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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
2
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
3
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.
5
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
7
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
11
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
20
HTWhat are the signs and symptoms pointing you to a DVT?
What about a PE?
DDx?
21
HTWhat are the signs and symptoms pointing you to a DVT? - Left thigh pain and swelling (no erythema)
What about a PE?- SOBOE
22
Diagnosis of DVTDVT...it’s as easy as 1,2,3:
• Well’s score • D-dimer• Ultrasound
23
[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
25
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”)
26
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
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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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
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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
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
30
Scoring Types- Wells Criteria (low, mod, high)
- Modified Wells Criteria (likely, unlikely)- Simplified Wells (likely, unlikely)
- Geneva
31
32
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
34
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)
36Thrombosis Canada - Thrombose Canada. (2019). Clinical Guides. [online] Available at: https://thrombosiscanada.ca/clinicalguides/# [Accessed 6 Nov. 2019].
HTCalculate the pre-test probability for HT.
Do you think she has a DVT?
Do you think she has a PE?
37
38
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
39
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?
40
Thrombosis Canada
41Thrombosis Canada - Thrombose Canada. (2019). Clinical Guides. [online] Available at: https://thrombosiscanada.ca/clinicalguides/# [Accessed 6 Nov. 2019].
Important Terminology + Risks
42
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)
45
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
46
PE Anatomy
https://pediaa.com/difference-between-pulmonary-artery-and-pulmonary-vein/
Subsegmental = distal veins
47
PE3 month mortality = 5-19%
When to treat:- Segmental = most instances- Subsegmental - concomitant
DVT? Risk of recurrence
48
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.
49
“OMG she needs
treatment!”
50https://giphy.com/gifs/what-confused-wide-eyes-3drmEWeOUgzKg
HT’s Goals of TherapyWhat are the goals of therapy for HT?
51
HT’s Goals of TherapyWhat are the goals of therapy for HT?- ↓ mortality- ↓ risk of progression- ↓ risk of PE- ↓ risk of bleed
52
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?
55
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)
56Smarter Decisions. Better Care. [Internet]. UpToDate. 2019 [cited 6 November 2019]. Available from: https://www.uptodate.com/
≥ 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
58
Stretch Time!
Treatment Options
59
Treatment Options- UFH- LMWH (dalt, enox, tinza)- Fondaparinux- Warfarin- NOACs
60
Clotting Cascade
https://step1.medbullets.com/hematology/111030/anticoagulants
61
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
62
Example of UFH Protocol
63https://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
66Smarter Decisions. Better Care. [Internet]. UpToDate. 2019 [cited 6 November 2019]. Available from: https://www.uptodate.com/
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)
67
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.
71
Volume of distrib: 50-70 21 107 50
https://www.aerjournal.com/articles/anticoagulant-therapy-atrial-fibrillation
72
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
73
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/#
76
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]
Recommended Durations
77Clinical Guides [Internet]. Thrombosis Canada - Thrombose Canada. 2019 [cited 6 November 2019]. Available from: https://thrombosiscanada.ca/clinicalguides/#
HTHow long would you treat?
Think about: risk of recurrence, bleed risk, extensiveness..
78
Recurrence (Provoked)
791. Clinical Guides [Internet]. Thrombosis Canada - Thrombose Canada. 2019 [cited 6 November 2019]. Available from: https://thrombosiscanada.ca/clinicalguides/#
Recommended Durations
80Clinical Guides [Internet]. Thrombosis Canada - Thrombose Canada. 2019 [cited 6 November 2019]. Available from: https://thrombosiscanada.ca/clinicalguides/#
Treatment Process Summary- When and length of treatment depend on:
- Size of vein occluded - Isolated or diffuse- Bleed risk - Risk of recurrence
81
Monitoring HTWhat are some efficacy outcomes for DVT?
What are some safety monitoring parameters?
82
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
83
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
85
What happened to HT?
86
Cancer Associated Thrombosis (CAT)
87
Cancer-Associated Thrombosis- 4-6x higher risk vs. general population- Mechanism:
- ↑ coagulability (↑ procoagulants)- blood vessel wall damage- stasis of blood flow
-
88
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
90
Considerations in Cancer- Think about:
- Type of cancer (i.e. ↑ bleed risk w/ GI)- Chemotherapy → N, V → malnutrition- Renal/Liver function - CBC (Plt)- Prognosis
91
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
92
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
94
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
95
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
96
CATCH (2015)
97
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)
98
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
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
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).
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
143O'Brien et al. Lancet. 2000 Apr 15;355(9212):1295-302.
144O'Brien et al. Lancet. 2000 Apr 15;355(9212):1295-302.
145
THA, TKA
● N=4088● 22 New
Zealand ● 67 years old● 53% women● 2% UFH● 35% LMWH● NSS
difference
O'Brien et al. Lancet. 2000 Apr 15;355(9212):1295-302.
146O'Brien et al. Lancet. 2000 Apr 15;355(9212):1295-302.
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
O'Brien et al. Lancet. 2000 Apr 15;355(9212):1295-302.
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
Anderson et al. N Engl J Med 2018; 378:699-707
152
Results
Anderson et al. N Engl J Med 2018; 378:699-707
153
Results
Anderson et al. N Engl J Med 2018; 378:699-707
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
Anderson et al. N Engl J Med 2018; 378:699-707
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
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).
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%
Major bleeding● NSS ↑ 1.1%
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
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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%
Major bleeding● NSS ↑ 0.1%
1° Efficacy● ARR 3.2%
Major bleeding● NSS ↑ 0.4%
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
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Dabigatran
179
Dabigatran in THA
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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
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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
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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
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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
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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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