Venous Thromboembolism - WordPress.com...Wells Score (DVT) Clinical Features Points Active Cancer 1 Paralysis, paresis, recent immobilization of lower extremities 1 Localized tenderness

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Venous Thromboembolism

Tracy Souza, BSc (Pharm), LMPS 2019-2020 ResidentJun Kim, BSc, E2P PharmD, LMPS 2019-2020 Resident

Learning Objectives• Describe the key pathophysiological steps involved in the development of a

VTE• Describe 3 potential signs and symptoms of a patient with DVT and/or PE• Describe 3 different drugs and regimens used to treat a DVT and/or PE• Describe the differences between treatment approaches for the DVT

subtypes. • Recommend VTE treatment and duration of therapy based on patient

specific factors (location, disease burden, cancer, etc.)• Assess a medical and a surgical (orthopedic) patient for the need for VTE

prophylaxis based on the risk factors for VTE and their risk of bleeding• Describe 3 drugs and regimens used for VTE prophylaxis and at least 1

potential positive and negative factor for choosing each option

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Learning Objectives• Recommend VTE prophylactic therapy and duration for medical and

surgical (orthopedic) patients based on patient specific factors (ie renal function, weight, adherence, etc)

• Describe the patient population where acetylsalicylic acid may be safely used for orthopedic VTE prophylaxis

• Describe the role and efficacy of mechanical VTE prophylaxis • Describe the key pathophysiologic steps involved in development of

heparin-induced thrombocytopenia (HIT)• Describe at least 2 potential signs and symptoms of a patient presenting

with HIT• Assess a patient using the 4 T’s score and determine their risk of HIT

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Overview 1. Case Intro2. Pathophysiology3. Signs/Symptoms4. Diagnosis + Scoring Tools + Bleed Assessment5. Treatment Options + Landmark Trials (4)6. Cancer Associated VTE + Landmark Trials (4)7. Prophylaxis of VTE8. HIT

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Introduction to HT78 y.o. female, 114.5kg admitted with L leg DVT

CC: L leg swelling + L thigh pain

HPI: Started having L thigh pain with ambulation. Unilateral L leg swelling. L leg numbness. No trauma to leg. No significant mobility changes relative to baseline but overall poor mobility due to obesity. Mild SOBOE. Initiated on dalteparin treatment.

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HTPMHx: Insulin dependent DM, HTN, hypothyroidism, mixed connective tissue disorder, ?residual menopausal symptoms, ?MI, ?drug induced lupus

SHx: unremarkable

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Review of Systems

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Vitals T: 36.9, BP: 142/45, HR: 66, RR: 18, O2 = 92% RA

CNS A/O x 3

HEENT Unremarkable

CVS Normal S1/S2, no murmurs, no extra heart sounds, no chest pain. JVP 3 cm ASA. No ECG.

RESP Normal AEBB, mild dyspnea, no cough, no hemoptysis

GI: soft, non-tender, abd dist., BS x 4, denies N/V, LBM = 2 days ago,

GU voiding normally

MSK/DERM ++ L leg thigh swelling and pain, no noted erythema, no mobilization

Labs/Invest

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Labs ID WBC = 12.4, Neuts = 8.4

Heme Hbg 145 (unknown BL), MCV 88, PLT 162, D-dimer = P

Renal SCr 121 → 163, BUN 6.6→ 11.8, GFR 26

Endo A1C 8.7%, TSH 0.02, T3 2.6, T4 10.3

Indication MedicationDiabetes Insulin glargine – dose unspecified – Last endocrine consult notes

23-29

Insulin lispro – dose unspecified – last endocrine consult notes 6-16, 9-22 and 12-21 with meals

Hypertension Atenolol 25 mg PO daily PRNCandesartan 4 mg PO daily PRNHydrochlorothiazide 25 mg PO daily PRN

Hypothyroidism Thyroid 120 mg PO daily

Hormone Replacement

Topical progesterone line applicator – 0.4 mL TOP daily

Food for Thought- Is it a DVT? How is a DVT Diagnosed?

- What are her risk factors for DVT/PE?- Are any of them modifiable?

- What would you treat her with and for how long?

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Clot Formation

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Clotting | BioNinja [Internet]. Ib.bioninja.com.au. 2019 [cited 6 November 2019]. Available from: https://ib.bioninja.com.au/standard-level/topic-6-human-physiology/63-defence-against-infectio/clotting.html

Physiology of Clot Formation

12Clotting | BioNinja [Internet]. Ib.bioninja.com.au. 2019 [cited 6 November 2019]. Available from: https://ib.bioninja.com.au/standard-level/topic-6-human-physiology/63-defence-against-infectio/clotting.html

Virchow’s Triad

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Inappropriate Clot formation

Khan F, Vaillancourt C, Bourjeily G. Diagnosis and management of deep vein thrombosis in pregnancy. 2019.

DVT → PE

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Turner M. MDNotes: Cardiology: Deep vein thrombosis (DVT) and Pulmonary Embolism (PE ) [Internet]. MDNotes. 2019 [cited 6 November 2019]. Available from: http://medicalnotesonline.blogspot.com/2011/01/cardiology-deep-vein-thrombosis-dvt-and.html

DVT → PE

15Pulmonary Embolism (PE) - Lung and Airway Disorders - MSD Manual Consumer Version [Internet]. MSD Manual Consumer Version. 2019 [cited 6 November 2019]. Available from: https://www.msdmanuals.com/en-nz/home/lung-and-airway-disorders/pulmonary-embolism/pulmonary-embolism-pe

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Galioto N, Danley D, Maanen R. Recurrent venous thromboembolism. [Internet]. Semanticscholar.org. 2019 [cited 6 November 2019]. Available from: https://www.semanticscholar.org/paper/Recurrent-venous-thromboembolism.-Galioto-Danley/dd9799d2f3a010b6b1397bbc28b3a317fa91cf88

DVT Symptoms

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[Sensitivity] (specificity)

MSK + Derm

Unilateral:- Swelling or edema [97%] (33%)- Pain [86%] (19%)- Warmth [72%] (48%)

UpToDate [Internet]. Uptodate.com. 2019 [cited 6 November 2019]. Available from: https://www.uptodate.com/contents/clinical-presentation-and-diagnosis-of-the-nonpregnant-adult-with-suspected-deep-vein-thrombosis-of-the-lower-extremity?search=dvt%20diagnosis&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1

DVT DDx- Calf muscle pull or tear- Cellulitis → elevated temperature - Superficial vein thrombophlebitis → palpable,

tender superficial veins - edema/heart failure → bilateral swelling, no

inflammatory signs (redness)

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PE Symptoms

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Vitals -↑ T, ↑ HR, ↑ RR, ↓ O2 (↓ BP = massive)

CNS orthopnea (28%)

CVS - ↑ JVP

Resp - Dyspnea (73%)- Pleuritic pain (66%)- Cough- wheeze (21%)- hemoptysis (13%)

CXR = possible effusion or atelectasis

UpToDate [Internet]. Uptodate.com. 2019 [cited 6 November 2019]. Available from: https://www.uptodate.com/contents/clinical-presentation-evaluation-and-diagnosis-of-the-nonpregnant-adult-with-suspected-acute-pulmonary-embolism?search=pe%20diagnosis&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1

PE DDx- Heart failure → bilateral edema, crackles, CXR- PNA → slower onset- MI → ECG, ↑ trop- Chronic lung disease → check for acuity and

history- Pneumothorax → trauma

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HTWhat are the signs and symptoms pointing you to a DVT?

What about a PE?

DDx?

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HTWhat are the signs and symptoms pointing you to a DVT? - Left thigh pain and swelling (no erythema)

What about a PE?- SOBOE

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Diagnosis of DVTDVT...it’s as easy as 1,2,3:

• Well’s score • D-dimer• Ultrasound

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[Internet]. 2019 [cited 6 November 2019]. Available from: http://www.contempclindent.org/article.asp?issn=0976-237X;year=2013;volume=4;issue=2;spage=236;epage=238;aulast=Babu

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Wells Score (DVT)Clinical Features Points

Active Cancer 1

Paralysis, paresis, recent immobilization of lower extremities 1

Localized tenderness along deep veins 1

Calf swelling >3cm vs. other limb 1

u/l pitting edema 1

Collateral non-varicose superficial 1

Previously documented DVT 1

Alternative diagnosis as likely or more likely than DVT -2

≥ 2 = DVT Likely

Low = 0Mod = 1-2High = ≥ 3

Clot Formation + D-Dimer

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D-Dimer = breakdown product of fibrin strands

D-Dimer• Not accurate if recent surgery• <500ng/ml → low probability • >500ng/ml → possible, correlate with

symptoms

>50yo + Wells Score <2: (Age x 10 = new d-dimer “cut offs”)

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Ultrasound• Doppler• Visualize blood flow• 95% sensitivity and specificity• Whole leg vs. proximal U/S

– may include clots which may not need treatment

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Thrombosis Canada

29Thrombosis Canada - Thrombose Canada. (2019). Clinical Guides. [online] Available at: https://thrombosiscanada.ca/clinicalguides/# [Accessed 6 Nov. 2019].

PE...same process at DVT?• Signs and symptoms• Well’s Score

– PE rule out criteria (PERC)• D-Dimer• Imaging

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Scoring Types- Wells Criteria (low, mod, high)

- Modified Wells Criteria (likely, unlikely)- Simplified Wells (likely, unlikely)

- Geneva

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Criteria Points

Clinical Sx of DVT 3

PE = most likely diagnosis or similar 3

HR >100 1.5

Immob. ≥ 3 days or surg. (past 4 wks) 1.5

Previous DVT/PE 1.5

Hemoptysis 1

Malignancy 1

PE Wells ScoreTraditional WellsLow: <2Mod: 2-6High: >6

Modified Wells:Unlikely: ≤ 4Likely >4

Simplified Wells (each criteria = 1 point):unlikely ≤ 1Likely >2

Mdcalc.com. (2019). Wells' Criteria for Pulmonary Embolism - MDCalc. [online] Available at: https://www.mdcalc.com/wells-criteria-pulmonary-embolism [Accessed 6 Nov. 2019].

PERC

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When to Use:- Wells <2

Why use it?- ↓ unnecessary d-dimer testing

Bottomline:- if all 8 criteria fulfilled, no need for d-dimer

https://www.uptodate.com/contents/clinical-presentation-evaluation-and-diagnosis-of-the-nonpregnant-adult-with-suspected-acute-pulmonary-embolism?search=perc%20pe&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1#H3765864891








PE Imaging

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Sensitivity Specificity Comments

CTPA*(CT pulmonary angiography)

Mod-high ~99% CI = GFR <30ml/min

V/Q Scan Very high ~90% more seen in critically ill

MR - PA 78% 99% $$

*negative CT does not rule out PE!MSD Manual Professional Edition. (2019). Pulmonary Embolism (PE) - Pulmonary Disorders - MSD Manual Professional Edition. [online] Available at: https://www.merckmanuals.com/professional/pulmonary-disorders/pulmonary-embolism-pe/pulmonary-embolism-pe#v915520 [Accessed 6 Nov. 2019].

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If

UpToDate [Internet]. Uptodate.com. 2019 [cited 6 November 2019]. Available from: https://www.uptodate.com/contents/clinical-presentation-evaluation-and-diagnosis-of-the-nonpregnant-adult-with-suspected-acute-pulmonary-embolism?search=pe%20diagnosis&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1

Thrombosis Canada (PE)


HTCalculate the pre-test probability for HT.

Do you think she has a DVT?

Do you think she has a PE?

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Wells Score (DVT)Clinical Features Points

Active Cancer 1

Paralysis, paresis, recent immobilization of lower extremities 1

Localized tenderness along deep veins 1

Calf swelling >3cm vs. other limb 1

u/l pitting edema 1

Collateral non-varicose superficial 1

Previously documented DVT 1

Alternative diagnosis as likely or more likely than DVT -2

≥ 2 = DVT Likely

Low = 0Mod = 1-2High = ≥ 3

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Criteria Points

Clinical Sx of DVT 3

PE = most likely diagnosis or similar 3

HR >100 1.5

Immob. ≥ 3 days or surg. (past 4 wks) 1.5

Previous DVT/PE 1.5

Hemoptysis 1

Malignancy 1

PE Wells ScoreTraditional WellsLow: <2Mod: 2-6High: >6

Modified Wells:Unlikely: ≤ 4Likely >4

Simplified Wells (each criteria = 1 point):unlikely ≤ 1Likely >2

Mdcalc.com. (2019). Wells' Criteria for Pulmonary Embolism - MDCalc. [online] Available at: https://www.mdcalc.com/wells-criteria-pulmonary-embolism [Accessed 6 Nov. 2019].

HT...diagnosis?You’ve calculated the PTP, what’s your next step?

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Thrombosis Canada


Important Terminology + Risks

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Superficial Vein ThrombosisVeins Great saphenous

Small saphenous

Mort. <1%

Treat? <3cm from saphenofemoral junction OR>3cm from saphenofemoral junction + ≥5cm in length

43Clinical Guides [Internet]. Thrombosis Canada - Thrombose Canada. 2019 [cited 6 November 2019]. Available from: https://thrombosiscanada.ca/clinicalguides/#Leg veins [Internet]. Myhealth.alberta.ca. 2019 [cited 6 November 2019]. Available from: https://myhealth.alberta.ca/Health/Pages/conditions.aspx?hwid=zm2346&lang=en-

Isolated Distal DVTVeins BELOW the knee (ant/post tibial,

dorsal venous arch)

Risks ~1%-5.7% extend proximally

Treat? Thrombosis Canada:- Symptomatic- Risk factors for extension

(>5cm, multiple veins, recurrent DVT, d-dimer >500)

44Clinical Guides [Internet]. Thrombosis Canada - Thrombose Canada. 2019 [cited 6 November 2019]. Available from: https://thrombosiscanada.ca/clinicalguides/#

Twitter [Internet]. Twitter.com. 2019 [cited 6 November 2019]. Available from: https://twitter.com/thromboadviser/status/1070008589106974721

Proximal DVTVeins ABOVE the knee (popliteal, great

saphenous, deep fem, superficial femoral vein, ext. Iliac)

Mort. 30 day mortality (3%), <1yr (13%)

Treat? ALL (high risk of progression to PE)

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HT = popliteal, saphenous, femoral, external iliac

UBC Library | EZproxy Login [Internet]. Www-dynamed-com.ezproxy.library.ubc.ca. 2019 [cited 6 November 2019]. Available from: https://www-dynamed-com.ezproxy.library.ubc.ca/condition/deep-vein-thrombosis-dvt

PE Anatomy

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PE Anatomy

https://pediaa.com/difference-between-pulmonary-artery-and-pulmonary-vein/

Subsegmental = distal veins

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https://pediaa.com/difference-between-pulmonary-artery-and-pulmonary-vein/

PE3 month mortality = 5-19%

When to treat:- Segmental = most instances- Subsegmental - concomitant

DVT? Risk of recurrence

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Smarter Decisions. Better Care. [Internet]. UpToDate. 2019 [cited 6 November 2019]. Available from: https://www.uptodate.com/

HT’s imagingDVT U/S:- Extensive hypoechoic occlusive thrombus throughout left

common and superficial femoral veins extending into greater saphenous vein and deep femoral vein with extension into left external iliac vein and some extension into upper popliteal vein resulting in partial occlusion.

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“OMG she needs

treatment!”

50https://giphy.com/gifs/what-confused-wide-eyes-3drmEWeOUgzKg

https://giphy.com/gifs/what-confused-wide-eyes-3drmEWeOUgzKg

https://giphy.com/gifs/what-confused-wide-eyes-3drmEWeOUgzKg

HT’s Goals of TherapyWhat are the goals of therapy for HT?

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HT’s Goals of TherapyWhat are the goals of therapy for HT?- ↓ mortality- ↓ risk of progression- ↓ risk of PE- ↓ risk of bleed

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Assessment of Bleed RiskRisk Factors for Bleed:- Age >65 (+1 if >75)- Hx of bleed- Cancer (metastatic cancer)- Renal or liver failure- Stroke Hx- Diabetes- Meds (antiplatelet, NSAID)

53Smarter Decisions. Better Care. [Internet]. UpToDate. 2019 [cited 6 November 2019]. Available from: https://www.uptodate.com/

Risk of Major Bleed0-3 months >3 months

(RF) BL % ↑ w/ AC % BL %/yr ↑ w/ AC %/yr

Low (0) 0.6 1.6 0.3 0.8

Mod (1) 1.2 3.2 0.6 1.6

High ( ≥ 2) 4.8 12.8 ≥ 2.5 ≥ 6.5%

3 month mortality: SVT (<1%), DVT (5%), PE (5-19%)

54UBC Library | EZproxy Login [Internet]. Www-dynamed-com.ezproxy.library.ubc.ca. 2019 [cited 6 November 2019]. Available from: https://www-dynamed-com.ezproxy.library.ubc.ca/condition/pulmonary-embolism-pe

HT’s Risk of BleedWhat is her 3 month risk of bleed without anticoagulation? With anticoagulation?

Extended treatment?

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Assessment of Bleed RiskRisk Factors for Bleed:- Age >65 (+1 if >75)- Hx of bleed- Cancer (metastatic cancer)- Renal or liver failure- Stroke Hx- Diabetes- Meds (antiplatelet, NSAID)


≥ 2

Risk of Major Bleed0-3 months >3 months

(RF) BL % ↑ w/ AC % BL %/yr ↑ w/ AC %/yr

Low (0) 0.6 1.6 0.3 0.8

Mod (1) 1.2 3.2 0.6 1.6

High ( ≥ 2) 4.8 12.8 ≥ 2.5 ≥ 6.5%

3 month mortality: SVT (<1%), DVT (5%), PE (5-19%)

57UBC Library | EZproxy Login [Internet]. Www-dynamed-com.ezproxy.library.ubc.ca. 2019 [cited 6 November 2019]. Available from: https://www-dynamed-com.ezproxy.library.ubc.ca/condition/pulmonary-embolism-pe

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Stretch Time!

Treatment Options

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Treatment Options- UFH- LMWH (dalt, enox, tinza)- Fondaparinux- Warfarin- NOACs

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Clotting Cascade

https://step1.medbullets.com/hematology/111030/anticoagulants

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https://step1.medbullets.com/hematology/111030/anticoagulants

Unfractionated Heparin

Dosing IV Bolus + target aPTT 2-3x

Caution/CI - Narrow TI- ↑ risk of HIT

Bioavailability SC = 30-70%

T1/2 elimination 1.5h

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Example of UFH Protocol

63https://www.semanticscholar.org/paper/Evaluation-of-Current-Heparin-Weight-Based-Protocol-Lafosse-Leung/874491915eb29a516655413e154b1d62a8b22cef/figure/0

https://www.semanticscholar.org/paper/Evaluation-of-Current-Heparin-Weight-Based-Protocol-Lafosse-Leung/874491915eb29a516655413e154b1d62a8b22cef/figure/0



LMWHDalteparin Enoxaparin Tinzaparin

Dosing 200 U/kg SC daily or 100 U/kg SC BID

1.5mg/kg SC ODOR 1mg/kg SC BID

175 U/kg SC once daily

Pearls Obese = BID Obese or ↓ CrCl = BID $$ (no pcare)

Comments Switch agents if CrCl <30ml/min

Dose adjustment req. if CrCl <30ml/min

Caution for CrCl <20ml/min,

[Internet]. Ahajournals.org. 2019 [cited 6 November 2019]. Available from: https://www.ahajournals.org/doi/pdf/10.1161/01.CIR.98.4.287

LMWH BID dosing- Once daily dosing = higher risk of bleed

and less effective in some populations- ↓ renal fx- Obese = ↑ clearance

- Consider BID dosing to avoid higher peaks from once daily dosing

65[Internet]. Ahajournals.org. 2019 [cited 6 November 2019]. Available from: https://www.ahajournals.org/doi/pdf/10.1161/01.CIR.98.4.287

Fondaparinux- Dosing based on weight:

- <50kg: 5mg sc once daily- 50-100kg: 7.5mg sc once daily- >100kg: 10mg sc once daily

- Renal adjustment required- Limited clinical utility (bridging or prophylaxis in pts with

hx of HIT)- not pharmacare covered


Warfarin- MOA: Vitamin K Epoxide reductase

inhibitor - VKOR = synthesis of II, VII, IX and X →

doesn’t affect factors already produced- T1/2: Factor II (3 days), Factor VII (4-6h)

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NOAC VTE Trials

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Dabigatran Rivaroxaban Apixaban Edoxaban

Trial RE-COVER I, II EINSTEIN DVT/PE AMPLIFY HOKUSAI-VTE

DB/DD yes no (OL) yes yes

Bridging ≥ 5d no no ≥ 5 d

Dosing 150mg BID 15mg BID x 21d → 20mg OD

10mg BID x7d → 5mg BID

60mg OD

Dose Adjust.

no no no 30mg OD if (1):- CrCl 30-50ml/min- wt ≤ 60kg- strong P-gp inhib

NIM 2.75 2 1.8 1.5

Recurrent VTE

Gómez-Outes A, Terleira-Fernández A, Lecumberri R, Suárez-Gea M, Vargas-Castrillón E. Direct oral anticoagulants in the treatment of acute venous thromboembolism: A systematic review and meta-analysis. 2019.

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Bleed

Half-life:D: 12-17h

R: 5-9h

A: 8-15h

E: 8-10h

Gómez-Outes A, Terleira-Fernández A, Lecumberri R, Suárez-Gea M, Vargas-Castrillón E. Direct oral anticoagulants in the treatment of acute venous thromboembolism: A systematic review and meta-analysis. 2019.

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Volume of distrib: 50-70 21 107 50

https://www.aerjournal.com/articles/anticoagulant-therapy-atrial-fibrillation

https://www.aerjournal.com/articles/anticoagulant-therapy-atrial-fibrillation

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NOAC Summary- NOACs have been shown to ↓ recurrent

VTE and have lower bleed rates vs. warfarin

- Apixaban = presenter’s preferred efficacy and safety profile

HTWould you treat HT? What are your options? Do you want to ask another other information?

- consider drug, dose, frequency

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Treatment Duration- ≥ 3 months:

- <3 months tx = 2x higher risk of recurrence - Recurrence risk with 1st unprovoked proximal DVT or

PE:- Within 1 year: 10%- Within 5 years: 30%- Within 10 years: 50%

746. Clinical Guides [Internet]. Thrombosis Canada - Thrombose Canada. 2019 [cited 6 November 2019]. Available from: https://thrombosiscanada.ca/clinicalguides/

Recurrence (Provoked)

751. Clinical Guides [Internet]. Thrombosis Canada - Thrombose Canada. 2019 [cited 6 November 2019]. Available from: https://thrombosiscanada.ca/clinicalguides/#

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Risk Factors Relative Risk for Recurrent VTEPersistent >2

Transient 0.5

Patient Risk Factors

Metastatic vs. non-metastatic 6-9

Cancer 3

D-dimer ↑ 2.2

Unprovoked (idiopathic) VTE >2

2nd vs. 1st episode 1.5

Distal vs. proximal DVT or PE 0.5

https://www.aafp.org/afp/2011/0201/p293.html]

https://www.aafp.org/afp/2011/0201/p293.html

Recommended Durations


HTHow long would you treat?

Think about: risk of recurrence, bleed risk, extensiveness..

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Recurrence (Provoked)

791. Clinical Guides [Internet]. Thrombosis Canada - Thrombose Canada. 2019 [cited 6 November 2019]. Available from: https://thrombosiscanada.ca/clinicalguides/#

Recommended Durations


Treatment Process Summary- When and length of treatment depend on:

- Size of vein occluded - Isolated or diffuse- Bleed risk - Risk of recurrence

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Monitoring HTWhat are some efficacy outcomes for DVT?

What are some safety monitoring parameters?

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Monitoring HTWhat are some efficacy outcomes for DVT?- at 1 month, repeat CTPA (physician) for ↓ clot

burden- PE symptoms (pt): dyspnea, orthopnea, hemoptysis

What are some safety monitoring parameters?- ↓ Hgb >20, platelets < 100 → physician q2w- blood in stools (pt) q2w

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Switching between Anticoags

842016 Guidelines of the Taiwan Heart Rhythm Society and the Taiwan Society of Cardiology for the management of atrial fibrillation [Internet]. 2019 [cited 6 November 2019]. Available from: https://www.sciencedirect.com/science/article/pii/S0929664616303096#fig14

Diag./Treatment Summary- Modifiable Risk Factors

-

- Diagnosis:- Pre-test probability (Wells)- Lab tests (D-dimer)- Imaging

- Treatment Options + Duration

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What happened to HT?

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Cancer Associated Thrombosis (CAT)

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Cancer-Associated Thrombosis- 4-6x higher risk vs. general population- Mechanism:

- ↑ coagulability (↑ procoagulants)- blood vessel wall damage- stasis of blood flow

-

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https://www.medscape.org/viewarticle/590378

https://www.medscape.org/viewarticle/590378

CAT Risk Factors- Malignancy vs. Localized- Site of Cancer (stomach, pancreas, brain)- Cancer Treatment- Hematological Markers:

- PLT ≥ 350 x 10^9/L

89Khorana A, Kuderer N, Culakova E, Lyman G, Francis C. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood. 2008;111(10):4902-4907.

Cancer- Past: LMWH ~5 days → Warfarin - Currently: LMWH > warfarin; however, p’care

only covers LMWH after warfarin has been failed

- Thrombosis Canada:- LMHW > NOACS (Edox/Riva) > Warfarin- Dalt >Tinza, Enox- Edox > Riva

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Considerations in Cancer- Think about:

- Type of cancer (i.e. ↑ bleed risk w/ GI)- Chemotherapy → N, V → malnutrition- Renal/Liver function - CBC (Plt)- Prognosis

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LMWHDalteparin Tinzaparin

Dosing in cancer pts

200 U/kg x 1/12 then 150 U/kg

175 IU/kg daily

Comments More common ↓ CrCl (down to 20ml/min)

Anti-Xa Level for dose adjustment = controversial- Possible use in renal fx

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Dalteparin (CLOT Trial)D Canadian, MC, R, Open label, 6 months

P N = 676Inclu: Symptomatic prox. DVT or PE + CA Exclu: <40kg, SCr 3x ULN, ECOG 3-4

I Dalteparin 200 U/kg x 1/12 then 150 U/kg

C Dalteparin 200 U/kg → warfarin

O E: Recurrent DVT or PES: Major bleed

93Lee A, Levine M, Baker R, Bowden C, Kakkar A, Prins M et al. Low-Molecular-Weight Heparin versus a Coumarin for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer. New England Journal of Medicine. 2003;349(2):146-153.

ECOG

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1 = limitations in ability to work

2 = unable to work (household or profession)

CLOT (2003)R E: Recurrent VTE

8% (D) vs. 15.7% (W), HR = 0.48 (0.3-0.77)S: Major Bleed6% (D) vs. 4% (W), p = 0.27 (no HR)

Limitations - 20/53 warfarin pts had recurrent VTE if INR <2…- Plt (50-99) = INR 1.5-2.5

- Mortality in 6 mo: D: 39% W: 41%, P = 0.53

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CLOT (2003)Authors conclusion:- Recurrent VTE: D > W- Bleed: D ~ W

Presenter Conclusions:- Dalteparin preferred in patients who are at high risk of GI

effects from chemo, pending surgical interventions- Warfarin may be an option for pts at low risk of fluctuating

INR and PLT >100

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CATCH (2015)

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D MC, randomized, open-label, superiority, 6 months

P N = 900Inclu: Symptomatic prox. DVT or PE + CA Exclu: CrCl<20ml/min, <6 mo life expectancy, Tx anticoag > 72h

I Tinzaparin 175 IU/kg once daily

C Warfarin: 5-10d of therapeutic LMWH → warf (INR 2-3)

O E: Recurrent DVT or PES: Major bleed

Lee A, Kamphuisen P, Meyer G, Bauersachs R, Janas M, Jarner M et al. Tinzaparin vs Warfarin for Treatment of Acute Venous Thromboembolism in Patients With Active Cancer. JAMA. 2015;314(7):677.

CATCH (2015)

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R E: RS-VTE- T = 6.9%, W = 10% (HR 0.65, 0.41-1.03)

S: Major Bleed- T = 2.7%, W = 2.4% (HR 0.89, 0.40-1.99)

CRNM Bleed:- T = 10.9%, W = 15.3% ( HR 0.58, 0.4-0.84)

Limitations - incidence of RS-VTE (warf) = 10% vs. expected = 12.6%

- ECOG = 0 or 1, less sick?- shorter duration?

99

CLOT(Dalteparin)

CATCH(Tinzaparin)

Author’s conclu. (E) D > W T ~ W

Author’s conclu (S) D ~ W T ≤ W

ECOG = 2 (%) 36 22

Active Cancer (%) 78 53

Metastatic disease (%) 67 55

P’care Limitations on LMWH

100

Criteria:- Rec.VTE while

on warfarin- Drug Interaction - Intolerance

Hokusai-VTE Cancer (2018)

101

D R, OL, Non-inferiority, MC (20% Canadian), modified ITT

P N = 1050Inclu: Cancer associated VTE, tx ≥ 6moExclu: ECOG ≥ 3, CrCl< 30ml/min

I Edoxaban: ≥ 5 days therapeutic LMWH → 60mg PO daily (↓ 30mg PO OD, ≥ 1 CrCl 30-50ml/min, ≤ 60kg, concomitant pgp inhibitors)

C Dalteparin 200 U/kg SC OD x 1 month → 150 U/kg SC OD

O Primary: composite of recurrent VTE or Major bleed

12. Raskob G, van Es N, Verhamme P, Carrier M, Di Nisio M, Garcia D et al. Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism. New England Journal of Medicine. 2018;378(7):615-624.

HOKUSAI-VTE Cancer (2018)

102

R Recurrent VTE OR major bleed:- 12.8% (E) vs. 13.5% (D)

Recurrent VTE:- 7.9% (E) vs. 11.3% (D)

Major bleed: - 6.9% (E) vs. 4% (D), HR 1.77 (95%CI: 1.03-3.04)- ?exposure, Upper GI, pancreatic

Limitations - Composite of efficacy and safety outcome - Included healthier patients than CLOT comparator

(ECOG 2 = 23.6% vs. 36%)

10.1056/NEJMoa1711948subgroup 10.1055/s-0038-1667001

SELECT-D (2018)

103

D R, OL, MC (UK), ITT

P N = 406Inclu: Cancer associated VTE, tx ≥ 6moExclu: ECOG ≥ 3, CrCl< 30ml/min

I Rivaroxaban 15mg BID x 3 weeks → 20mg OD

C Dalteparin 200 U/kg SC OD x 1 month → 150 U/kg SC OD

O E: Recurrent VTES: Major bleeding, CRNMB

Young A, Marshall A, Thirlwall J, Chapman O, Lokare A, Hill C et al. Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism: Results of a Randomized Trial (SELECT-D). Journal of Clinical Oncology. 2018;36(20):2017-2023.

SELECT-D (2018)

104

R Recurrent VTE:- 4% (R) vs. 11% (D), HR 0.43 (95%CI: 0.19-0.99)

Major Bleed: NSS- 6% (R) vs. 4% (D), HR 1.83 (95%CI: 0.68-4.96)

CRNM Bleed:- 13% (R) vs. 4% (D), HR 3.76 (95%CI: 1.63-8.69)- bladder cancer

Limitations - high early mortality (70% survival at 6 months)- short duration (6 months)

CAT Trial Summary

105

https://current-oncology.com/index.php/oncology/article/view/4266/2983#t1-conc-25-329



CAT Treatment Summary- LMWH preferred in most patients:

- ↓ bleed risk (frail, active cancer, GI cancers)- ↓ interactions (GI absorption, Chemo-induced N/V)

- NOACS preferred if compliance issues - Rivaroxaban → P’care coverage

106

CAT Treatment Failure- NOAC or Warfarin → LMWH- LMWH → ↑ to next prefilled syringe size

107

Break!

108https://slideplayer.com/slide/5700288/

https://slideplayer.com/slide/5700288/

DVT Prophylaxis

109

Hospital-Associated VTE• Significant prevalence• Preventable • Hospital-associated risks

– Medical– Surgical

• Non-orthopedic• Orthopedic

• Comorbidities add risk• Risks with pharmacological

prophylaxis

110

Image from Know Hospital-Associated VTE. World Thrombosis Day. https://www.worldthrombosisday.org/issue/hospital-associated-vte/#footnote8

Medically HospitalizedVTE Prophylaxis

111

VTE Risk Assessment• Thrombosis risk assessment models (RAM)• Medically hospitalized patients

– IMPROVE– Padua Prediction Score– Kucher, Geneva, Intermountain, MITH

112

IMPROVE● Spyropoulos et al. 2011

○ VTE assessment model○ 7 items: ImPACT-ILL○ 3-tiered: Low, Moderate, High○ Includes ICU/CCU stay○ Externally validated → VTE-VALOURR 2014

113

Mahan CE, Liu Y, Turpie AG, Vu JT, Heddle N, Cook RJ, Dairkee U, Spyropoulos AC. External validation of a risk assessment model for venous thromboembolism in the hospitalised acutely-ill medical patient (VTE-VALOURR). Thrombosis and haemostasis. 2014;112(10):692-9.

114

IMPROVE

V. Yousefi., AM. Tejani IMPROVE score. Fraser Health. (Accessed on October 30, 2019)

115

Padua Prediction Score● Barbar et al. 2010

○ 15 common risk factors for VTE combined into 11 items

○ Simple stratification■ < 4 points = Low risk (0.3%)■ ≥ 4 points = High risk (11%)■ 30 fold difference in risk

○ Recommended in 2012 ACCP guidelinesBarbar S, Noventa F, Rossetto V, Ferrari A, Brandolin B, Perlati M, De Bon E, Tormene D, Pagnan A, Prandoni P. A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the Padua Prediction Score. Journal of Thrombosis and Haemostasis. 2010 Nov;8(11):2450-7.

116

Padua Prediction Score

Kahn SR, Lim W, Dunn AS, Cushman M, Dentali F, Akl EA, Cook DJ, Balekian AA, Klein RC, Le H, Schulman S. Prevention of VTE in nonsurgical patients: antithrombotic therapy and prevention of thrombosis: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012 Feb 1;141(2):e195S-226S.

117

Thrombosis CanadaVTE Risk

• Age > 70• Previous VTE• Immobility ≥ 3 days• Surgery within 1 month• Stroke• MI• Active CA• Known thrombophilia

• Sepsis• Acute inflammatory

conditions• Acute infectious disease• Obesity (BMI > 30)• Hormone therapy• Respiratory/Cardiac failure

Thromboprophylaxis: Hospitalized Medical Patients. Thrombosis Canada 2019. https://thrombosiscanada.ca/wp-content/uploads/2019/05/Thromboprophylaxis-Medical-Patients-2019Apr30.pdf (Accessed on October 30, 2019).

IMPROVE BRS

118

Kahn SR, Lim W, Dunn AS, Cushman M, Dentali F, Akl EA, Cook DJ, Balekian AA, Klein RC, Le H, Schulman S. Prevention of VTE in nonsurgical patients: antithrombotic therapy and prevention of thrombosis: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012 Feb 1;141(2):e195S-226S.

119

Thrombosis CanadaBleeding Risk

• Active gastroduodenal ulcer• Previous bleeding (< 3 MO before hospitalization)• Advanced age• Severe renal failure (CrCl < 30 mL/min)• Hepatic failure• Active CA• Low platelet count (< 50)• Concurrent medications


120

Therapeutic Alternatives● Low VTE risk

○ Thromboprophylaxis is not recommended in low VTE risk patients, and in those with contraindications (eg. active bleed or at high risk of bleeding)

● Increased VTE risk○ Active bleed or high risk of bleeds → Mechanical

prophylaxis○ No active bleed or not high risk of bleeds

■ LDUH, LMWH, fondaparinux

121

Duration of Prophylaxis● Continue until acute care hospital discharge and not be

extended beyond the period of hospitalization○ EXCLAIM 2010

■ 10 vs 28 days of prophylactic LMWH dose■ ↑ major bleeding with benefits to certain VTE high-risk

population■ Extended prophylaxis not recommended

Tao DL, Bien JY, DeLoughery TG, Shatzel JJ. Extended thromboprophylaxis with direct oral anticoagulants for medical patients: a systematic review and meta-analysis. Blood. 2017 Feb 2;129(5):653-5.

122

DOAC?● Not recommended

○ ADOPT 2011■ Extended Apixaban vs enoxaparin

● NSS difference in primary efficacy outcomes● ↑ bleeding events

○ MAGELLAN 2013■ Extended Rivaroxaban vs enoxaparin

● Superior for primary efficacy outcomes● ↑↑ bleeding events

○ APEX 2016 → Extended betrixaban possibly superiorGoldhaber et al. N Engl J Med 2011;365:2167-77Cohen et al. N Engl J Med 2013; 368:513-523Beyer-Westendorf et al. European Heart Journal Supplements (2018) 20 (Supplement E), E16–E22

123

Stroke● Can receive if ischemic stroke → limited mobility● Mechanical thromboprophylaxis (eg. IPC) if contraindicated

for LMWH/UFH until anticoagulant prophylaxis can be used

Images from Google images. IPC devices. (Accessed on Nov 7, 2019)

GCS in Hospitalized Patients

124

CLOTS 1 CLOTS2

Design Randomized, outcome-blinded, ITT Randomized, outcome-blinded, PP

P N=2518, ischemic stroke, 76 y/o N=3114, ischemic stroke, 76 y/o

I Thigh length GCS + Routine care Knee-length stockings + routine

C Routine care Thigh-length stockings + routine

O ASx/Sx DVT in popliteal or femoral:● NSS ARR 0.5%

Skin breaks, ulcers, blisters, skin necrosis● OR 4.18, 5% vs 1%

ASx/Sx DVT in popliteal or femoral:● SS ARR 2.5% in thigh-length

Skin breaks● 3.9% vs 2.9% NSS difference

Conclusion GCS not recommended More DVT in knee vs thigh length

CLOTS Trials Collaboration. The Lancet. 2009 Jun 6;373(9679):1958-65.CLOTS Annals of internal medicine. 2010 Nov 2;153(9):553.

IPCD in Hospitalized Patients

125

CLOTS3

Design Randomized, outcome-blinded, allocation concealed, ITT, low loss to f/u

P N=2876, 85% ischemic stroke, 76 y/o, 5% Hx of DVT, 30% obese, 90% independent

I Intermittent pneumatic compression

C No IPC

O ASx/Sx DVT in proximal veins:● SS ARR 3.6%

Skin breaks● 3% vs 1% SS difference

Conclusion IPC effective in immobilized stroke after stroke

CLOTS (Clots in Legs Or sTockings after Stroke) Trials Collaboration. Effectiveness of intermittent pneumatic compression in reduction of risk of deep vein thrombosis in patients who have had a stroke (CLOTS 3): a multicentre randomised controlled trial. The Lancet. 2013 Aug 10;382(9891):516-24.

VCH PPO - Mechanical Prophylaxis

126

Non-orthopedic SurgeryVTE Prophylaxis

127

VTE Risk Assessment● Individual risk assessment (RAM)

○ Caprini Score■ Validated in large retrospective studies

○ Roger Score■ Not externally validated

● Group-based Approach

128

129

Risk Category

Score Estimated VTE Risk

Very low 0 < 0.5%

Low 1-2 ~1.5%

Moderate 3-4 ~3.0%

High ≥ 5 ~6.0%

Caprini Score

Gould MK, Garcia DA, Wren SM, Karanicolas PJ, Arcelus JI, Heit JA, Samama CM. Prevention of VTE in nonorthopedic surgical patients: antithrombotic therapy and prevention of thrombosis: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012 Feb 1;141(2):e227S-77S.

Group-based Approach● Very low risk

○ Outpatient or same day procedures■ Laparoscopic cholecystectomy■ Appendectomy■ Transurethral prostatectomy■ Inguinal herniorrhaphy■ Unilateral or bilateral mastectomy

● Low risk ○ Spinal surgery for non-malignant disease

130

Group-based Approach● Moderate/High Risk

○ Gynecologic noncancer surgery○ Cardiac surgery○ Most thoracic surgery○ Spinal surgery for malignant disease

131

132

Risk Category Caprini Score Estimated VTE Prophylaxis

Very low 0 < 0.5% None

Low 1-2 ~1.5% IPC

Moderate 3-4 ~3.0% LDUH, LMWH or IPC

High ≥ 5 ~6.0% LDUH or LMWH + IPC or ES

Therapeutic Recommendation

Therapeutic Alternatives

133

Agent LDUH vs Placebo

LMWH vs Placebo

Fondaparinuxvs LMWH

Benefit ↓ risk of death, ↓ fatal PE ↓ nonfatal PE

↓ VTE?↓ risk of death

vs LDUH

?↓ VTE

?↓DVT

Risk ↑ nonfatal major bleeding

↑ major bleeds ↑ major bleeds

Therapeutic Considerations● Duration → until discharge

○ In high-risk cancer surgery → LMWH up to 30 days● Consider fondaparinux for those with Hx of or active

heparin-induced thrombocytopenia● Refer to PPO sets for further guidance● High bleed risk patients

○ Mechanical prophylaxis in most cases until bleed risk diminishes to start pharmacological prophylaxis

134

BRS in Surgical Patients• No validated models• Suggestion by CHEST 2012 guidelines

135

Gould MK, Garcia DA, Wren SM, Karanicolas PJ, Arcelus JI, Heit JA, Samama CM. Prevention of VTE in nonorthopedic surgical patients: antithrombotic therapy and prevention of thrombosis: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012 Feb 1;141(2):e227S-77S.

Other Considerations● Cardiac Surgery

○ DAPT + pharmacological DVT prophylaxis = higher bleeding risk!

○ Consider benefit vs risk for pharmacologic DVT prophylaxis or Mechanical prophylaxis

● Craniotomy○ Intracranial hemorrhage is a complication commonly in

first 12 to 24 hours○ Consider mechanical prophylaxis unless high VTE risk

(eg. for malignancy) until adequate hemostasis

136

Orthopedic SurgeryVTE Prophylaxis

137

VTE Risk Assessment● All patients undergoing major orthopedic surgeries are

at high risk for VTE○ Hip fracture surgery (HFS)○ Total knee replacement/arthroplasty (TKA)○ Total hip replacement/arthroplasty (THA)

● No validated RAM and BRS available

138

139

Falck-Ytter, Y. et al.. Prevention of VTE in orthopedic surgery patients: antithrombotic therapy and prevention of thrombosis: American College of Chest Physicians evidence-based clinical practice guidelines. Chest, 141(2), pp.e278S-e325S.

Therapeutic Choices● As per CHEST guidelines, all therapies outweigh the

risk for thromboprophylaxis compared to no prophylaxis● THA or TKA

○ LDUH, LMWH, VKA, ASA, fondaparinux, apixaban, rivaroxaban, dabigatran, IPCD

● HFS○ LMWH, fondaparinux, LDUH, VKA, ASA, IPCD

● LMWH vs LDUH○ 20% RRR for ASx DVT → Favors LMWH

140

ASA - PEP trial 2000

141

Design Multicentre, randomized, double-blinded, ITT

P Patients undergoing HFS, THA, TKA from 1992-1998 in 148 hospitals (Australia, New Zealand, South Africa, Sweden, UK)

I ASA 160 mg po daily started preoperatively and continued for 35 days

C Placebo

O Mortality and in-hospital morbidity up to day 35 postop- nonfatal events (DVT, PE, MI, stroke, bleeding) during hospital stay- fatal events from hospital stay to after up to day 35

Bleeds

O'Brien et al. Lancet. 2000 Apr 15;355(9212):1295-302.

142O'Brien et al. Lancet. 2000 Apr 15;355(9212):1295-302.

HFS

● N=13356 ● 79 years old● 79% women● Fatal PE: 58% RRR (p=0.002)● Definite or probable PE: 43%

RRR (p=0.002)● Sx DVT: 29% RRR (p=0.03)● NSS difference in mortality

Results



145

THA, TKA

● N=4088● 22 New

Zealand ● 67 years old● 53% women● 2% UFH● 35% LMWH● NSS

difference



PEP trial 2000

147

Author’s Conclusion

ASA reduces the risk of PE and DVT by at least 33% in the period of increased risk

Limitation Unclear primary vs secondary outcome → all primary outcomes?Selection bias → patients included were those who did not either have clear indication or contraindication to ASAOther prophylactic measures, previous use of aspirin or other NSAIDs did not preclude entry in the trial

Conclusion Consider ASA 160 mg (162 mg) po once daily for elderly patients without an indication or contraindication to ASA undergoing HFS


LMWH vs ASA

148

● CHEST 2012○ Pooled data → 325 mg po BID & 650 mg po BID

■ RR 1.87 ASx DVT in ASA■ PE rates were too few to analyze■ No major bleeds or deaths reported

● EPCAT I○ Extended prophylaxis with ASA or dalteparin for

prevention of symptomatic VTE after THA at 12 tertiary care orthopedic centers in Canada

Anderson et al. Ann Intern Med. 2013 Jun 4;158(11):800-6

EPCAT I

149

Design Multicentre, randomized, non-inferiority (2%)

P n=380 (2080), 58 years old, 53-60% men, ~30% obese, primary THA,

I ASA 81 mg po daily for 28 days after 10 days of dalteparin

C Dalteparin 5000 U sc daily continued for 28 days after initial 10 days

O Primary outcome: NSS difference in VTE

Conclusion ASA noninferior and safe as dalteparin

Limitation Trial halted early; intended sample size (1100) not met

Anderson et al. Ann Intern Med. 2013 Jun 4;158(11):800-6

EPCAT II

150

Objective To study the effectiveness and safety of extended prophylaxis with ASA compared to rivaroxaban for prevention of VTE after TKA or THA in patients who have received a short course of rivaroxaban

Anderson et al. N Engl J Med 2018; 378:699-707

EPCAT II

151

Design Multicentre, randomized, double-blinded, noninferiority

P Patients undergoing elective TKA or THA

I ASA 81 mg po daily for additional 9 (TKA) or 30 days (THA) following 5 days of rivaroxaban 10 mg po daily

C Rivaroxaban 10 mg po daily for 14 (TKA) or 35 (THA) days

O Primary Outcome: ● Efficacy: Symptomatic VTE or PE by day 90 postop● Safety: Major or clinically relevant non-major bleeding


152

Results


153

Results


EPCAT II

154

Author’s conclusion

ASA was not significantly different from rivaroxaban in prevention of symptomatic VTE after an initial 5-day postoperative course of rivaroxaban

Limitation ITT analysis in non-inferiority trial, low VTE rates which can bias towards non-inferiority, concerns with adherence

Conclusion Consider this regimen in patients undergoing elective THA, TKA surgeries who also have:● Low risk for VTE● No other pre existing comorbidities requiring ongoing anticoagulation


155

More ASA...

156M. Faour et al. The Journal of Arthroplasty 33 (2018) S131eS135

Faour et al. 2018

157

Objective To compare the 2 ASA regimens post TKA

Design Retrospective trial, 0.25% difference as non-inferiority margin

P N=5666 (1327 in 81 mg BID; 4339 in 325 mg BID)

I ASA 81 mg po BID x 4-6 weeks post TKA

C ASA 325 mg po BID

O VTE 0.7% vs 1.5% (p=0.02); Symptomatic DVT 0.3% vs 1.4% (p=0.0009)

Conclusion ASA 81 mg po BID non-inferior to 325 mg po BID for VTE prevention post TKA

M. Faour et al. The Journal of Arthroplasty 33 (2018) S131eS135

Limitations● Retrospective design● All patients received pneumatic compression stockings● Physical therapy at initiated on day of or post-op day 1

158

Limitations Continued...● Under discussion...● “This study showed similar findings to what have been

previously reported in the literature that aspirin is an effective treatment for the prevention of VTE after TKA [10,26,29,31].”○ 10 → ASA as effective as warfarin○ 26 → EPCAT I○ 29 → PEP○ 31 → Does not evaluate or even mention ASA

159

VKA

160

Comparator Placebo UFH LMWH

Efficacy 44% RRR DVT77% RRR PE

ASx DVTNSS difference

VKA less effective RR ~1.5 NSS for PE, death

Safety 2.91 RR ↑ in wound hematoma

NSS difference wound hematoma

NSS difference wound hematoma

Conclusion VKA is not a preferred alternative unless patients was previously taking VKA for another indication can cannot use an alternative agent

PleASAnt Option?● PEP → ASA vs placebo in HFS; no benefit in TKA, THA● EPCAT I → LMWH vs ASA inconclusive results● EPCAT II → ASA non-inferior to Rivaroxaban*● So, who can go home on ASA?

○ Post HFS in elderly○ Patient not at high risk of VTE

■ Who? Revisit VTE risk assessment tool○ No contraindications for ASA, ○ Caution in PUD, Hx of UGIB/LGIB, ++EtOH

161*after 5 days of Rivaroxaban

162

Thrombosis CanadaVTE Risk

• Age > 70• Previous VTE• Immobility ≥ 3 days• Surgery within 1 month• Stroke• MI• Active CA• Known thrombophilia

• Sepsis• Acute inflammatory

conditions• Acute infectious disease• Obesity (BMI > 30)• Hormone therapy• Respiratory/Cardiac failure


ASA may be appeASAble● EPCAT III

○ Rivaroxaban 10 mg x 5 days → ASA 81 mg (EPCAT II regimen) vs

○ ASA 81 mg post op x 14 (TKA) or 35 (THA) days● PEPPER

○ ASA vs warfarin vs rivaroxaban post THA, TKA

163

164

Break Time

Factor Xa InhibitorsTherapeutic alternatives: Orthopedic Surgery

165

Fondaparinux

166Bergqvist D. Review of fondaparinux sodium injection for the prevention of venous thromboembolism in patients undergoing surgery. Vascular health and risk management. 2006 Dec;2(4):365.

Fondaparinux vs LMWH● Meta-analysis (Kumar et al. 2019)

○ Primary efficacy outcome:■ VTE (composite of Sx/ASx DVT and PE)

● OR 0.49 in fondaparinux than LMWH● No difference in symptomatic DVT, PE, mortality

○ Major bleeding ● OR 1.48 in fondaparinux than LMWH

○ Subgroups by ethnicity■ Benefits seen in North American, Australian,

European population, but not in Asian

167

Kumar A, Talwar A, Farley JF, Muzumdar J, Schommer JC, Balkrishnan R, Wu W. Fondaparinux Sodium Compared With Low‐Molecular‐Weight Heparins for Perioperative Surgical Thromboprophylaxis: A Systematic Review and Meta‐analysis. Journal of the American Heart Association. 2019 May 21;8(10):e012184.

PENTHIFRA Plus

168

Objective To evaluate the benefit vs risk of fondaparinux 2.5 mg sc once daily in HFS

Design Multicentre, 16 countries, double-blinded,

P N=428, HFS, 79 year old, THA 10%, half prosthesis 25%

I Fondaparinux 2.5 mg sc once daily for 4 weeks

C Placebo for 19 to 23 days after 6 to 8 days of fondaparinux

O Efficacy: VTE → RRR 95.9%; Safety: Major bleeding → NSS difference

Conclusion Extended prophylaxis with fondaparinux x 3 wks after HFS ↓ VTE by 96%

Limitation ⅛ drop out per arm during double-blind period, not ITT

Eriksson BI, Lassen MR. Duration of prophylaxis against venous thromboembolism with fondaparinux after hip fracture surgery: a multicenter, randomized, placebo-controlled, double-blind study. Archives of Internal Medicine. 2003 Jun 9;163(11):1337-42.

Fondaparinux● Consider fondaparinux as an alternative agent if:

○ Patient is undergoing HFS, TKA, THA○ Did not receive LMWH preop○ Low bleed risk○ ≥ 50kg, not frail○ Patient had a history of HIT○ eGFR ≥ 30mL/min

169

Apixaban

170

APROPOS

171

Objective To test the efficacy and safety of apixaban in various doses (5,10,20 mg daily) as daily or divided regimens in post TKA patients

Design Multicentre, randomized, eight-arm, parallel group, Phase II

P N=856, 67 years old, predominately white, female, 82kg, BMI=30

I Apixaban 5,10,20 mg daily or 2.5,5,10 mg BID x 12 day ± 2

C Enoxaparin 30 mg sc q12h and warfarin INR targeted to 1.8-3.0 x 12 ± 2

O Primary outcome: ● Composite of VTE and death from any cause: NSS difference● Major bleeding: ?increase in bleeds

Conclusion Apixaban 2.5 mg BID or 5 mg daily may be beneficial

Lassen MR, Davidson BL, Gallus A, Pineo G, Ansell J, Deitchman D. The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement 1. Journal of Thrombosis and Haemostasis. 2007 Dec;5(12):2368-75.

Apixaban in TKA

172

ADVANCE ADVANCE-2

Design Multicentre, randomized, double-blinded, noninferiority, per-protocol analysis

P N=2166, 66 y/o, <4% Hx of VTE, BMI 31 N=3057, 67 y/o, <3% Hx of VTE, BMI 29

I Apixaban 2.5 mg BID x 10-14 days

C Enoxaparin 30 mg q12h x 10-14 days Enoxaparin 40 mg daily x 10-14 days

O 1° Efficacy: ● RR 1.02

(0.78-1.32)

Safety outcome:● 0.7% vs 1.4%

1° Efficacy:● RR 0.62

(0.51-0.74)

Safety outcome● No difference

Conclusion Did not meet noninferiority Apixaban is more effective

Lassen et al. N Engl J Med 2009; 361:594-604Lassen et al. The Lancet. 2010 Mar 6;375(9717):807-15.

Apixaban in THA

173

ADVANCE-3

Design Multicentre, randomized, double-blinded, noninferiority, per-protocol analysis

P N=3866, 61 y/o, BMI 28, <2% Hx of VTE

I Apixaban 2.5mg po BID x 35 days

C Enoxaparin 40 mg sc daily x 35 days

O 1° Efficacy:● RR 0.36 (0.22-0.54)● ARR 2.5%

Safety Outcome● No difference

Conclusion Apixaban was associated with lower rates of VTE without increased bleeding.

Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. New England Journal of Medicine. 2010 Dec 23;363(26):2487-98.

Apixaban Summary● Apixaban seems more effective than LMWH with no

increased risk in bleeding● Could consider in post THA, TKA patients who have no

adherence issues and no contraindication

174

Rivaroxaban

175

Rivaroxaban in THA

176

RECORD-1 RECORD-2

Design Multicentre, randomized, double-blinded, modified ITT analysis

P N=4591, 63 y/o, BMI 28, <3% Hx of VTE N=2509, 62 y/o, BMI 27, <2% Hx of VTE

I Rivaroxaban 10 mg po daily x 35 days Rivaroxaban 10 mg po daily x 35 days

C Enoxaparin 40 mg sc daily x 35 days Enoxaparin 40 mg sc daily x 10-14 days

O 1° Efficacy● ARR 2.6%

Major bleeding● NSS ↑ 0.2%

1° Efficacy● ARR 7.3%


Conclusion Non-inferior and Superior Superior

Eriksson et al. N engl j med 358;26Kakkar et al. Lancet 2008; 372: 31–39

Rivaroxaban in TKA

177

RECORD-3 RECORD-4

Design Multicentre, randomized, double-blinded

P N=2531, 68 y/o, BMI 30, <4% Hx of VTE N=3148, 65 y/o, BMI 31, <3% Hx of VTE

I Rivaroxaban 10 mg po daily x 14 days Rivaroxaban 10 mg po daily x 14 days

C Enoxaparin 40 mg sc daily x 14 days Enoxaparin 30 mg sc q12h x 14 days

O 1° Efficacy● ARR 9.2%


1° Efficacy● ARR 3.2%


Conclusion Non-inferior and Superior Non-inferior and Superior

Lassen et al. N Engl J Med 2008;358:2776-86.Turpie et al. Lancet 2009; 373: 1673–80

Rivaroxaban Summary● Could consider in post THA, TKA patients who have no

adherence issues and no contraindication● Consider in low bleeding risk patients

○ Possible increase in non-major bleeding → pooled data

178

Dabigatran

179

Dabigatran in THA

180

RE-NOVATE RE-NOVATE II

Design Multicentre, randomized, double-blinded, non-inferiority

P N=3494, 64 y/o, 3% Hx of VTE N=2055, 62 y/o, BMI 27, 2.5% Hx of VTE

I Dabigatran 220 mg or 150 mg po daily x 28-35 days

Dabigatran 220 mg po daily x 28-35 days

C Enoxaparin 40 mg sc daily x 28-35 days Enoxaparin 40 mg sc daily x 28-35 days

O 1° Efficacy - ARR 0.7%Major bleeding - NSS difference

1° Efficacy - ARR 1.1%Major bleeding - NSS difference

Conclusion Non-inferior Non-inferior

Eriksson et al. Lancet 2007; 370: 949–56Eriksson et al. Thromb Haemost 2011; 105: 721–729

Dabigatran in TKA

181

RE-MOBILIZE RE-MODEL

Design Multicentre, randomized, double-blinded, non-inferiority

P N=2615, 66 y/o, N=2067, 68 y/o,

I Dabigatran 220 mg or 150 mg po daily x 12-15d Dabigatran 220 mg or 150 mg po daily x 6-10d

C Enoxaparin 30 mg sc q12h x 12-15 days Enoxaparin 40 mg sc daily x 6-10 days

O 1° Efficacy● 33.7% vs 31.1% vs 25.3%

Major bleeding - NSS difference

1° Efficacy● 40.5% vs 36.4% vs 37.7%

Major bleeding - NSS difference

Conclusion Inferior to enoxaparin Non-inferior

Ginsberg et al. The Journal of Arthroplasty Vol. 24 No. 1 2009Eriksson et al. J Thromb Haemost. 2007 Nov;5(11):2178-85.

Dabigatran Summary• Flaw in RCTs with possibly large non-inferiority margin• 1 trial in TKA shown to be inferior → due to higher

enoxaparin dosing?• SS increase in ALT in one RCT• If considering, 220 mg seems to be the best option

182

When to start prophylaxis• THA, TKA, HFS

– if receiving LMWH• start ≥ 12 hr preoperatively or• ≥ 12 h postoperatively

– DOAC• 6-8 hours after wound closure

– ASA• started pre-operatively

183

184

Dosing in Medical/Non-orthopedic

Unadjusted < 40 kg 101 to 120 kg CrCl < 30 mL/min

Dalteparin 5000 U sc daily 2500 U sc daily 5000 U sc BID Avoid < 10 mL/min

Enoxaparin 40 mg sc daily 30 mg sc daily 40 mg sc BID 30 mg sc daily

UFH 5000 U sc q8-12h

Fondaparinux 2.5 mg sc daily Use only if ≥ 50kg Unadjusted Contraindicated

VCH PPO

185

Dosing in Orthopedic Surgery

186

THA,TKA Duration HFS Duration

Rivaroxaban 10 mg po daily

TKA14 days

THA35 days

Not studiedApixaban 2.5 mg po BID

Dabigatran 220 mg po daily

Enoxaparin 30 mg sc BID or 40 mg sc daily Post-op 40 mg sc daily35 days

Dalteparin 5000 U sc daily Post-op 5000 U sc daily

Fondaparinux 2.5 mg sc once daily 2.5 mg sc once daily 28 days

ASA 81 mg po daily x 30 d (THA) or x 9 d (TKA)*after 5 days of rivaroxaban 10 mg po daily

162 mg po once daily 35 days

IPCD in Orthopedic Surgery• vs LMWH → THA and TKA

– Non-fatal PE was observed in IPCD/VFP group– Use of device was associated with trend towards

increase in ASx DVT– Less major bleeding occurred in IPCD group

• IPCD + ASA vs LMWH– No difference in PE due to low number of events– Fewer ASx DVT & major bleeds– Overall, poor quality of evidence

187

Monitoring• Signs & Symptoms of clots (refer to

earlier sides for PE and DVT)• Bleeds

188Image from Clots. Thrombosis Canada https://thrombosiscanada.ca/clots/?gclid=Cj0KCQiA2ITuBRDkARIsAMK9Q7N8ZaABL2zJFX9nhwh7F9EpgOcuX77pzJ-Hw6hwNQD4ltGUQSkpBMYaAtQkEALw_wcB

Monitoring - Bleeds• Signs and symptoms may include (not limited to):

– Minor: nosebleeds, bleeding in gums, bruising, delay in clot formation

– Serious: altered LOC, seizures, hematemesis, tarry stools, blood in urine, pale, cool, clammy extremities

– Signs: ↓BP, ↑HR, drop in hemoglobin (≥ 20g/L)• Bleeding definitions

– ISTH, TIMI, GUSTO, CURE, PLATO etc.

189

Heparin-induced Thrombocytopenia (HIT)

190

HIT

191Heparin-induced thrombocytopenia. Jorge Muniz. 2019 https://medcomic.com/medcomic/heparin-induced-thrombocytopenia/ (Accessed on October 26, 2019).

192Greinacher. N Engl J Med 2015;373:252-61.

HIT

193

Type I Type II

● Benign ● Non-immunologic● Mild thrombocytopenia

○ Platelet clumping ● First 48-72 hours

● Clinically relevant● Immune-related

response● ↑ risk of thrombosis

○ Platelet activation

HIT● > 50% PLT count drop in 5-10 days after starting heparin ● Hypercoagulability● Presence of heparin-dependent IgG antibodies● Risk

○ 10x higher in UFH vs LMWH○ Women > men○ Major surgery > minor surgery or medical therapy

● Recent heparin use in past 90 days (especially < 30 days)○ HIT can occur abruptly upon re-exposure○ Can be anaphylactoid within 30 min

194

195

Heparin-induced thrombocytopenia. Thrombosis Canada. https://thrombosiscanada.ca/wp-content/uploads/2019/01/37.-Heparin-Induced-Thrombocytopenia-16Nov2018.pdf

4 T’s Score

196

Heparin-Induced Thrombocytopenia (HIT), Kumar N, Law A, Choudhry NK. Teaching Rounds: A Visual Aid to Teaching Internal Medicine Pearls on the Wards; 2016. Available at: https://accessmedicine.mhmedical.com/content.aspx?sectionid=130944591&bookid=1856&Resultclick=2 Accessed: October 26, 2019

HIT● Lab tests

○ Immunologic (eg. ELISA, particle gel immunoassay, latex particle agglutination assay)→ antibodies to PF4-heparin

○ Functional Assay (eg. serotonin release assay, heparin-induced platelet aggregation)

○ Therapeutic decisions should not be delayed by pending laboratory results if suspicion of HIT is not low

197

HIT● Treatment

○ Stop heparin (if still being administered)○ Start alternative anticoagulant at therapeutic dose →

prophylactic dose is insufficient even if patient has no apparent thrombosis

○ Avoid VKA until PLT count stable >150 stable for 2 consecutive days due to increased risk of venous limb gangrene and limb loss

198

Anticoagulant Pharmacology Dosing

ArgatrobanDirect thrombin inhibitor

Continuous infusion 0.5-1.5 mcg/kg/min IV

Bivalirudin Continuous infusion 0.1-0.2 mg/kg/hr IV

Fondaparinux

Factor Xa-Inhibitor

7.5 mg sc daily

Danaparoid Bolus: weight-based dosingContinuous Infusion: 400 units/h IV then 300 U/h IV x 4h, then 200 U/h IV

Rivaroxaban Thrombosis 15 mg po BID x 3 weeks, then 20 mg po dailyHIT: 15 mg BID until PLT recovery then 20 mo po daily

Warfarin Vitamin K antagonist INR 2-3 (only after achieving PLT > 150 x 2 days

Therapeutic Alternatives

Heparin-induced thrombocytopenia. Thrombosis Canada. https://thrombosiscanada.ca/wp-content/uploads/2019/01/37.-Heparin-Induced-Thrombocytopenia-16Nov2018.pdf

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