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Venous Thromboembolism

BEAT THE CLOT

Pennsylvania Academy of Family PhysiciansNovember 7, 2015Allentown, PA

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Faculty and curriculum development teamOur faculty and planners have completed disclosure of interest statements. Drs. Olson and Dressner, and Mss. Shelly Rodrigues, Jerri Davis and Mary Ales declare that in the past 12 months neither they nor any members of their families have had a financial interest in organizations supporting this activity. Dr. Flores declares that in the past 12 months he has received Advisory Board honoraria from Aerocrine and ResMed. Dr. Garcia declares that in the past 12 months he has served as a consultant for Boehringer Ingelheim, Bristol Myers Squibb, Daiiichi Sankyo and Pfizer and received research support from Daiichi Sankyo and Janssen.

CAFP’s Committee on Continuing Professional Development reviews and resolves all COI disclosures.

David Garcia, MDHematology and Internal MedicineProfessor of Medicine, Division of HematologyUniversity of Washington School of Medicine

Christopher Flores, MDFamily MedicineFaculty, Loma Linda University School of Medicine

Mark Dressner, MDFamily MedicineLong Beach, CA

Cheri Olson, MDFamily MedicineFaculty, La Crosse Mayor Family Medicine Residency Program

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Today’s faculty

William R. Sonnenberg, MDPast President, PAFP

Titusville, PA

Dr. Sonnenberg declares that in the past 12 months neither he nor his spouse/partner have had any financial relationships commercial entities who might support this project.

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Sponsors and support

This activity is sponsored by the California Academy of Family Physicians.

It has been developed as part of the work of the TEAM-A Partnership, a 10-organization collaboration seeking to improve the care of patients with AFib and VTE conditions.

This initiative is supported by an unrestricted educational grant from Bristol-Meyers-Squibb/Pfizer.

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VTE: Beat the Clot

• Online VTE community for youfacilitated by us

• Private! Secure!• Interact, share, learn

REQUEST an invitation to join via email: CME-CPD@familydocs.orgtype “yammer” in subject line

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Questions for today

1.How do I complete the initial assessment and management ?

2.How long do I treat?

3.What about peri-operative and peri-procedural care?

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DVT and PE

• Kills 4-5 times as many as breast cancer

• 300,000 deaths per year

• Number one preventable cause of hospital related deaths

• 10% of hospital deaths

• #1 killer of pregnant women

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Initial Assessment and Management 8

Claire

49-year-old woman. Unilateral leg pain and swelling 4 days

after completing a 10.5 hour air flight..

HR 104, BP normal, pO2 91% on room air

No history of DVT/PE in primary relatives.

Left leg swollen, no circulatory insufficiency.

Compression ultrasonography shows acute femoral vein thrombosis (left leg).

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Classic Signs of DVT

• All have low predictive value

• Homans’ sign

• Edema

• Tenderness

• Warmth

• Redness

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Differential Diagnosis of DVT

• 75% of suspected DVT will have other cause

• Ruptured Baker’s cyst

• Cellulitis

• Muscle tear or cramp

• Muscle hematoma

• Superficial phlebitis

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Wells Criteria for DVT

Clinical Feature PointsActive Cancer 1

Leg paralysis, immobile 1

Bedridden > 3 days 1

Local vein tenderness 1

Entire leg swollen 1

Unilateral swelling > 3 cm 1

Unilateral pitting edema 1

Superficial veins 1

Likely alternative -2

Pts Risk

≥3 High 75%

1 -2 Mod 17%

0 Low 3%

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D-Dimer Tests

• Vary widely in sensitivity and specificity

• Positive test does not raise likelihood of DVT

• Good sensitivity

• Wells < 2 and negative D-dimer less than 0.4% likelihood

• Negative predictive value 94%

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Doppler Ultrasonography

• Most widely used• Normal study in high risk patient not

good enough • Repeat in 7 days

• Old clot, new clot - same on U/S• Inaccurate in pelvis or small calf vessels• Obesity or edema hurts accuracy• False positive in superficial phlebitis,

popliteal cysts, or abscess

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Superficial Femoral Vein

• DEEP VEIN!

• 24% of respondents would have anticoagulant (FP, IM, Chairpersons, lab directors)

• 93% of vascular labs use term

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Assuming Claire’s diagnosis is correct:

The most important next step in the management of this patient is:

A. Measure d-dimer concentration

B. Perform CT angiogram (helical/spiral CT) of the chest

C. Administer anticoagulation (in therapeutic doses)D. Administer systemic thrombolysis (IV tissue

plasminogen activator)

E. Perform pharmaco-mechanical thrombolysis (local therapy)

You can download medical apps, like the Wells

scale, to assist you in your assessment.http://www.mdcalc.com/wells-criteria-for-

dvt/

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As you continue to treat Claire:

Which of the following would NOT be an indication for treatment over and above anticoagulation?

A. Pulmonary embolism with systemic hypotension and tachycardia, but normal arterial oxygen saturation

B. Iliac vein thrombosis with phlegmasia cerulea dolens(possibly compromised circulation)

C. Common femoral vein thrombosis greater than 6 cm in length

D. Pulmonary embolism with biochemical and echocardiographic evidence of right ventricular strain

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Claire

Does this information change your treatment of Claire?

She has a diagnosis of VTE

Is Claire at risk for complications of pulmonary embolism? Would you assign her high or low risk?

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Low-risk PE may be treated out of hospital

Outcome90-day Event Rate

(95% CI)

Recurrent VTE 1.47% (0.47 to 3.0%)

Fatal PE 0.47% (0.16 to 1.0%)

Major Bleeding 0.81% (0.37 to 1.42%)

Fatal ICH 0.29% (0.06 to 0.68%)

Overall Mortality 1.58% (0.71 to 2.80%)

Piran et al. Thromb Res. 2013 Nov;132(5):515-9.

Pooled analysis of > 1,200 patients with acute low-risk PE(all treated as outpatients; 11 studies)

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The Pulmonary Embolism Severity Index (PESI) ScorePredictors B‐Coefficients

(95% C1)Points Assigned

Demographic characteristics

Age, per year 0.03 (0.02‐0.03) Age, in years

Male sex 0.17 ((0.02‐0.032) + 10

Co‐morbid conditions

Cancer 0.87 (0.71‐1.03) + 30

Heart failure 0.31 (0.14‐0.49) + 10

Chronic lung disease 0.30 (0.12‐0.47) + 10

Clinical findings

Pulse > 110/min 0.60 (0.44‐0.76) + 20

Systolic blood pressure < 100mm Hg 0.86 (0.67‐1.04) + 30

Respiratory rate > 30/min 0.41 (0.23‐0.58) + 20

Temperature <36 C 0.42 (0.25‐0.59) + 20

Altered mental status 1.50 (1.30‐1.69) + 60

Arterial oxygen saturation <90% 0.58 (0.37‐0.79) + 20

Point total and risk classes:  < 65=Class I, 66‐85=Class II, 86‐105=Class III, 106‐125+Class IV, >125=Class VAujesky, D. et al J Respir Crit Care Med. 2005;172,1041-1046.

Multiple screening tools exist to assist you in

assigning risk.

What does this mean for Claire?

Class 1 – Low risk Class 5 – Jump on this right now!

In a study reported by Jimenez et al Chest 2007 vol. 132(1):P 7-8, of 10,354 patients with 30-day PE risk stratification, 953 died:

Class DeathPESI I 1.1 (0.7–1.7)PESI II 3.1 (2.5–4.0)PESI III 6.5 (5.5–7.6)PESI IV 10.4 (9.0–11.9)PESI V 24.5 (22.7–26.9)

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Is anticoagulation sufficient? Yes/No, why?

Can I treat Claire outside the hospital? If Yes. Why, and how?

If No. What are the situations that merit in-hospital treatment?

Discussion questions 21

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Of the following treatments for acute DVT/PE, which does not require an antecedent course of heparin (i.e. can be given as monotherapy from the outset)?

A. Dabigatran 150 PO BIDB. Rivaroxaban 15 mg PO BIDC. Edoxaban 5 mg PO QDD. Warfarin 5 mg PO QD

What medication should I prescribe for Claire? 22

Of the following treatments for acute DVT/PE, which does not require an antecedent course of heparin (i.e. can be given as monotherapy from the outset)?

A. Dabigatran 150 PO BIDB. Rivaroxaban 15 mg PO BIDC. Edoxaban 5 mg PO QDD. Warfarin 5 mg PO QD

What medication should I prescribe for Claire? 23

Traditional Preferred Treatment Plan for Most Patients *

Prescribe 5-7 days of injectable anticoagulant (e.g. LMWH 1 mg/kg BID)

Prescribe 7 days of warfarin (e.g. 5 mg daily)

Arrange appropriate follow-up appointments, care and activities

*Long-term LMWH preferred for cancer-associated VTE

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Unfractionated Heparin

• APPT 1.5 to 2.3 control

• Bleeding, thrombocytopenia

• Higher in >65, recent surgery, PUD, liver disease, occult cancer, bleeding problems

• Major complications 2%

• Can stop when INR exceeds 2.0, 4-5 days

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Heparin-Induced Thrombocytopenia

• Develops 5-10 days after start of heparin, surgery resets the clock

• May happen within 100 days of previous Rx

• 19 days after stopping heparin

• Mean platelet count 60,000

• Hypercoagulability, thrombosis occurs 1/3 of the time

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Risk of HIT

• 1/5000

• 1-2% in cardiac surgery

• 10x higher in unfractionated heparin

• Higher with major surgery

• Medical therapy

• Rare in obstetrical patients

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Heparin-Induced Thrombocytopenia 28

Management HIT

• Platelet factor 4-heparin antibody test if clinical features suggest HIT

• High negative predictive value

• Low positive predictive value

• Stop heparin immediately

• Use alternative anticoagulants• Argatroban, danaparoid, fondaparinux, or

bivalirudin

• Cannot use LMWH or Coumadin

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Low-Molecular-Weight Heparin

• Longer ½ life

• Fixed, weight based dosing

• Thrombocytopenia less likely

• Equal to heparin in DVT

• Out patient therapy safe and cost effective• Stable hemodynamically

• No renal failure

• Stable home environment

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Nonpharmacologic Measures

• Limb elevation

• Local heat

• Minimal activity

• Bathroom, kitchen

• Graded compression stockings

• 50% reduction in postphlebitic syndrome

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Challenges with Warfarin

Delayed onset/offset

Unpredictable dose response

Narrow therapeutic range

Drug-drug, drug-food interactions

Problematic monitoring INR should be determined at least

weekly during initiation and at least monthly when INR is in range and stable

Slow reversibility

Ansell J, et al. Chest. 2001;119(1 Suppl):22S-38S.Hirsh J, et al. Chest. 2001;119(1 Suppl):64S-94S.January CT, et al. J Am Coll Cardiol. 2014;64(21):e1-76. doi: 10.1016/j.jacc.2014.03.022. Epub 2014 Mar 28.

Are there similar challenges with the DOACS? Aspirin?

Clopidogrel?

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Warfarin Necrosis

• Typically in first several days

• Mainly in Protein C deficiency

• Inhibition of Protein C stronger than K-dependent coagulation factors

• Protein C is anticoagulant

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Warfarin Herbal Interactions

• Ginkgo – increase bleeding

• St. John Wort – interfere with warfarin

• Ginseng – increase bleeding

• Garlic – not dietary, only supplement; increase bleeding

• Ginger – increase bleeding

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Inferior Vena Cava Filter

• Indicated when PE reoccurs on anticoagulation

• Lower 12 day rate but no difference at two years

• Not first line therapy

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AC alone vs. AC + Filter for PE

A study done by Mismetti et al. JAMA. 2015;313(16):1627-1635, showed:

When do you treat more aggressively?

399 Patients randomized

200 Randomized to the retrievable inferior vena cava plus the anticoagulation group (filter group)

199 Randomized to the anticoagulation group alone (control group)

Clinical Outcomes for Patients with at Least 1 Event in the PREPIC2 TrialGroup, No. with Events (%)

Clinical Outcomes Filter Group n=200 Control Group n=199

At 3 MonthsRecurrent pulmonary embolism (primary efficacy outcome) c 6 (3.0) 3 (1.5)Fatal 6 (3.0) 2 (1.0)Nonfatal 0 (0.0) 1 (0.5)Recurrent deep vein thrombosis 1 (0.5) 1 (0.5)Recurrent venous thromboembolism 7 (3.5) 4 (2.0)Major bleeding 8 (4.0) 10 (5.0)Death 15 (7.5) 12 (6.0)At 6 MonthsRecurrent pulmonary embolism  c 7 (3.5) 4 (2.0)Fatal 6 (3.0) 3 (1.5)Nonfatal 1 (0.5) 1 (0.5)Recurrent deep vein thrombosis 1 (0.5) 2 (1.0)Recurrent venous thromboembolism 8 (4.0) 6 (3.0)Major bleeding 13 (6.5) 15 (7.5)Death 21 (10.6) 15 (7.5)

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ACCEPTED indications for?

IVC placement?Recent DVT/PE with absolute contraindication to anticoagulants

tPA in PE?

Hypotension, not corrected with volume resuscitation

Deterioration (falling BP, increased HR or O2requirement) despite AC therapy

? Evidence of RV “strain”; ? Elevated troponin

tPA in DVT?

Compromise of tissue perfusion (dusky, painful, swollen extremity)

?Ilio-femoral thrombosis?

long term follow-up data suggest reductionof post-thromboticsyndrome)

More data to comefrom the ‘ATTRACT’ trial

Meyer et al. N Engl J Med 2014;370:1402-11.Konstantinides S. N Engl J Med 2008;359:2804-13.

Enden et al. Lancet. 2012 Jan 7;379(9810):31-8.Vedantham et al. Am Heart J. 2013 Apr;165(4):523-530.

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Catheter-Directed Thrombolysis

• No mortality improvement (1.2% vs 0.9%)

• More bleeding and transfusions (11.1% vs 6.5%)

• Pulmonary embolus (17.9% vs 11.4%)

• Vena cava filter (34.8% vs 15.6%)

• Longer LOS and cost

JAMA Intern Med. 2014;174(9):1494-1501

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DOACs for Venous Thrombosis

Dabigatran

PRADAXA®

150 mg b.i.d.

5 days of parenteral treatment needed before dabigatran

Rivaroxaban

XARELTO®

15 mg b.i.d. for 3 weeks

then 20 mg once daily

Can be used WITHOUT parenteral heparin treatment first

Apixaban

ELIQUIS®

10 mg b.i.d. for 7 days

then 5 mg b.i.d.

Can be used WITHOUT parenteral heparin treatment first

Edoxaban

SAVAYSA®

Daily (60 mg; or 30 mg for renal impairment or low weight)

5 days parenteral (LMWH) treatment needed before edoxaban

FDA Approval Status (for VTE)

Approved Apr 2014Approved Nov 2012 Approved Aug 2014 Approved Jan 2015

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Novel Anticoagulants 40

Reasons NOT to treat acute PE/DVT with DOACs

Severe renal insufficiency (Cr Cl < 30 mL/min)

Weight > 120 kg or < 50 kg

tPA use contemplated

PATIENT CANNOT AFFORD MEDICATION

No reversal agent in the case of severe/life-threatening bleed

Known “pro-thrombotic state”

HIT, cancer, antiphospholipid syndrome Clinicians’ own discomfort using DOACs can also be a barrier to

prescribing these agents to

patients.

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Warfarin and DOACs

Warfarin Coumadin

Dabigatran1

PradaxaRivaroxaban2

XareltoApixaban3

EliquisEdoxaban4

Savaysa

TargetVKORC1

Factors II, VII, IX, X Thrombin Factor Xa

T (max) 72-96 hours 2 hours 2.5-4 hours 3 hours 2-3 hours

Half-life 40 hours 14-17 hours 5-9 hours healthy, 9-13 hours elderly 8-15 hours 8-10 hours

Monitoring Every 4 weeksor PRN Not needed

Administration Once daily Twice daily Once daily Twice daily Once daily

Metabolism Cytochrome P450

80% renal, 20% fecal 35% renal 25% renal 35% renal

Assay PT/INR Ecarin clotting time, thrombin time Anti-Xa activity

1. Connolly SJ, et al. N EnglJ Med. 2009;361(12):1139-1151.2. Patel MR, et al. N Engl J Med. 2011;365(10):883-891.3. Granger CB, et al. N EnglJ Med. 2011;365(11):981-992. 4. Giugliano RP, et al. N Engl J Med. 2013;369(22):2093-2104.

QuickComparison

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Limitations and Concerns

Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban

Continuous monitoring X

Heparin overlap often necessary X

Limited experience with reversal X X X X

Accumulation in renal dysfunction X X +/- X

Lack of experience treating bleeding X X X X

Limited experience in elderly, obese X X X X

High acquisition cost X X X X

Wartak SA, Bartholemew JR. Cleve Clin J Med. 2011;78(10):657-664. Gulseth MP, et al. Pharmacotherapy. 2011;31(12):1232-1249. Patel JP, et al. Br J Haematol. 2011;155(2):137-149. Connolly SJ, et al. N Engl J Med. 2011;364(9):806-817. Granger CB, et al. N Engl J Med. 2011;365(11):981-992.Giugliano RP, et al. N Engl J Med. 2013;369(22):2093-2104.

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DOACs: Comparing risk of bleeding among different anticoagulant medications This is for Afib,

but the bottom line is

important!

30‐day event rates (%)

Trial RE‐LY ROCKET‐AF ARISTOTLE

dabigatran warfarin rivaroxaban warfarin apixaban warfarin

Stroke or systemic embolism

0.5 0.5 0.3 0.4 0.4 0.6

Major bleed 5.1 4.6 0.99 0.79 1.6 1.9

Healey et al. Circulation. 2012.Sherwood et al. Circulation. 2014.Garcia et al. Blood. 2014.

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Meta-Analysis: NOACS VS Warfarin

-51 -52

-10-14

25

-60

-50

-40

-30

-20

-10

0

10

20

30

HemorrhagicStroke

IntracranialHemorrhage

All-CauseMortality

MajorHemorrhage

GIHemorrhage

REL

ATIV

E R

ISK

TO

WA

RFA

RIN

(%

)

Adapted from Ruff CT, et al. Lancet 2013 Online; S0140-6736(13)623

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General Comments

• Reduce hemorrhagic strokes by 50%

• Tissue factor in CSF??

• No dietary interaction

• All are non-inferior to warfarin

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Reversal Agents?

• Aripazone – D-arginine compound• Apixaban, edoxaban, rivaroxaban, dabigatran, heparin,

LMWH

• Single injection

• Andexanet – modified factor Xa molecule• Apixaban, edoxaban, Rivaroxaban

• Sops up anti-Xa anticoagulant

• Idarucizumab – antibody fragment against dabigatran

• dabigatran

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Idarucizumab for Dabigatran Reversal

• Monoclonal antibody fragment binds dabigatran 350x more than thrombin

• Complete reversal in 88% – 98% of patients within minutes

• 1/90 patients had thrombotic event within 72 hours

• Approved Oct 2016

• $3500 per dose

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Treatment Duration 49

Claire

Clot provoked by travel

Prescribed rivaroxaban

Under your care for 3 months

She’s asked how long she has to remain on the medication

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Clots: Provoked or Unprovoked?

Provoked blood clot

Unprovoked clot

Management and workups different

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Provoked Clots

Better in near term mortality and in long term limb health

Little work up or additional testing is needed

Stop anticoagulation after the appropriate duration

Claire’s clot – caused by extended air travel – is a provoked clot.

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Unprovoked Clots

Fare poorly / limb threatening

Commonly associated with an underlying condition

Need work up

According to Bagin, Lancet, 2000, unprovoked clots are

nearly 2x more likely to recur as provoked clots.

According to Kearon et al. Annals

of Internal Medicine, males are at higher risk for recurrence than

females.

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100 Patients with First Unprovoked DVT

☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺☺☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺☺☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺☺☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺

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One Year off Anticoagulation Medications

☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺☺☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺☺☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺☺☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺

Kearon, et al. NEJM 1999, vol 340.Agnelli, et al. Ann Int Med 2003, vol139.Ridker, et al. NEJM April, 2003

☺= recurrent VTE

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Two Years off Anticoagulation Medications

☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺☺☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺☺☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺☺☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺ ☺

☺= recurrent VTE

Kearon, et al. NEJM 1999, vol 340.Agnelli, et al. Ann Int Med 2003, vol139.Ridker, et al. NEJM April, 2003.

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D-dimer for Warfarin Duration?

• D-dimer abnormal in 223/608 pts one month after stopping warfarin for PE or DVT

• Resumption of warfarin or placebo in + D-dimer group

• 15% events in stopped group

• 2.9% events in treated group

• Hazard ratio of 4.26

N Engl J Med. 2006 Dec 28;355(26):2797

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DVT/PE Risk Factors

Genetic

Acquired

Circumstantial

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Genetic Clotting Problems

• Anticlotting deficiencies far more common than clotting deficiencies

• Failure to neutralize or control generation of thrombin

• 50% of DVT or PE’s have anticlotting deficiencies

Bauer KA et al. Ann Intern Med 2001;135: 367-73

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Age of Onset of Thrombophilia's

• Mean age 35-40

• As young as second decade with multiple hereditary risk factors

Martinelli I et al. Blood 92:2352 1998

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Genetic Risk Factors - Common

• Factor V Leiden (1993)

• Prothrombin mutation G20210A (1996)

• Methylenetetrahydrofolate reductase gene mutation

• 5-15% of white and East Asian

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Genetic Risk Factors - Rare

• Protein C deficiency

• Protein S deficiency

• Antithrombin III deficiency

• Hyperhomocystinemia

• Dysfibrinogenemia

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Factor V Leiden

• Identified 1993

• Autosomal dominant

• Variant of Factor V that cannot be inactivated by activated Protein C

• 5% of North American Caucasians

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Leiden V

Suspect withSuspect with

• Thrombosis under age 45

• Family history

• 30% of DVT have mutation

• Doubles lifetime risk of DVT

Increased Risk ofIncreased Risk of

• Miscarriage

• Clots in pregnancy

• Clots on BCP’s (35x risk)

• Clots with smokers (30x risk)

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Leiden V and other Risk Factors

Risk Factor Relative Risk

Obesity 8

OCP 11-41

3rd Gen OCP 50

HRT 7-16

Air travel 14-16

Minor injury 50

Cancer 12

Homocysteine 22Genetics in Medicine (2011) 13, 1–16; doi:10.1097/GIM.0b013e3181faa0f2

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Why so Common?

• Less blood loss during • Menses • Childbirth• Cardiac surgery

• No increased risk• Arterial thrombosis• MI in older pts• CVA

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Gene Mutation 20210A

• 2.3% in healthy persons

• More common in Southern Europeans

• Rare in Asians and Africans

• Relative thrombosis risk 2.8%

• 18% of patients with thrombosis

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Antithrombin Deficiency

• Breaks up fibrin and factor X

• Relatively resistant to heparin

• Autosomal dominant, 1/2000

• Two types

• Type 1 – quantitative

• Type 2 – qualitative

• Acquired in renal failure – lost in urine

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Timing of Tests

• Thrombosis ↓ antithrombin III, protein C, protein S

• Heparin ↓ antithrombin III 30%

• Warfarin ↓↓ protein C and S

• Perform tests 2 weeks after completing warfarin

• Can check factor V Leiden, hyperhomocysteinemia, and antiphospholipid antibody anytime

Ramzi DW and Leeper KV. AFP, June 15, 2004

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Acquired Risk Factors

• Antiphospholipid antibodies

• Renal disease (renal loss of thrombin)

• Paroxysmal nocturnal hemoglobinuria

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Antiphospholipid Antibody

• Primary in 53%

• Secondary to SLE, RA, TA

• Consider in thrombosis and recurrent miscarriages

• May promote placental thrombosis

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Circumstantial Risk Factors

• Immobilization after trauma or surgery• Medications

• Oral contraceptives

• Estrogen

• Evista

• Tamoxifen

• Pregnancy• Cancer (Trousseau’s Syndrome)

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Hospital Risk Factors

• Age over 40• Immobility• CHF• Stroke• COPD• Anesthesia• Obesity

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Strong Risk Factors (OR > 10)

• Fracture (hip or leg)

• Hip or knee replacement

• Major general surgery

• Major trauma

• Spinal cord injury

Anderson FA Jr, Spencer FA. Risk factors for venous thromboembolism. Circulation. 2003;107(23 suppl 1):19–116

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Intermediate Risk Factors (OR 2-9)

• Arthroscopic knee surgery

• Central venous lines

• Chemotherapy

• Chronic heart or respiratory failure

• Hormone therapy

• Malignancy

• Oral contraceptive therapy

• Paralytic stroke

• Pregnancy/postpartum

• Previous venous thromboembolism

• Thrombophilia

Anderson FA Jr, Spencer FA. Risk factors for venous thromboembolism. Circulation. 2003;107(23 suppl 1):19–116

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Weak Risk Factors (OR <2)

• Bed rest longer than three days• Immobility due to sitting (e.g., car

or air travel longer than eight hours)• Increasing age• Laparoscopic surgery• Obesity (BMI > 40 kg per m

2)

• Pregnancy/antepartum• Varicose veins

Anderson FA Jr, Spencer FA. Risk factors for venous thromboembolism. Circulation. 2003;107(23 suppl 1):19–116

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Oral Contraceptives

• 4x increase in thromboembolism

• 3rd generation progesteronescarry twofold greater risk than earlier generations

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Thrombophilia Summary

Antiphospholipid antibody testing is probably appropriate for many patients with spontaneous VTE

More comprehensive testing may be indicated with strong family history

Testing may be indicated for selected patients with a high risk of recurrence For example, in some patients with prior VTE who are

planning pregnancy

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Trousseau’s Syndrome

• 8% of idiopathic DVT will found to have cancer within 2 years

• 60% of occult cancers dx after unprovoked thromboembolism

• Low grade DIC from a pro-coagulant tissue factor

• Armand Trousseau diagnosed own fatal pancreatic carcinoma

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Cancer Screening after Unprovoked Thromboembolism?

• 854 pts with unprovoked DVT• Labs, CXR, breast, cervical, prostate

screen

• Above and abdominal/pelvic CT

• 33 occult cancers found (3.9%)• 14 occult cancers in limited screen (3.2%)

• 19 occult cancers in limited screen + CT (4.5%)

• No mortality benefit

Carrier M et al. N Engl J Med 2015. DOI: 10.1056/NEJMoa1506623

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Pregnancy

• Relative risk of 4.3

• C-section relative risk 13.3 v. vaginal delivery

• PE more common postpartum

• D-dimer increases in pregnancy, normal not established

Dresang Lee T. et al. AFP, June 15, 2008, p 1709

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Risk Factors in Pregnancy

• Hyperemesis – dehydration and immobility

• High BMI

• Immobility

• Thrombophilia

• C-section

Greer, IA; N Engl J Med 2015; 373:540-547

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Differences in Pregnancy

Pregnancy Nonpregnant

Clinical Suspicion Confirmed 4% 30%

Left leg 78-90% 55%

Illofemoral vein 72% 9%

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Treatment in Pregnancy

• LMWH heparin preferred

• Coumadin contraindicated in pregnancy, ok in breast feeding

• No direct thrombin inhibitors –cross placenta

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Increased Major Bleeding Risk?

Concomitant Antiplatelet and other meds

Advanced Age

Prior Major Bleeding

Anemia

Uncontrolled Hypertension

INR variability and target range

Alcohol

Predominantly derived from data in patients with Atrial Fibrillation.Lip et al. Thrombosis and Hemostasis, 2011. 106: 997-1011.

Risk Factors

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Assessing Bleeding Risk: HAS-BLED

Hypertension

Abnormal liver/renal function

Stroke history

Bleeding predisposition

Labile INRs

Elderly (>65)

Drugs/alcohol use

HAS-BLED Score Bleeds/100 Patients*

0 1.13

1 1.02

2 1.88

3 3.74

4 8.70

5 12.50

Any score 1.56

*p=.007 for trend of increasing bleeding risk with increasing score.Lip GY, et al. J Am Coll Cardiol. 2011;57(2):173-180, Omran H, et al. Thromb Haemost. 2012;108(1):65-73.Camm AJ, et al. Europace. 2010;12(10):1360-1420., Caims JA, et al. Can j Cardiol. 2011;27:74-90.

Score 3 is highly predictive of bleeding events

HAS-BLED is recommended by major international

guidelines

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Treat Proximal DVT or PE (unprovoked) at least 3 months

Ensure the patient is up-to-date on age-appropriate cancer screening and perform careful physical exam and review of systems.

Discuss risks/benefits of extended therapy with all patients

Encourage extended therapy for patients who:

Male

Previous VTE

PE (rather than DVT) as their index event

Poor cardiopulmonary reserve

Low risk of AC-related bleeding

Test young patients for antiphospholipid syndrome before permanently discontinuing.

Consider d-dimer testing if other factors equivocal.

A Suggested Approach

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Warfarin Duration

Event MinimumDuration

Strength of Recommendation

First with reversible risk factor 3 months A

First embolic episode 6 months A

Recurrence 12 months B

Continuing Risk Factor 12 months B

Isolated calf vein thrombosis 6-12 weeks A

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Long Term Aspirin After Discontinuation of Anticoagulation

• Meta-analysis of 2 trails, 1225 patients

• 100 mg aspirin after warfarin

• Recurrent DVT 1/3 lower in aspirin group

• 5.1% vs. 7.5% recurrent DVT

• No difference in bleeding

• Less MI, CVA or CV death in aspirin group

Simes J, Becattini C, Agnelli G, et al. Aspirin for the prevention of recurrent venous thromboembolism: the INSPIRE collaboration. Circulation. 2014;130(13):1062-1071.

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Peri-Operative and Peri-Procedural Care 90

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Claire

At 2.5 months under your care …

She is still taking the AC medication as prescribed

She recently had a gall bladder attack

She is now scheduled to have the gallbladder removed

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What is Claire’s bleed risk?

Higher RiskHigher Risk

Urological

Pacemaker

Large colonic polyps

Bowel

Extensive tissue injury

Pericardial/intracerbral/epidural

Lower RiskLower Risk

Minor dental

Derm

Cataract

Is Claire at HIGH risk for a bleed

during the procedure?

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Risk for VTE

High Recent VTE Severe thrombophilia

Moderate VTE 3-12 mos Nonsevere thrombophilia Recurrent VTE Active cancer

Low VTE > 12 mos and no other risk factors

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For patients on Warfarin

Most can simply interrupt withoutbridging

Bridging increases the risk of bleeding and likely has no benefit for any patient except those at the highest risk of thrombosis

Clark NP. JAMA Intern Med. 2015 Jul;175(7):1163-8Douketis J. NEJM. 2015 (this is a study of AF pts but shows that bridging clearly increases the risk of post-procedure bleeding)

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Is bridging necessary?

• Should I consider alternative anticoagulants during the postoperative period when risk of bleeding is high or if postoperative bleeding occurs?

• How long do I hold patients on anticoagulation medications?

These questions are important as family physicians complete pre-op

physicals.

Warfarin Coumadin

Dabigatran1

PradaxaRivaroxaban2

XareltoApixaban3

EliquisEdoxaban4

Savaysa

Half-life 40 hours 14-17 hours 5-9 hours healthy, 9-13 hours elderly 8-15 hours 8-10 hours

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Many procedures can be performed safely without NOAC interruptionNeed more data to select patients and procedures

Short-term interruption of DOAC (in AF) is associated with low 30-day risk of strokeBridging likely not needed (except for patients who cannot take oral medication)

For patients whose procedure requires interruption24 – 48 hours likely sufficient if renal function normalLonger interruptions if renal impairment and/or high-risk procedure

More data anticipated from P.A.U.S.E.* Prospective cohort study with standardized interruption schedule

Procedures and interruptions summary* NCT 02228798

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She had an uncomplicated provoked DTV. She was treated with a DOAC for three months. During her treatment she had her gallbladder removed with no issues. Claire is no longer taking AC medications and is flying to Barcelona to meet her family for her 50th

birthday celebration!

Claire has ongoing questions about DVTs and is excited to use the EMMI Solutions app recommended by her family physician to learn more about prevention.

How is Claire? 97

Flying and Aspirin for DVT Prevention

• Risk is between 0-40/100,000

• 29% risk reduction with aspirin

• NNT 8,600 for high risk

• NNT 34,000 for low risk

Ferrari et al. Chest 1999 115:400-444

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Tools and resources are available

February 2012; 141(2_suppl) Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

www.teamanticoag.com

http://bit.ly/1jr35aS

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VTE: Beat the Clot

• Online VTE community for youfacilitated by us

• Private! Secure!• Interact, share, learn

REQUEST an invitation to join via email: 

CME‐CPD@familydocs.org

type “yammer” in subject line

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