Stroke and Clot Prevention:

New Guidelines and New Drugs?

Glenda Carr, PharmD

Clinical Assistant Professor of Pharmacy Practice

Disclosure

The planners and presenter of this presentation have disclosed no conflict

of interest, including no relevant financial relationships with any commercial

interests

Learning Objectives

Assess patient risk factors for developing stroke and VTE.

Cite and discuss recent anticoagulation guidelines for

stroke and VTE prevention.

Develop a therapeutic plan for first and recurrent stroke

and VTE prevention utilizing guideline recommendations

and incorporating individual patient factors.

Abbreviations AF- atrial fibrillation

PAF- paroxysmal atrial fibrillation

TE- thromboembolism

VTE- venous thromboembolism

PE- pulmonary embolism

DVT- deep vein thrombosis

NOAC- novel oral anticoagulant

VKA- vitamin K antagonist

CHF- congestive heart failure

LMWH- low molecular weight heparin

UFH- unfractionated heparin

COR- Class of recommendation

MVR- mechanical valve replacement

January CT, et al. Circulation 2014;130:e199–e267.

Brand/Generic

Thrombin Inhibitor

Dabigatran- Pradaxa®

Factor Xa Inhibitor

Rivaroxaban- Xarelto®

Apixaban- Eliquis®

Edoxaban- Savaysa®

Vitamin K Antagonist

Warfarin- Coumadin®

Considerations for Long Term

Anticoagulation

Risk of bleeding

HAS-BLED

ORBIT

Risk of stroke

A fib

Valve replacement

Risk of recurrent VTE

Distal vs. proximal location

Provoked vs. idiopathic

Other considerations

Patient preference

HAS-BLED

Hypertension (uncontrolled SBP >160 mmHg)

Abnormal renal and/or liver function

Previous Stroke

Bleeding history or predisposition (anemia)

Labile INR (only for VKA users)

Elderly (age ≥65)

Concomitant Drugs (antiplatelet, NSAIDs, alcohol excess)

Scoring

“Low risk” 0-1

“Moderate/intermediate risk” 2

“High risk” ≥3

ORBIT-AF Older than 74

Reduced Hb/presence of anemia/abnormal Hb/Hct

(<13 g/dl or Hct <40% in males and Hb <12 or Hct <36% in

females)

Bleeding history

Insufficient kidney function (GFR <60)

Treatment with antiplatelet

Scoring

“Low risk” 0-2

“Moderate/intermediate risk” 3

“High risk” ≥4

Calculate the bleeding risk using the HAS-

BLED for a 68 year old woman with a BP of

162/84, hx of CVA, and an AST level of 72.

A. 0

B. 1

C. 2

D. 3

E. 4

0 1 2 3 4

20% 20% 20%20%20%

Kearon C, et al. CHEST 2016;149:315-352.

Considerations for Long Term

Anticoagulation

Risk of bleeding

HAS-BLED

ORBIT

Risk of stroke

A fib

Valve replacement

Risk of recurrent VTE

Distal vs. proximal location

Provoked vs. idiopathic

Other considerations

Patient preference

Further Defining AF1

Summary of Recommendations1

Recommendations COR

Selection of therapy based on risk of TE I

CHA2DS2-VASc score to assess stroke risk I

Warfarin for mechanical heart valves I

Dabigatran should not be used with a

mechanical heart valve III

Treat atrial flutter like AF I

Utilize creatinine clearance to guide

therapy IIa-III

CHA2DS2-VASc

CHA2DS2 VASC Clinical characteristic Points

C Congestive heart failure 1

H Hypertension: Consistently >140/90

mmHg (or on medication)

1

A2 Age ≥ 75 2

D Diabetes Mellitus 1

S2 Stroke or TIA or Thromboembolism 2

V Vascular Disease (e.g. peripheral artery

disease, myocardial infarction, aortic

plaque

1

A Age 65-74 1

SC Sex Category (i.e. female gender) 1

Interpreting the Score1

CHA2DS2 VASC score Annual risk of stroke

0 0

1 1.3%

2 2.2%

3 3.2%

4 4.0%

5 6.7%

6 9.8%

7 9.6%

8 12.5%

9 12.2%

No

anticoagulation

required- IIa

May

consider

long term

treatment-IIb

Long term

treatment

should be

considered- I

If the earlier patient was a first degree

relative, would you consider long term

anticoagulation for atrial fibrillation?

Discuss your rationale with your neighbor

Treatment Selection for CHA2DS2-VASc

Score 0

Reasonable to omit therapy

Score 1

Aspirin may be considered

Score 2 or more

Warfarin (LOE A)

NOAC (LOE B)

Warfarin vs. NOAC: Meta-Analysis2

Randomized phase 3 trials

Safety and efficacy outcomes reported

Warfarin compared to NOAC

4 major trials included

RE-LY (Randomized Evaluation of Long Term Anticoagulation Therapy)

ROCKET-AF (Rivaroxaban Once Daily Oral Direct Factor Xa

Inhibition Compared With Vitamin K Antagonism for Prevention

of Stroke and Embolism Trail In Atrial Fibrillation)

ARISTOTLE (Apixaban for Reduction in Stroke and Other

Thromboembolic Events in Atrial Fibrillation)

ENGAGE AF-TIMI 48

Over 71,000 people included in analysis

Primary Outcomes2

Secondary Outcomes2

Stroke or Systemic Embolic Events2

Major Bleeding2

Nishimura RA, et al. Circulation. 2014; 129: e57-185.

MVR and Dabigatran6

RE-ALIGN trial (warfarin vs. dabigatran)

Dabigatran renal dosing

Warfarin dosed based on appropriate INR

Trial stopped early (252 enrolled)

Stroke 0% vs. 5% (n=9)

Valve thrombosis 0% vs. 3% (n=5)

Bleeding 12% vs. 27%

Major bleeding 2% (n=2) vs. 4% (n=7)

Considerations for Long Term

Anticoagulation

Risk of bleeding

HAS-BLED

ORBIT

Risk of stroke

A fib

Valve replacement

Risk of recurrent VTE

Distal vs. proximal location

Provoked vs. idiopathic

Other considerations

Patient preference

Chance of Recurrence

First unprovoked episode

10% at year one

30% at year five

5% per year after the first year

Prior treatment duration does not affect recurrence

Cancer 3x higher risk of recurrent VTE, 10x mortality rate

Harder to determine provoked recurrence rates

Definitions7

Guideline Recommendations3

Recommendations COR

Long term treatment is better than no treatment in proximal

DVT or PE

Ib

Long term NOAC treatment preferred to VKA in DVT of the

leg or PE (no cancer)

IIb

DVT of the leg or PE with cancer LMWH long term treatment

preferred over VKA/NOAC, regardless of bleeding risk

extended treatment recommended

IIb/IIc

Ib/IIb

Provoked DVT of leg or PE long term treatment over shorter,

longer time-limited period, or extended treatment

Ib

Unprovoked DVT of leg or PE long term treatment over

shorter, longer time-limited period, or extended treatment

Ib

Unprovoked first VTE with low-moderate bleeding risk

recommend extended treatment over long-term treatment

IIb

Unprovoked first VTE with high bleeding risk recommend

long-term treatment over extended treatment

Ib

Recurrent VTE3

Recommendation COR

Low bleeding risk extended anticoagulation therapy over

long term treatment

Ib

Moderate bleeding risk extended therapy over long term

treatment

IIb

High bleeding risk long term treatment over extended

treatment

IIb

While on treatment switch to LMWH at least temporarily IIc

Rivaroxaban or aspirin for extended

treatment of venous thromboembolism9

Inclusion 18 years of age or older

Symptomatic DVT or PE

Previous treatment for 6-

12 months

Exclusion Contraindication to

continued

anticoagulation

Required extended

anticoagulation

Creatinine clearance of

less than 30ml/min

Hepatic disease

N Engl J Med. 2017 Mar 30;376(13):1211-1222. doi: 10.1056/NEJMoa1700518. Epub 2017 Mar 18

N Engl J Med. 2017 Mar 30;376(13):1211-1222. doi: 10.1056/NEJMoa1700518. Epub 2017 Mar 18

Kearon C, et al. CHEST 2016;149:315-352.

Recommendations when using

warfarin1

During initiation, check INR at least weekly

Check INR monthly

Base bridging considerations on risk of clot with

bleeding risk

Consider NOAC if unable to maintain therapeutic INR

Why use a NOAC?2

Rapid onset and offset action

Lack of dietary interactions

Fewer drug interactions

No routine lab monitoring

Better outcomes?

Effectiveness8

Apixaban

(Eliquis)

Dabigatran

(Pradaxa)

Rivaroxaban

(Xarelto)

Edoxaban

(Savaysa)

A Fib • Per 1000

patients

treated per

year

o Prevents 3

more strokes

o Prevents 4

deaths

• Per 1000

patients treated

per year

o Prevents 5 more

strokes

o 2 more MIs

• Comparable for

stroke or

systemic

embolism

• Lower rate of

hemorrhagic

stroke

• Comparable

DVT/PE

(treatment/

prevention)

• Comparable • Comparable • Comparable • Comparable

Bleeding Events8

Apixaban (Eliquis) Dabigatran

(Pradaxa)

Rivaroxaban

(Xarelto)

Edoxaban

(Savasya)

A fib • Avoids 10 major

bleeds per 1000

patients treated

• Lower rate of

hemorrhagic

and ischemic

stroke

• Higher rate of

major GI Bleed

• Comparable

overall bleeding

• Higher rate of GI

bleeds

• Per 1000 patients per year 6

fewer bleeds

DVT/PE • Less bleeding • Comparable

major bleeding

• DVT-

comparable

major bleeding

or clinically

relevant non-

major bleeding

• PE- lower rate of

major bleeding

• Per 1000 patients per year 18

fewer bleeds

Apixaban (Eliquis®)8

Dosing

DVT and PE treatment: 10 mg BID x7 days, then 5 mg BID x6

months, then 2.5 mg BID

Non-valvular Atrial Fibrillation: 5 mg BID

2.5 mg BID if 2 of the following: Age ≥80 years, weight ≤60 kg,

or Sr Cr ≥1.5 mg/dL

Switching anticoagulation therapies

From warfarin: d/c warfarin when INR is <2 and initiate apixaban

To warfarin: d/c apixaban and begin a parenteral anticoagulant

with warfarin when the next dose of apixaban is due

Apixaban may interfere with initial INR readings

Drug Interactions

Avoid strong inducers of both CYP 3A4 and P-gp

Dabigatran (Pradaxa®)8

Dosing

DVT and PE treatment: 150 mg BID

Non-valvular Atrial Fibrillation: 150 mg BID

Switching anticoagulation therapies

From warfarin: d/c warfarin, start dabigatran when INR <2

To warfarin: start warfarin 1-3 days prior to d/c dabigatran

Drug Interactions

P-gp inhibitors increase levels

P-gp inducers decrease efficacy

Antacids reduce efficacy

Antidote: idarucizumab (Praxbind®)

Rivaroxaban (Xarelto®)8

Dosing

DVT and PE treatment: 15mg QD x3 weeks then, 20mg daily

Non-valvular Atrial Fibrillation: 20mg QD

Switching anticoagulation therapies

From warfarin: d/c warfarin and start rivaroxaban when INR <3

To warfarin: d/c rivaroxaban and begin a parenteral anticoagulant with warfarin when the next dose of rivaroxaban is due

Rivaroxaban may interfere with initial INR readings

Drug Interactions

Inducers of both CYP 3A4 and P-gp may decrease efficacy

Avoid strong inhibitors of both CYP 3A4 and P-gp

Edoxaban (Savasya®)8

Dosing

DVT and PE treatment: 60 mg QD, unless weight ≤60 kg then 30mg QD

Non-valvular Atrial Fibrillation: 60 mg QD

Switching anticoagulation therapies

From warfarin: d/c warfarin, then start edoxaban when INR ≤2.5

To warfarin: reduce edoxaban dose by 50% and start warfarin then continue until INR ≥2

Drug Interactions

Inducers of both CYP 3A4 and P-gp may decrease efficacy

Avoid strong inhibitors of both CYP 3A4 and P-gp

Renal Dosing1

If you had to use a long term anticoagulant,

which one would you choose?

A. Dabigatran (Pradaxa®)

B. Rivaroxaban (Xarelto®)

C. Apixaban (Eliquis®)

D. Edoxaban (Savaysa®)

E. Warfarin (Coumadin®)

Dabiga

tran (P

radaxa

®)

Rivaro

xaban

(Xare

lto®)

Apixaban

(Eliq

uis®)

Edoxa

ban (S

avays

a®)

Warfa

rin (C

oumad

in®)

20% 20% 20%20%20%

Why did you choose what you did?

Patient Preference and

Other Considerations8

Cost

Adherence

Medications

INR monitoring

Drug/food/alcohol interactions

GI bleed risk/history

Concern for anticoagulation reversal

Pregnancy

Dabigatran (Pradaxa®) $333.57

Rivaroxaban (Xarelto®) $333.27

Apixaban (Eliquis®) $359.92

Edoxaban (Savaysa®) $291.30

Warfarin (Coumadin®) <$5.00

Idaho Medicaid4

Selected References

1. January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC Jr, Conti JB, Ellinor PT, Ezekowitz MD, Field ME, Murray KT, Sacco RL, Stevenson WG, Tchou PJ, Tracy CM, Yancy CW. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Circulation 2014;130:e199–e267.

2. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with

warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014; 383:955-62.

3. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE Disease: CHEST guideline and expert panel report. CHEST 2016;149:315-352.

4. http://healthandwelfare.idaho.gov/Medical/PrescriptionDrugs/PriorAuthorizationForms/tabid/206/Default.aspx (accessed 2/7/17)

5. Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP III, Guyton RA, O’Gara PT, Ruiz CE, Skubas NJ, Sorajja P, Sundt TM III, Thomas JD. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014; 129: e57-185.

6. Eikelboom, JW, Connolly SJ, Brueckmann M, et al. Dabigatran versus warfarin in patients with mechanical heart valves.

N Engl J Med 2013; 369:1206-14.

7. Kearon C, Akl EA, Comerota AJ, et. al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. CHEST 2012; 141:e419-494.

8. PL Detail-Document, Comparison of Oral Anticoagulants. Pharmacist’s Letter/Prescriber’s Letter. May 2016.

9. Weitz JI, Lensing AWA, Prins MH, et al. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med 2017;376:1211-22.