30mg, 60mg

CrCl > 50 to < 95mL/min: 60 mg dailyCrCl 15 to 50mL/min: 30 mg dailyAvoid CrCl < 15cc/min and > 95cc/min

NOACs in NVAF:Dosing recommendations

61

Oral anticoagulationClinical indications

• Venous thromboembolism• Treatment• Prophylaxis

• Arterial thrombosis (including PE)• LV thrombus / post-myocardial infarction• Atrial fibrillation (valvular, nonvalvular)• Prosthetic heart valves• CVA (stroke)

62

Oral anticoagulationClinical indications for Pulmonary Embolus and Deep Vein Thrombosis

Comparison of NOAC in VTE Treatment

FDA Approved 1-8-2015

• Provide an overview of coagulation and highlight

potential targets for pharmacotherapy in thrombosis

• Detail the MOA of warfarin and the novel oral

anticoagulants (NOACs) with a focus on practical

considerations related to anticoagulation

• Review the data for use of NOACs in approved clinical

indications

• Outline initiation and transition strategies

• Briefly highlight pipeline agents and combination

therapies

Objectives

66

Medication Transition

Triple therapy and risk of bleeding

Sørensen R, et al. Lancet 2009; 374: 1967–1974. 68

Factors when choosing a NOAC

Summary

70

• Systemic anticoagulation has demonstrated significant benefit

(reduced vascular morbidity/mortality) across a wide range of

thrombosis states

• NVAF remains a large (and growing) global medical problem which

exacts in large part, through increased thromboembolic risk

• AF-associated CVAs are more likely to be more morbid and more

likely fatal than non-AF associated CVAs

• Warfarin anticoagulation has proven benefit across a wide variety of

thrombosis states but is frequently associated with unacceptably low

TTR and management challenges

Summary

71

• The novel oral anticoagulants (NOACs) when used appropriately, offer

more homogeneous treatment effect than dose-adjusted warfarin with

comparable or lower rates of major bleeding

• Hepatic function, renal function and co-administration of medications

impacting NOAC metabolism serve as important considerations when

electing to switch to a NOAC

• Co-administration of oral anticoagulants with oral antiplatelet therapy

increases the risk of major bleeding