Disclosure Statement

Novel (new) Oral Anticoagulants It is the policy of the AAFP that all individuals in a position to control
content disclose any relationships with commercial interests upon
(NOAC’s) nomination/invitation of participation. Disclosure documents are
reviewed for potential conflicts of interest. If conflicts are identified,
they are resolved prior to confirmation of participation. Only
Robert Dachs, MD, FAAFP
participants who have no conflict of interest or who agree to an
Asst. Director, Dept of Emergency Medicine
identified resolution process prior to their participation were
Ellis Hospital, Schenectady, NY
Clinical Associate Professor and Director of Research
involved in this CME activity.
Ellis Hospital Family Medicine Residency All faculty and staff in a position to control content for this session
Albany Medical College have indicated they have no relevant financial relationships to
disclose.

Learning Objectives The NOAC: Who are the players?

1. Utilize a systematic process of care, including initiation and assessment of
therapy and dosing adjustments, to optimize effectiveness and minimize dabigatran (Pradaxa)
adverse effects of patients taking warfarin.
2. Consider new agents in patients with atrial fibrillation and at least one other rivaroxaban (Xarelto)
risk factor for stroke that do not require frequent laboratory monitoring and are
as effective as warfarin for prevention of stroke or systemic embolism and
have comparable risks of major bleeding.
apixaban (Eliquis)
3. Develop collaborative care plans with patient education to counsel patients on
safe and effective self-administration of anticoagulants, emphasizing self-
edoxaban - not yet FDA-approved
monitoring to prevent complications.
4. Establish or revise existing practice-level protocols for anticoagulation
management, based on current evidence-based recommendations and
guidelines, including having clearly defined staff roles and responsibilities.

The NOAC: How do they work? NOAC’s: Approved for….

Intrinsic Extrinsic • Atrial fibrillation
Pathway Pathway

dabigatran: direct thrombin inhibitor Xa

• VTE (DVT/PE)

rivaroxaban: Factor Xa inhibitor Prothrombin • Joint replacement

Thrombin

apixaban: Factor Xa inhibitor (VTE prophylaxis)

Fibrinogen CLOT

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 Atrial fibrillation and anticoagulation:
The NOAC’s Question #1: Which statement below is false?
Pros Cons A. Cardioembolic strokes due to aAfib (without
anticoagulation) have greater morbidity and mortality than
No monitoring needed No approved reversal agent thrombotic strokes
Cost B. Older patients are at a greater risks for sustaining a
Long term experience cardioembolic stroke (than a younger patient) with
untreated Afib
C. The annual risk of developing a cardioembolic CVA in
How do these compare with warfarin? patients with Afib that remain off anticoagulation is 4.5%/yr.
- Afib? D. Placing patients with Afib on anticoagulation results in an
- VTE (DVT/PE)? absolute risk reduction of CVA of 66%

Atrial Fibrillation and Stroke Atrial Fibrillation:

8 Warfarin Harms/Benefits
7
6
5 • Decreases CVA by 4.5% -> 1.4%
4 CVA rate
3
(% per yr) (ARR: 3% NNT = 30, RRR 64%)
2 vs. ASA 22%
• Rate of ICH 0.1 - 0.6%
1
0
< 65 yrs 65-75yrs > 75 yrs

 The older the patient with atrial fibrillation, the higher the risk of –Increased with advanced age, HTN
cardioembolic stroke.
 Strokes due to Afib have higher mortality and morbidity.
• Major bleeding rates: 1.2%/yr
 Warfarin decreases absolute annual risk from 4.5% --> 1.4%
(NNT=30).

Atrial fibrillation: Who is at risk for embolism (CVA)? Atrial fibrillation: Who should get anticoagulation?

• Do you like using a Scoring System?

Moderate-risk factors
Age > 75yrs High-risk factors – CHADS2
HTN Previous CVA,TIA,embolism
CHF Mitral stenosis – CHA2DS2Vasc
LV ejection fraction < 35%
DM
Prosthetic heart valve
• Which one?

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 Atrial Fibrillation: Who Gets Warfarin? CHADS2 vs. CHA2DS2-VASc?
Would the CHADS2 Score Help? CHADS2 Score Score CHA2DS2-VASc
CHADS2 Risk Criteria Score • CHF 1 1 •CHF
• CHF …………………. Risk Category • HTN
1 1 1 •HTN
• HTN………………. 0: Low-risk (ASA) • Age >75 yrs
1 1 2 •Age >75 yrs
• Age > 75 yrs………. 1: Moderate (ASA or warfarin) • DM
1 1 1 •DM
• DM…………………. 2+: High-risk (warfarin) • Prior Stroke or TIA
1 2 2 •Prior Stroke or TIA
• Prior Stroke or TIA… 2 •Vascular disease
1
Pts. (N=1733) CVA Rate (%/yr) (95%CI)CHAD2 Score NNT 1 •Age 65-74 yrs
120 1.9 (1.2 - 3.0) 0 417
463 2.8 (2.0 - 3.8) 1 125 1 •Female sex
523 4.0 (3.1 - 5.1) 2 81 N=1733 VS. N= 1,084 pts
337
220
5.9 (4.6 - 7.3)
8.5 (6.3 - 11.1)
3
4
33
27
with Afib, not on warfarin x 1 year
65 12.5 (8.2 - 17.5) 5 Gage BF, et al JAMA 2001; 285:2864-70 Yip GB, et al. Chest 2010; 137:263-72
5 18.2 (10.5 -27.4) 6

CHADS2 vs. CHA2DS2-VASc? March 28, 2014

CHADS2 CVA Rate @ 1yr CHA2DS2-VASc

NEW!!! AHA/ACC Guideline for the management
- Low risk = 0 points 1.67% vs. 0.78% - Low risk = 0 points
of patients with Atrial Fibrillation
- Intermediate = 1 pt 4.75% vs. 2.0% - Intermediate = 1 pt

N= 73,538 pts with Afib, not on warfarin “In patients with nonvalvular AF, the CHA2DS2-VASc score is
10 year period in Denmark recommended for assessment of stroke risk. (Level of Evidence: B)”

A large external validation study -

That’s what we like to see…
Olesen, JB, et al. BMJ 2011; 342:d124

2014 AHA/ACC guideline on atrial fibrillation Atrial Fibrillation:

• Nonvalvular AF and a CHA2DS2-VASc, Score = 0,
Warfarin Harms/Benefits
it is reasonable to omit antithrombotic therapy
(Class IIA, Level of Evidence: B) • Decreases CVA by 4.5% -> 1.4%
• Nonvalvular AF and a CHA2DS2-VASc, Score = 1, (ARR: 3% NNT = 30, RRR 64%)
no antithrombotic therapy or treatment with an oral anticoagulant vs. ASA 22%
or aspirin may be considered (Class IIB, Level of Evidence: C) • Rate of ICH 0.1 - 0.6%
• Nonvalvular AF and a CHA2DS2-VASc, Score of > 2 –Increased with advanced age, HTN
Or prior CVA/TIA
• Major bleeding rates: 1.2%/yr
oral anticoagulants are recommended (Class 1, Level of evidence A)

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 Who needs to avoid anticoagulation??
Two new scoring systems: HAS-BLED
Points Definition
HAS-BLED and ATRIA 1 H Hypertension Sys BP > 160
1 or2 A Abnormal Renal and/or dialysis/transplant
• A novel User-friendly Score (HAS-BLED) to assess (1pt each) liver function cirrhosis/T. Bili 2x or
AST/ALT 3x normal
1-year risk of major bleeding in patients with atrial 1 S Stroke
fibrillation. Pisters R, et al. Chest 2010; 138: 1093-1100. 1 B Bleeding previous bleed/predisposition
1 L Labile INR < 60% in therapeutic range
1 E Elderly (> 65 yrs)
• A new risk scheme to predict Warfarin-associated 1 or2 D Drugs or alcohol excess antiplatelet or NSAID’s
hemorrhage: The ATRIA study. Fang MC, et al. J AM (1pt each)
Coll Card 2011; 58: 395-401 A score of > 3 is considered “high risk”
ESC recommends “caution” using warfarin1
1ESC Guidelines for the management of atrial fibrillation, 2011
19

HAS- BLED: Results ATRIA: 13,559 pts in Kaiser system

Derivation Cohort Validation Cohort Derivation:Validation = 2 :1 ratio
# of Bleeds per # of Bleeds per Score
Score n bleeds 100 pt yrs n bleeds 100 pt yrs •Anemia: Hgb <13 male, <12 female… 3
0 1517 9 0.59 798 9 1.13 •GFR < 30……………………………… 3
1 1589 24 1.51 1286 13 1.02 •Age > 75 yrs………………………….. 2
2 219 7 3.20 744 14 1.88
------------------------------------------------------------------------------------ •Any prior hemorrhage Dx…………….. 1
3 41 8 19.51 187 7 3.74 •HTN…………………………………….. 1
4 14 3 21.43 46 4 8.70
5 1 0 - 8 1 12.50 Risk category, points Events/100 pt/yrs
6 - - - 2 0 0 Derivation Validation
“Major bleeds” defined as:
• Low risk (0-3) 0.72 0.83
1) bleeding requiring hospitalization 2) require transfusion • Intermediate (4) 2.71 2.41
3) drop in Hgb > 2 g/L 4) Hemorrhagic CVA • High (5-10) 5.99 5.32
21 22

Atrial fibrillation: Lets do a case…. Atrial fibrillation: Lets do a case….

• 87 y/o female, newly recognized Afib • 87 y/o female, newly recognized Afib
– No associated symptoms (palpitations, CP, – No associated symptoms (palpitations, CP,
syncope/lightheadedness) syncope/lightheadedness)
– PMHx: HTN, mild CHF, hypercholesterolemia – PMHx: HTN, mild CHF, hypercholesterolemia
– Meds: HCTZ, Coreg, atorvastatin, baby ASA – Meds: HCTZ, Coreg, atorvastatin, baby ASA
– Past surgery: GB, TAH/BSO, Hip fracture – Past surgery: GB, TAH/BSO, Hip fracture
– ROS: has fallen 3 times in past 6 months – ROS: has fallen 3 times in past 6 months

• PE: In office BP: 150/82, P=60, RR=20 • PE: In office BP: 150/82, P=60, RR=20
CHA2DS2-Vasc = 5/10 (high-risk for CVA)
Would you start anticoagulation? HAS-BLED = 1 points (low risk for bleed)

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 Atrial fibrillation: Lets do a case…. “But I Am Fearful of My Elderly Patient
• 87 y/o female, newly recognized Afib Falling (ie, Subdural)”
– No associated symptoms (palpitations, CP, • Using an analytic model …
syncope/lightheadedness)
– PMHx: HTN, mild CHF, hypercholesterolemia • A patient over age 65 with Afib must sustain
– Meds: HCTZ, Coreg, atorvastatin, baby ASA 295 falls in one year for the risk of subdural
– Past surgery: GB, TAH/BSO, Hip fracture to outweigh benefit of stroke prevention
– ROS: has fallen 3 times in past 6 months Man-Son-Hing, et al. Arch Intern Med. 1999;159(7):677-85.

• PE: In office BP: 150/82, P=60, RR=20 Note 1: Pts on warfarin, spontaneous ICH more common than subdural
Note 2: Model uses assumptions - are they correct?
One of my favorite websites:
www.mdcalc.com
26

Incidence of ICH in patients with Afib You are going to start anticoagulation…
who are prone to fall
but, which one????
• Methods: Retrospective study, pts 80+ yrs of age
Cons:
1,245 “high risk” for falls vs. 18,261 “controls” • Warfarin •Frequent monitoring
•Drug interactions
•Dietary restrictions
High risk Controls
• Results: ICH per 100pt/yrs 2.8 1.1

However… a 25% RRR in death, stroke and hemorrhage

(including ICH) in high risk group persists
Gage BF, et al. Am J Med 2005; 11: 612-17.

Warfarin Dose Assessment every 4 weeks versus every 12 weeks You are going to start anticoagulation…
in patients with Stable INR’s. Schulman S, et al. Ann Int Med 2011; 155:653-59.
but, which one????
Cons:

• Methods: 250 pts, with stable INR x 6 months, randomized: • Warfarin •Frequent monitoring
•Drug interactions
q 4week q12 week • Clopidogrel (Plavix)? •Dietary restrictions

• Results:
– Time in therapeutic range 74% 71%

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 What About Clopidogrel + ASA vs Warfarin? You are going to start anticoagulation…
Don’t Go There!!!
• Methods: 6,706 pts with Afib, randomized double blind:
but, which one????
Cons:
•Frequent monitoring
• Results: ASA + Clopidogrel vs Warfarin • Warfarin •Drug interactions
•Dietary restrictions
Rate of CVA (%/yr) 2.39% 1.4% • clopidogrel (Plavix)
CVA/embolus/MI, 5.6% 3.9% • dabigatran (Pradaxa)
vascular death
• rivaroxaban (Xarelto)
Hemorrhage 15.4% 13.2%
Total mortality No difference • apixaban (Eliquis)
Trial stopped early because of superiority of warfarin!!
ACTIVE W Writing Group, et al. Lancet. 2006;367(9526):1903-1912.

Dabigatran: Is it really 35% better????? What about dabigatran (Pradaxa)?

• RE-LY trial: NEJM 2009; 361: 1139-51.
• Methods: 18,113 pts with Afib , randomized to: followed for 2yrs
dabigatran dabigatran warfarin
110mg BID 150mg BID
• Results
–CVA/embolism 1.53% 1.11%* 1.69%
–Major bleeding/yr 2.71% 3.11% 3.36%
–Mortality rate/yr 3.75% 3.64% 4.13%
ARR = 0.58% NNT=172
Cost: Pradexa = $343 per month, $4116 per year
Price accessed @ CVS, accessed 11/10/13 .
33

What about rivaroxaban (Xarelto)? What about apixaban (Eliquis)?

• ROCKET-AF: NEJM 2011; 365: 883-91 • ARISTOLE: NEJM 2011; 364: 816-17.
• Methods: 18,201 pts with Afib , randomized to: followed for 1.8 yrs
• Methods: 14,264 pts with Afib , randomized to: followed approx 2 yrs
apixaban warfarin
rivaroxaban warfarin 5mg BID
20mg qd • Results
• Results –CVA/embolism 1.27% 1.60%
–CVA/embolism 2.1% 2.4% –Major bleeding/yr 2.13% 3.09%
–Major/minor bleeding/yr 5.6% 5.4% –Mortality rate 3.52% 3.94%
No difference
ARR = 0.33% NNT=303
Cost: Xarelto = $329 per month, $3948 per year
Price accessed @ CVS, accessed 11/10/13 . Cost: Eliquis = $316 per month, $3792 per year
Price accessed @ CVS, accessed 11/10/13 .

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 The NOAC’s The NOAC’s
Pros Cons Pros Cons
No monitoring needed No approved reversal agent No monitoring needed No approved reversal agent
Slightly better outcomes (?) Cost Slightly better outcomes (?) Cost
Long term experience Long term experience

How do these compare with warfarin? Remember: efficacy vs. effectiveness

- Afib ?
- VTE (DVT/PE)?

You are going to start anticoagulation…

Dabigatran associtian with higher risk of acute coronary events:
but, which one???? meta-analysis of noniferiority randomized controlled trials
Cons: Uchino K et al. Arch Intern Med 2012; 172: 397-402
•Frequent monitoring
• Warfarin •Drug interactions
• clopidogrel (Plavix) •Dietary restrictions
• Methods: 7 trials, compared:
• dabigatran (Pradaxa) ? Increase MI’s? dabigatran controls
• Results:
• rivaroxaban (Xarelto)
– AMI/ACS: 237/20,000 83/10,514
• apixaban (Eliquis)
(1.19%) (0.79%)

Update: May 13, 2014 What happened to dabigatran 110mg dose?

• Not FDA approved
• FDA review announces no increase risk of MI • The lower dose has similar efficacy, decreased bleeding
associated with dabigatran dabigatran dabigatran warfarin
110mg BID 150mg BID
– 134,000 Medicare pts (age 65+) with Afib • Results
– CVA/embolism 1.53% 1.11%* 1.69%
– Major bleeding/yr 2.71% 3.11% 3.36%

– Controversy: includes observational studies, not just
randomized trials.
• Company knew single-dose strategy was risky because there are
5-fold variations in plasma levels in 80% of pts -
– Especially in elderly pts
– Company was reluctant to share this with regulators fearing
increased monitoring and disadvantage with competitors.

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 Dabigatran: watch the dosing Dabigatran: Nuances
• Ingested as pro-drug
• No food interaction • Unstable if not store in original bottle (desiccant in lid)
• PPI’s decrease absorption 20-30% or blister pack
• Renal excretion…….. • Must be used within 60 days (if maintained in original
– change dose in renal impairment
bottle or blister packs)
•CrCl 30-50 mL/min: + P-gp inhibitor
- Decrease dose to 75 mg PO BID • No pill boxes
•CrCl 15-30 mL/min:
- Decrease dose to 75 mg PO BID
•CrCl 15-30 mL/min + P-gp inhibitor: Avoid concurrent use
•CrCl <15 mL/min or dialysis:
- No data available; not recommended

Can you monitor dabigatran effect? You are going to start anticoagulation…
but, which one????
• Currently….No Cons:
•Frequent monitoring
• Hemoclot Thrombin Inhibitor assay • Warfarin •Drug interactions
– A dilute Thrombin time (TT) with internal dabigatran • clopidogrel (Plavix) •Dietary restrictions

calibrators. • Increase MI’s

• dabigatran (Pradaxa) •Renal dosing
– Correlates closely and linearly with dabigatran levels. •Bleeding risks?
• rivaroxaban (Xarelto)
– Company tested and noted “This rapid, standardized and
calibrated assay should provide accurate and consistent results” • apixaban (Eliquis)

Rivaroxaban: Nuances Apixaban: Nuances

• Onset within 4 hours • Onset within 3- 3.5 hours
• Factor Xa does not return to normal for 24 hours • 1/2 life 8-15 hours (BID dosing)
• 80 - 100% absorption/bioavailability, take with food • 27% renal excretion, 73% metabolic degradation
• 33% renal excretion, 66% metabolic degradation •CrCl >30 mL/min: 5 mg PO BID
•Decrease dose to 2.5 mg PO BID if…
•CrCl >50 mL/min: 20 mg PO QD with evening meal • A. CrCl <15- 29 mL/min OR
•CrCl 15-50 mL/min: Decrease dose to 15 mg PO QD, with evening meal • B. if any of 2 of the following:
•CrCl <15 mL/min or dialysis: No data available; not recommended - Age > 80 yrs
- Body weight < 60kg
- Serum Creatinine > 1.5
• Drug interactions: Inhibitors of CYP3A4 and P-gp
(e.g., ketoconazole, itraconazole, ritonavir, or clarithromycin) • Drug interactions: Inhibitors of CYP3A4 and P-gp
(e.g., ketoconazole, itraconazole, ritonavir, or clarithromycin)

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 You are going to start anticoagulation… Atrial fibrillation: Is there an easy way to decide?
• 87 y/o female, newly recognized Afib
but, which one????
Cons:
– No associated symptoms (palpitations, CP,
•Frequent monitoring syncope/lightheadedness)
• Warfarin •Drug interactions – PMHx: HTN, mild CHF, hypercholesterolemia
•Dietary restrictions
• clopidogrel (Plavix) – Meds: HCTZ, Coreg, atorvastatin, baby ASA
• Increase MI’s
• dabigatran (Pradaxa) •Renal dosing – Past surgery: GB, TAH/BSO, Hip fracture
• rivaroxaban (Xarelto)
•Bleeding risks? – ROS: has fallen 3 times in past 6 months
• apixaban (Eliquis) •Renal dosing • PE: In office BP: 150/82, P=60, RR=20

www.Afib .ca

Step 1

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Step 2

Step 3

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 The NOAC’s
Pros Cons
No monitoring needed No approved reversal agent*
Slightly better outcomes (?) Cost
Long term experience

Remember: efficacy vs. effectiveness

Question #2: 65 y/o with Afib on warfarin with acute ICH.

The ACCP recommends: FFP and Vitamin K
FFP - normalize INR 13-48 hours
A. Start FFP and Vitamin K 10mg IV – Need ABO testing
B. Start FFP and Vitamin K 10mg IM – 30-60 minutes to thaw
C. Start Activated Factor VII – 15ml/kg - approx 1L (4units) for 70kg
+ Vitamin K 10mg IV • May need 30ml/kg
D. Start a Prothrombin Complex
Concentrate (PCC) Vit K - normalize INR 12-24 hours
+ Vitamin K 10mg IV – 10mg IV (over 30min) - 3/100,000 anaphylaxis

rFVIIa Prothrombin Complex Concentrate (PCC)

Only indication in US is use in hemophilia
–97% of use is off-label Pooled human plasma
Will reverse INR in 10minutes Stored as a powder
–INR is sensitive to factors VII and X, not II or IX – ABO testing not required
–***So clinical impact is unknown
• Study healthy adults given warfarin, then rVIIa ===> – Volume <100ml
Normalized INR, but persistent bleeding punch biopsy Contains II, IX, X, varying amounts VII and Protein C and S
–Dose - unknown with Short-half life Rapidly reverse INR: 3-15 minutes
Up to 10-20% ==> thrombosis
–Black Box warning
Skolnick BE, et al. Blood 2010; 116:693-701.

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 Prothrombin Complex Concentrate (PCC) These organizations recommend PCC for
warfarin-associated bleeding
Profilnine SD - 3 factor
ACCP (2008, 2012)
Feiba NH - 3 factor“activated” Dose: 25-50 IU/kg
AHA/ASA
Kcentra - 4 factor European Stroke Organization
Most studies are limited by: Australasian Society of Thrombosis and Haemostasis
Differing brands, doses, adjunctive therapy, Canadian Advisory Committee on Blood and Blood
Retrospective designs, small sample sizes, Products
Lack of controls, randomization or comparisons
Heterogeneous populations

Question #3: Which of the following PCC’s are Question #3: Which of the following PCC’s are
FDA-approved for reversing life-threatening FDA-approved for reversing life-threatening
bleeding associated with warfarin? bleeding associated with warfarin?
A. Profilnine SD - 3 factor A. Profilnine SD - 3 factor
B. Feiba NH - 3 factor “activated” B. Feiba NH - 3 factor “activated”
C. Kcentra - 4 factor C. Kcentra - 4 factor
D. None of the above D. None of the above
- Approved 4/29/13 for
Warfarin-induced bleed
– Contains small amt. heparin - avoid in HIT

Suggested Protocol Kcentra Cost

In life-threatening bleeding, on warfarin
Vitamin K 10mg IV + Kcentra 70 kg: 25IU = $2363
INR 2-4, give 25U/kg 70 kg: 50IU = $4725
INR 4-6, give 35U/kg
INR> 6, give 50U/kg

B. If hx of HIT: Profilnine 50IU/kg

C. If blood product contraindicated..
Consider rFVIIA 1-2mg (off-label)

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 What about bleeding Question #4: Which of the following new oral
anticoagulants is approved for the management
associated with NOAC’s? of DVT/PE?

Only anectodal, animal models and small • A. dabigatran (Pradaxa)

human (healthy) volunteer studies • B. rivaroxaban (Xarelto)
• C. apixiban (Eliquis)
• D. A and B
PCC’s may be useful • E. All of the above

Consider hemodialysis for dabigatran (not protein bound)

Question #4: Which of the following new oral

anticoagulants is approved for the management of
DVT/PE? April 7, 2014
Dabigatran (Pradaxa) gains FDA approval for DVT/PE treatment
• A. dabigatran (Pradaxa)
• B. rivaroxaban (Xarelto)
• C. apixiban (Eliquis)
• D. A and B
• E. All of the above

Dabigatran versus Warfarin in the Treatment of Acute Question #4: Which of the following new oral
Venous Thromboembolism. RE-COVER Study, NEJM, 2009 anticoagulants is approved for the management
of DVT/PE? Warning!!!!

• Methods: double-blind, randomized, non-inferiority trial, After 5-10 days of

• A. dabigatran (Pradaxa) parenteral anticoagulation
After 9 days of parenteral anticoagulation,
• B. rivaroxaban (Xarelto)
• Results: after 6 months warfarin dabigatran • C. apixiban (Eliquis)
• Recurrent VTE 2.1% 2.4% • D. A and B
• Bleeding 1.9% 1.6% • D. All of the above

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 Question #4: Which of the following new oral
anticoagulants is approved for the management
Rivaroxaban for Symptomatic Venous
of DVT/PE?
Study #1 Thromboembolism
Warning… The EINSTEIN Investigators
Change in dosing! NEJM 2010
• A. dabigatran (Pradaxa)
15mg BID x 3weeks,
• B. rivaroxaban (Xarelto) then 20mg qd
• C. apixiban (Eliquis) Oral Rivaroxaban for the Treatment of
Symptomatic Pulmonary Embolism
• D. A and B Study #2
The EINSTEIN Investigators
• E. All of the above
NEJM 2012

Rivaroxaban for Symptomatic Venous Oral Rivaroxaban for the Treatment of

Thromboembolism Symptomatic Pulmonary Embolism
The EINSTEIN Investigators The EINSTEIN Investigators
Study #1 Study #2
NEJM 2010 NEJM 2012

• Methods: open-label, non-inferiority study, followed 12 months • Methods: open-label, non-inferiority study, followed 12 months

Enoxaparin + rivaroxaban 15mg x 3wks, Enoxaparin + rivaroxaban 15mg x 3wks,

• Results: Warfarin (N=1718) then 20mg qd (N=1731) • Results: Warfarin (N=2413) then 20mg qd (N=2419)
• Recurrent VTE 51 (3.0%) 36 (2.1%) • Recurrent PE 44 (1.8%) 50 (2.1%)
Hazard Ratio 95%CI (0.44-1.04) Hazard Ratio 95%CI (0.75-1.68)
• Bleeding 8.1% 8.1% • Bleeding 11.4% 10.3%

Rivaroxaban for VTE:

who should not receive it?
• Exclusion criteria:
– Vena cava filters
– CrCl < 30
– Clinically significant liver dz, AST > 3X normal
– Pregnancy
– Potent CYP3A4 inhibitors (HIV drugs, rifampin, carbamazepine, ect…)

Cancer patients????? Wells, PS

JAMA, Feb 2014

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 LMWH vs. vitamin K antagonists for With a NOAC (rivaroxaban),
cancer associated VTE can you now treat PE as an outpatient?
• Methods: systematic literature review
• 2 randomized trials have suggested safety of
• Results: 9 randomized studies, N= 1,908 patients outpatient therapy for PE
• Meta-analysis of 7 trials ==>
LMWH cont. LMWH/warfarin • 30-50% of PE are considered “low risk”/candidates for
- Recurrent VTE: **RRR 0.47; (95% CI 0.32 - 0.71) outpatient therapy
- Mortality No difference
- Bleeding No difference
Akl EA, et al. Cochrane Database Syst Rev, 2011

Outpatient Management of PE
• Methods: Open-label non-inferiority trial
–19 ED’s (international)
–Patients with acute, symptomatic PE
• Low risk of death (PESI class I and II)
–Enoxaparin + oral anticoagulation

• Measured outcomes:
• Recurrent PE within 90 days
• Major bleeding
Wells, PS • Mortality
JAMA, Feb 2014 Aujesky: Lancet 2011

– PE Severity Index PESI..

• Age in years Add up the points
• Male: 10
• Cancer: 30
30-day mortality rates
Severity Class I: < 65 points
• CHF: 10 • Class I - < 65 points 0 - 1.6%
Severity Class II: 66 - 85 points
• COPD: 10
• Class II - 65-85 1.7 - 3.5%
• Pulse >/= 110: 20
• SBP < 100: 30* • Class III - 86-105 3.2 - 7.1%
• RR >/= 30: 20 • Class IV - 106-125 4.0 - 11.4%
• T < 36 C: 20
• Altered mental status: 60 • Class V - > 125 10.0 - 24.5%
• O2 sat < 90%: 20*

Aujesky: Lancet 2011 Aujesky D, et al. Am J Resp Crit Care 2005

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 Outpatient Management of PE Inpatient vs. Outpatient PE care
• Results • How many patients would qualify?
–171 outpatients, 168 inpatients 470/1543 (30%)
–OP vs. IP
• Recurrent PE: 1 (0.6%) vs. 0
– ****Upper 95%CI 2.7%

• Major bleeding @ 90 ds: 3 (1.8%) vs. 0

– ****Upper 95%CI 4.5%

• Death: 1 (0.6%) in both groups

• Mean LOS: 0.5 vs. 3.9 days Aujesky: Lancet 2011

Inpatient vs. Outpatient PE care Inpatient vs. Outpatient PE care

• Excluded from trial: • Excluded from trial: + PESI Score
– O2 sat < 90%, pO2 < 60 – O2 sat < 90%, pO2 < 60
– BP sys < 90 – BP sys < 90
– Chest pain requiring opioids – Chest pain requiring opioids
– Active bleeding – Active bleeding
– Psychosis/dementia – Psychosis/dementia
– Platelets < 75,000 – Platelets < 75,000
– CrCl <30mL – CrCl <30mL
– Weight > 150kg – Weight > 150kg
– HIT or allergy to heparins – HIT or allergy to heparins
– INR > 2.0 – INR > 2.0
– Barriers to follow up (eg. Substance abuse)/imprisonment – Barriers to follow up (eg. Substance abuse)/imprisonment
– Pregnancy – Pregnancy
– CVA < 10 days or GI bleed < 14 days – CVA < 10 days or GI bleed < 14 days

Conclusions
• Anticoagulation is underutilized and beneficial in
patients with Afib. Thank you for your time
• The NOAC’s may provide some advantages and and consideration!!!
disadvantages compared to warfarin
• Be aware of the various dosing issues involving the
NOAC’s (one size does not fit all). Contact info: dachsmd@aol.com
• If you are going to prescribe a NOAC, you must make
certain your patient can afford it and be compliant.

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