Updates in

VTE
Management
Dr Tan Jiunn Liang
Consultant Chest Physician
Respiratory Medicine Division
Department of Medicine
Universiti Malaya Medical Centre
Outline
2019

• Overview of VTE
• Updates in Management of Acute VTE
• Thrombolysis – systemic vs CDT
• Anticoagulation
• Follow-up & thrombophilia testing
• Updates on Ca-VTE
2020
• What’s new?
• Take Home 2021
2023
 Venous More deaths than RTA, cancers
& AIDS combined
thromboembolism Incidence increased with age
(VTE)

Beckman MG et al. Venous thromboembolism: A public health

concern. Am J Prev Med 2010; 38(4S) S495-S501
 High sensitivity &
age adjusted
Low or intermediate
probability D-dimer

Yes High probability

+ve

CTPA

Risk stratisfication
Konstantinides SV, Meyer G, Becattini C, et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS), Eur Heart J
doi/10.1093/eurheartj/ehz405.
Risk adjusted Mx strategies

Konstantinides SV, Meyer G, Becattini C, et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS), Eur Heart
J doi/10.1093/eurheartj/ehz405.
Risk stratification of PE

Piazza G. Advanced Management of Intermediate- and High-Risk Pulmonary Embolism: JACC Focus Seminar. J Am Coll Cardiol. 2020 Nov 3;76(18):2117-2127.
Significance of clinical classification

MASSIVE = Intermediate High & High risk

MICHAEL R. JAFF. Advanced Endovascular Interventions With Ultrasound-Accelerated Thrombolysis in Intermediate-Risk Pulmonary Embolism, INSERT TO ENDOVASCULAR TODAY OCTOBER 2020 VOL. 19, NO. 10
 Risk adjusted Mx strategies

Konstantinides SV, Meyer G, Becattini C, et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS),
Eur Heart J doi/10.1093/eurheartj/ehz405.
 Recommendation for thrombolysis
• Haemodynamically compromised PE
• Systemic thrombolysis over catheter-directed thrombolysis
• Extensive DVT
• catheter-directed thrombolysis over systemic thrombolysis
Anticoagulation over thrombolysis if:
1. Proximal DVT
2. Submassive PE (PE with RV dysfunction but hemodynamically stable)

Thomas L. Ortel et.al ; American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. Blood Adv 2020; 4 (19):
4693–4738; Konstantinides SV, Meyer G, Becattini C, et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory
Society (ERS), Eur Heart J doi/10.1093/eurheartj/ehz405.
Approved thrombolytic regimens

• Streptokinase • rtPA (alteplase)

• 250 000 IU as a loading dose over 30 • 100 mg over 2 h
min, followed by 100 000 IU/h over • 0.6 mg/kg over 15 min (maximum
12–24 h dose 50 mg)
• Accelerated regimen: 1.5 million IU
over 2 h

• Urokinase
• 4400 IU/kg as a loading dose over 10
min, followed by 4400 IU/kg/h over
12–24 h
• Accelerated regimen: 3 million IU
over 2 h
Better outcome….
but may have increase risk of bleeding
Any other way???
Embolectomy

• considered when patient's presentation is severe enough to warrant

thrombolysis (e.g., persistent hypotension), but thrombolysis either
fails or is contraindicated.

• Via catheter or surgery

Or
Surgical embolectomy

• Performed on cardiopulmonary bypass with clots extracted from the

opened PAs under direct visualization
• Estimates of mortality: ~ 10-60%
• Main indication
• systemic hypotension due to PE in a patient in whom thrombolysis is
contraindicated
• Limited to large medical centers because an experienced surgeon
and cardiopulmonary bypass are required
Catheter embolectomy

Shah KJ, Roy TL. Catheter-Directed Interventions for the Treatment of Lower Extremity Deep Vein Thrombosis. Life (Basel). 2022 Nov 27;12(12):1984
 Meta-analysis

Ismayl M, Machanahalli Balakrishna A, Aboeata A, Gupta T, Young MN, Altin SE, Aronow HD, Goldsweig AM. Meta-Analysis Comparing Catheter-Directed Thrombolysis Versus Systemic Anticoagulation Alone
for Submassive Pulmonary Embolism. Am J Cardiol. 2022 Sep 1;178:154-162.
Recommendation in Intermediate-high
risk PE

CDL, catheter-directed lysis; PCDT, pharmacomechanical catheter-directed therapy; PMCT, pharmacomechanical catheter thrombectomy

MICHAEL R. JAFF. Advanced Endovascular Interventions With Ultrasound-Accelerated Thrombolysis in Intermediate-Risk Pulmonary Embolism, INSERT TO ENDOVASCULAR TODAY OCTOBER 2020 VOL. 19, NO. 10
 Anticoagulation

Konstantinides SV, Meyer G, Becattini C, et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS),
Eur Heart J doi/10.1093/eurheartj/ehz405.
 Anticoagulantion in VTE

Thomas L. Ortel et.al ; American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. Blood Adv 2020; 4 (19):
Before prescribing anticoagulation:

1. Look at the special consideration

2. Consider the options – oral vs parenteral
3. Check for DDI
4. Decide on the duration
Special consideration
before prescribing anticoagulant
Extremes of body weight (<50 kg or >120 kg)
Renal impairment or established renal failure (estimated creatine
clearance between 15 ml/min and 50 ml/min)
Active cancer
—(take into account the tumour site, interactions with other drugs including
those used to treat cancer, and the person’s bleeding risk)
Triple positive antiphospholipid syndrome.
 Clinical complexity of anticoagulation

*Dose adjustment recommended in NVAF patients with ≥2 of: body weight ≤60 kg, age ≥80 years, serum creatinine ≥133 μmol/L
APTT, activated partial thromboplastin time; INR, international normalised ratio; iv, intravenous; LMWH, low-molecular-weight heparin; sc, subcutaneous
1. Warfarin Approved PI. Available at: www.ebs.tga.gov.au; 2. Drug Guideline: Heparin. Available at: http://www.bhs.org.au/airapps/Services/au/org/bhs/govdoc/files/references/32993.pdf; 3. Enoxaparin Approved PI. Available at: https://quest3plus.bpfk.gov.my; 4. Fondaparinux Approved PI. Available at:
https://quest3plus.bpfk.gov.my; 5. Dabigatran Approved PI. Available at: https://quest3plus.bpfk.gov.my; 6. Apixaban Approved PI. Available at: https://quest3plus.bpfk.gov.my; 7. Rivaroxaban Approved PI. Available at: https://quest3plus.bpfk.gov.my
Check for DDI
 (Edoxaban)

We have been using

Warfarin
for
 RECOVER I & II
6 NOAC
Trials
(2009-
2013) with
27,023
patients

All with
exteded VTE Rx
up to 1 year
LOWER RISK OF MAJOR BLEEDING
 Evolution of guidelines for VTE treatment
(non-cancer patients)

1. Hyers TM, et al. Chest 1995;108:335S–51S; 2. Hyers TM, et al. Chest 1998;114:561S–78S; 3. Hyers TM, et al. Chest 2001;119:176S–93S; 4. Büller HR, et al. Chest 2004;126(3 Suppl):401S–28S; 5. Hirsh
J, et al. Chest 2008;133(6 Suppl):71S–109S; 6. Kearon C, et al. Chest 2012; 141(2 Suppl):e419S–96S; 7. Kearon C, et al. Chest 2016;149:315–52; 8. Torbicki A, et al. Eur Heart J 2000;21:1301–36; 9.
Torbicki A, et al. Eur Heart J 2008;29:2276–315; 10. Konstantinides S, et al. Eur Heart J 2014;35:3033–69; 11. Konstantinides SV, et al. Eur Heart J 2019; doi:10.1093/eurheartj/ehz405.
Malaysia Guideline for
VTE Management in Covid-19 Patients
 Increasing DOAC use Claims database 1/1/2010 – 31/12/2020

In this large cohort study of 298 609 patients with VTE, we observed a substantial shift in the use of OACs over
the course of a decade, with DOACs (especially apixaban) becoming overwhelmingly preferred over warfarin.

Iyer GS, Tesfaye H, Khan NF, Zakoul H, Bykov K. Trends in the Use of Oral Anticoagulants for Adults With Venous Thromboembolism in the US, 2010-2020. JAMA Netw Open. 2023 Mar 1;6(3):e234059.
 How long to anticoagulated?

Terminology such as ‘provoked’ vs.

‘unprovoked’ PE/VTE is no longer supported
by the Guidelines,

 as it is potentially misleading
 not helpful for decision-making regarding
the duration of anticoagulation.
ASH recommended against routine use of
1. prognostic scores
2. D-dimer testing, or
3. ultrasound (to detect residual vein thrombosis)
to guide the duration of anticoagulation.

Thomas L. Ortel et.al ; American Society of Hematology 2020 guidelines for

management of venous thromboembolism: treatment of deep vein
Kearon C; Chest 2016; 149(2); 315-352 thrombosis and pulmonary embolism. Blood Adv 2020; 4 (19): 4693–4738.
 Main new recommendation for
chronic/extended treatment

(2.5 mg b.i.d.) (10 mg o.d.)

Konstantinides SV, Meyer G, Becattini C, et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS),
Eur Heart J doi/10.1093/eurheartj/ehz405.
Balance between bleeding & recurrence
 Estimated risk for recurrence

Konstantinides SV, Meyer G, Becattini C, et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS),
Eur Heart J doi/10.1093/eurheartj/ehz405.
 Bleeding risk?
2019

VTE-BLEED score

a Cancer diagnosed within 6 mo before diagnosis of VTE (excluding basal‐cell or

squamous‐cell carcinoma of the skin), recently recurrent or progressive cancer.
b Males with uncontrolled arterial hypertension were defined by values of systolic
blood pressure ≥140 mm Hg at baseline.
c Hemoglobin <13 g/dL in men or <12 g/dL in women.
d Including prior major or nonmajor clinically relevant bleeding event, rectal bleeding,
frequent nose bleeding, or hematuria.
e The estimated glomerular filtration rate (eGRF) <60 mL/min defined the presence of
renal dysfunction: calculated at baseline with the Cockcroft‐Gault formula

Klok, FA, Presles, E, Tromeur, C, et al.; for the PADIS‐PE Investigators. Evaluation of the predictive value of the bleeding prediction score VTE‐BLEED for recurrent venous thromboembolism. Res Pract Thromb
Haemost. 2019; 3: 364– 371.
 Recurrence VTE risk calculator

https://vtepredict.com

15,141 VTE patients

de Winter MA, Büller HR, Carrier M, Cohen AT, Hansen JB, Kaasjager KAH, Kakkar AK, Middeldorp S, Raskob GE, Sørensen HT, Visseren FLJ, Wells PS, Dorresteijn JAN, Nijkeuter M; VTE-PREDICT study group.
Recurrent venous thromboembolism and bleeding with extended anticoagulation: the VTE-PREDICT risk score. Eur Heart J. 2023 Apr 7;44(14):1231-1244.
Extended DOAC trials: ≥ 80% ↓ in VTE

Kearon C; Chest 2016; 149(2); 315-352

Andreozzi GM; Circulation 2015; 132(20); 1891-7
What else can be done?
 Follow-up strategies &
Diagnostic work-up (1)

Konstantinides SV, Meyer G, Becattini C, et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS),
Eur Heart J doi/10.1093/eurheartj/ehz405.
 Follow-up strategies &
Diagnostic work-up (2)

Konstantinides SV, Meyer G, Becattini C, et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS),
Eur Heart J doi/10.1093/eurheartj/ehz405.
 Thrombophilia testing
NOT to test if
1. Women on COC
2. Unprovoked VTE
3. Surgery associated VTE

Middeldorp S, Nieuwlaat R, Baumann Kreuziger L, Coppens M, Houghton DE, James AH, Lang E, Moll S, Myers T, Bhatt M, Chai-Adisaksopha C, Colunga-Lozano LE, Karam SG, Zhang Y, Wiercioch W, Schünemann
HJ, Iorio A. American Society of Hematology 2023 Guidelines for Management of Venous Thromboembolism: Thrombophilia Testing. Blood Adv. 2023 May 17:bloodadvances.2023010177.
 Who else to test?

Middeldorp S, Nieuwlaat R, Baumann Kreuziger L, Coppens M, Houghton DE, James AH, Lang E, Moll S, Myers T, Bhatt M, Chai-Adisaksopha C, Colunga-Lozano LE, Karam SG, Zhang Y, Wiercioch W, Schünemann
HJ, Iorio A. American Society of Hematology 2023 Guidelines for Management of Venous Thromboembolism: Thrombophilia Testing. Blood Adv. 2023 May 17:bloodadvances.2023010177.
Let’s quickly look at Ca-VTE
 Overview of CA-VTE CA-VTE incidence increased over time

20%

20% - symptomatic
50% - VTE on autopsy

1.Lee AY, Levine MN. Circulation 2003;107:23 Suppl 1:I17 I21;

2. Noble S, et al., Br J Cancer 2010;102:S2 S9;
3. Stein PD, et al., Am J Med 2006;119: 60 68.
4. Khorana AA, Mackman N, Falanga A, Pabinger I, Noble S, Ageno W, Moik F, Lee AYY. Cancer-associated venous thromboembolism. Nat Rev Dis Primers. 2022 Feb 17;8(1):11.
Increase risk of VTE in cancer population

Rao MV, et al. In: Khorana and Francis, eds. Cancer-Associated Thrombosis;2007.
 LMWH: Better efficacy in Ca-VTE

1. Carrier M, Prandoni P, Expert Rev Hematol 2017;10:15–22; 2. Lee AYY et al, N Engl J Med2003;349:146–153; 3. Hull RD et al, Am J Med2006;119:1062–1072; 4. Deitcher SR et al, Clin Appl Thromb
Hemost2006;12:389–396; 5. Romera A et al, Eur J Vasc Endovasc Surg2009;37:349–356; 6. Lee AYY et al, JAMA2015;314:677–686
<50% of CAT patients persistent with
LMWH

Ageno W et al, Thromb Res 2015;135:666–672

DOAC in Ca-VTE

Vedovati MC, Giustozzi M, Becattini C. Venous thromboembolism and cancer: Current and future role of direct-acting oral anticoagulants. Thromb Res. 2019 May;177:33-41.
 Summary of guidelines on CA-VTE treatment
Guidelines

Year 2011 2019 2022 2023 2020 2021 2021 2021

Initial LMWH 200 UFH or LMWH, UFH, LMWH, 1. Weight-adjusted LMWH, Rivaroxaban, LMWH / DOAC DOAC
 Most recent guidelines recommend: DOAC over LMWH in initial treatment
Treatment IU/kg OD or
UFH
fondaparinux.
Rivaroxaban or
Apixaban,
Rivaroxaban, or
Fondaparinux,
Rivaroxaban or
LMWH or Edoxaban, or
Apixaban.
(Rivaroxaban;
Apixaban)
(Rivaroxaban;
Edoxaban;
Edoxaban Edoxaban Apixaban 2. Alternative: Apixaban)
following ≥5 following ≥5 Rivaroxaban; * Fondaparinux, VKA
days of days of Edoxaban or Dabigatran also
 Almost all guidelines prefer DOAC as maintenance treatemt
LMWH/UFH parenteral
anticoagulation
may be use (if ↑
contraindicated)
Maintenance LMWH LMWH / DOAC LMWH / DOAC LMWH / DOAC DOAC
Treatment (Rivaroxaban; (Rivaroxaban; (Rivaroxaban; (Rivaroxaban;
 Special precautions for use of DOAC in GI/GU cancers Edoxaban) Edoxaban;
Apixaban)
Edoxaban;
Apixaban)
Edoxaban;
Apixaban)
*VKA (if ↑ NA)
GI/GU - Cautions: Cautions: DOAC Cautions: DOAC DOAC not use Preferred LMWH. - Preferred:
Duration
Duration
cancer
of treatment:
6 months Min 6 months Min 6 months
DOAC
Min 6 months Min 6 months or Min 3 months Min 6 months
Rivaroxaban not use. Apixaban
Indefinite period
 at least 6 months or indefinite (> 6 monthsperiod
metastatic
if for
until cancer is active
cured (indefinite
cancers
(> 3 months if active
cancer/ treatment)
(Indefinite period
for active cancer)
disease or on period).
chemotherapy)
1. Khorana AA et al. J Thromb Haemost 2018;16:1891–1894; 2. Key NS et al. J Clin Oncol 2020;38:496–520; 3. Farge D et al. Lancet Oncol 20209;38:496–520; 4. Streiff MB et al. J Natl Compr Canc Netw 2018;16:1289–1303; 5. Konstantinides SV et al. Eur Heart J 2020;41:543–603; 6.
Ramcharitar, R. K., Man, L., Khaja, M. S., Barnett, M. E., & Sharma, A. (2022). A Review of the Past, Present and Future of Cancer-associated Thrombosis Management; 7. Shah S, Karathanasi A, Revythis A, Ioannidou E, Boussios S. Cancer-Associated Thrombosis: A New Light on an Old
Story. Diseases. 2021 May 4;9(2):34; 8. Attard LM, Gatt A, Bertoletti L, Delluc A, Riva N. Direct Oral Anticoagulants for the Prevention and Acute Treatment of Cancer-Associated Thrombosis. Vasc Health Risk Manag. 2022 Oct 13;18:793-807.
Special consideration in CA-VTE

 Brain cancer: LMWH or DOACs

 Thrombocytopenia:
 Platelet <20 – contraindicated
 Platelet 20 – 50 – relative contraindication
 Platelet > 50 – full dose

 Renal impairment: LMWH or UFH with careful monitoring

 Obesity: LMWH preferred

 Pregnancy: LMWH preferred (ITAC)

Xiong W. Current status of treatment of cancer-associated venous thromboembolism. Thromb J. 2021 Mar 31;19(1):21.
 Incidental PE vs symptomtic PE

• Suggest same initial and long-term anticoagulation as for comparable

patients with symptomatic PE

Giustozzi M, Connors JM, Ruperez Blanco AB, Szmit S, Falvo N, Cohen AT, Huisman M, Bauersachs R, Dentali F, Becattini C, Agnelli G. Clinical characteristics and outcomes of incidental venous
thromboembolism in cancer patients: Insights from the Caravaggio study. J Thromb Haemost. 2021 Jul 14.
 Practical

B.T. Samuelson Bannow, A. Lee, A.A. Khorana, J.I. Zwicker, S. Noble, C. Ay, et al., Management of cancer-associated thrombosis Ay, C et al. “Treatment of cancer-associated venous thromboembolism in the age of direct oral anticoagulants.” Annals of oncology :
in patients with thrombocytopenia: guidance from the SSC of the ISTH, J. Thromb. Haemost. 16 (6) (2018) 1246–1249. official journal of the European Society for Medical Oncology, vol. 30,6 897–907. 27 Mar. 2019, doi:10.1093/annonc/mdz111
 Targeting Factor XI
1. Congenital FXI deficiency  a mild
bleeding disorder (bleeding after
surgery in areas such as the mouth and
GU system)

2. Deficiency of FXI is not associated with

spontaneous bleeding.

3. There is an association between high

FXI levels and thrombosis.

4. There is a surprisingly high prevalence

of congenital FXI deficiency, suggesting
that may even be a possible survival
advantage to having lower levels of FXI.
Fredenburgh JC, Weitz JI. Factor XI as a target for new anticoagulants. Hamostaseologie. 021;41(2):104-10.
Bolton-Maggs PHB. Factor XI deficiency - resolving the enigma? Hematology Am Soc Hematol Educ Program. 2009;2009(1):97-105.
Nopp S et al. Factor XI inhibitors for prevention and treatment of venous thromboembolism: a review on the rationale and update on current evidence. Front Cardiovasc Med. 2022;9:903029.
Asselta R et al. Exploring the global landscape of genetic variation in coagulation factor XI deficiency. Blood. 2017;130(4):e1-6.
 Targeting Factor XI
ANT-005 TKA Phase II trial

Verhamme P et al. Abelacimab for prevention of venous thromboembolism. N Engl J Med. 2021;385(7):609-17.
Anthos Therapeutics, Inc. A study comparing abelacimab to apixaban in the treatment of cancer-associated VTE (ASTER). NCT05171049. https://clinicaltrials.gov/ct2/show/NCT05171049.
Anthos Therapeutics, Inc. A study comparing abelacimab to dalteparin in the treatment of gastrointestinal/genitourinary cancer and associated VTE (MAGNOLIA). NCT05171075.https://clinicaltrials.gov/ct2/show/NCT05171075.
Some of the known FXI/XIa inhibitor

Bentounes NK, Melicine S, Martin AC, Smadja DM, Gendron N. Development of new anticoagulant in 2023: Prime time for anti-factor XI and XIa inhibitors. J Med Vasc. 2023 Apr;48(2):69-80.
 Take Home
Anticoagulation

Piazza G. Advanced Management of Intermediate- and High-Risk Pulmonary Embolism: JACC Focus Seminar. J Am Coll Cardiol. 2020 Nov 3;76(18):2117-2127.
Take Home

• Important of risk stratification in acute PE

• Well’s score  PESI score

• Identifying high risk PE  systemic thrombolysis is recommended

• Major Guidelines recommend DOACs as anticoagulants of choice for

most patients
• Exceptions where DOACs aren’t appropriate include:
• pregnancy, severe renal insufficiency, severe liver disease, non-compliant patients,
mechanical valves, or if rapid reversal is needed
Take Home

Renner E, Barnes GD. Antithrombotic Management of Venous Thromboembolism: JACC Focus Seminar. J Am Coll Cardiol. 2020 Nov 3;76(18):2142-2154.
 Take Home

• A reduced dose of apixaban or rivaroxaban for extended

anticoagulation should be considered after the first 6 months of
treatment.

• Apixaban, Edoxaban or rivaroxaban is recommended in Ca-VTE

• with caution in gastrointestinal cancer due to the increased bleeding risk with
rivaroxaban & edoxaban.

Konstantinides SV, Meyer G, Becattini C, et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS),
Eur Heart J doi/10.1093/eurheartj/ehz405.
Tailored anticoagulation

Renner E, Barnes GD. Antithrombotic Management of Venous Thromboembolism: JACC Focus Seminar. J Am Coll Cardiol. 2020 Nov 3;76(18):2142-2154.
Simple algorithm

Renner E, Barnes GD. Antithrombotic Management of Venous Thromboembolism: JACC Focus Seminar. J Am Coll Cardiol. 2020 Nov 3;76(18):2142-2154.
Optimal
duration

Agnelli G, Becattini C. N Engl J Med 2010;363:266-274

Thank you