Venous Thromboembolism“Hey doc, my leg hurts”

Anthony Battad MD, MSc., MPH. FRCPCDirector // Directeur

Ambulatory Care, St. Boniface Hospital // Soins ambulatoire, Hôpital St. BonifaceMedical Director //Directeur médical

Master of Physician Assistant Studies // Mâitre d’études assitants-médicineUniversity of Manitoba // Université du Manitoba

abattad@sbgh.mb.ca

Disclosure

• Conference expenses paid for by University of Manitoba• No financial conflicts to disclose

Case # 162 year old male with pMHx:

• Prostate Ca

• HTN

Noticed unilateral right leg swelling and pain over the last 3 days

Recently returned from a 16 hour bus tour

Case # 254 year old female with PMHx:

• HTN, controlled

• Anxiety

Presents with SOBOE, worsening over the past 2 weeks

Denies any infectious symptoms

Objectives

• Know the impact of VTE disease on health

• Describe the pathogenesis of VTE (DVT and PE)

• Recognize the risk factors for VTE

• Name the signs and symptoms of DVT and PE

• Identify the appropriate diagnosis and treatment of VTE

VTE is a prevalent and severe disease compared with other public health burdens

500 000

VTE-related deaths

Breast cancer

Prostatecancer

Transport accidents

AIDS

400 000

300 000

200 000

100 000

600 000Annual mortality rate in Europe

(25 member-state countries)

Adapted from Cohen et al. Thromb Haemost 2007;98:756-64

543 454

86 83163 636 53 599

5860

0

Annu

al n

o. o

f dea

ths

VTE is a Major International Health Problem: Millions of Cases Annually

0100,000200,000300,000400,000500,000600,000700,000800,000

Nonfatal DVT Nonfatal PE Fatal VTEPa

tient

s pe

r Yea

r With

VTE

Patie

nts

per Y

ear W

ith V

TE

0

100,000

200,000

300,000

400,000

Nonfatal DVT Nonfatal PE Fatal VTE

~900,000 VTE events occur each year in the US

~1.6 million VTE events occur each year in the EU

VTE = venous thromboembolism; DVT = deep vein thrombosis; PE = pulmonary embolism.Heit JA et al. Abstract #910 appears in Blood. 2005;106.

Adapted from Cohen AT et al. Thromb Haemost. 2007;98:756-764.

• An estimated 45,000 patients in Canada are affected by deep vein thrombosis (DVT) each year1

• Among those who develop DVT2:• One-third will have long term complications such as chronic lower leg

edema, post-phlebitic syndrome, pain, pigment changes • One-third will develop a recurrent event within 10 years

• Despite adequate therapy, 1% to 8% of patients in whom pulmonary embolism develops, will die2

1. Thrombosis Canada, 2013, Clinical Guides, Venous Thromboembolism; http://thrombosiscanada.ca/ 2. Scarvelis et al, CMAJ 2006; 175(9) 1087-92

Incidence of VTE in Canada

Annual Event Rates of Recurrent VTE• Patients with unprovoked VTE had the highest risk of recurrence

9

Duration of Follow-Up

Provoked bySurgery

Provoked byNonsurgical Factor

Unprovoked(idiopathic)

12 months 1.0%/yr 5.8%/yr 7.9%/yr

24 months 0.7%/yr 4.2%/yr 7.4%/yr

Data from Iorio A, Kearon C, Filippucci E, et al. Risk of recurrence after a first episode of symptomatic venous thromboembolism provoked by a transient risk factor: a systematic review. Arch Intern Med. 2010;170:1710–1716.

Kaatz S et al. Cleve Clin J Med. 2011;78(9):609-618.

Pathophysiology of VTE

10

Virchow’s

Triad

Hypercoagulability

Endothelial InjuryStasis of Venous

Blood Flow

Adapted from Kyrle PA et al. Blood 2009; 114: 1138-1139

VTE: Clot Formation Within the Venous Circulation

Pulmonary embolism (PE)

Deep vein thrombosis (DVT)

MigrationEmbolus

1

2

Tapson VF. N Engl J Med. 2008;358:1037-1052.Image adapted from Tapson VF.

Thrombus

11

Clinical-setting–related Risk Factors

Patient-related Risk FactorsClinical Inherited Acquired

Type or duration of surgery

Orthopedic surgery Pelvic or hip fracture Type of anesthesia Congestive heart

failure Intensive care Multiple trauma

Previous VTE Varicose veins Age >70 years Obesity Prolonged bed rest Level of hydration Severe medical illness Cancer Infection or sepsis Pregnancy or childbirth Combined oral

contraceptives Stroke Myocardial infarction

Activated protein C resistance

Deficiencies in: antithrombin, heparin cofactor II, protein C, protein S

Prothrombin mutation

Hyperhomo-cysteinemia

Lupus anticoagulant Anticardiolipin

antibodies Myelopro-liferative

disease Hyperhomo-

cysteinemia

Arcelus JI et al. Orthopedics. 2006;29(6):506-516.12

Anatomy Review

Image from Thrombosis Adviser. http://www.thrombosisadviser.com/en/resources/image-library/index.php. Accessed September, 2015

Proximal vs. Distal DVT

Proximal DVT• > 90% of acute PE due to

proximal DVT• Iliac, femoral, and popliteal veins• Associated with chronic risk

factors:• Active malignancy, CHF, age > 75,

chronic respiratory disese• ~ 50% untreated DVT PE within

3 months• Higher 3 month mortality than

distal DVT

Distal DVT• Small veins of the calf• Associated with transient risk

factors:• Recent surgery• Immobilization• Travel

• 25% - 33% of untreated and symptomatic distal DVT extend proximally

• Proximal extensions treated as if they originated in proximal vein

Upper Extremity DVT

• 4% to 11% of all DVT 1

• Risk Factors• CVL placement• Malignancy• Hospitalization

• Less incidence of pain• Less likely to have PE at time of diagnosis• Rates of recurrent VTE and death similar to lower extremity VTE

1. Muñoz FJ et al. Chest. 2008;133(1):143-148. http://dx.doi.org/10.1378/chest.07-1432 2. Joffe HV et al. Circulation. 2004;110:1605-1611.3. Mai C, Hunt D. Am J Med. 2011;124(5):402-407.

Clinical Presentation: Signs and Symptoms1-4

DVT• Pain• Swelling• Tenderness• Discoloration• Pitting edema

PE• Shortness of breath• Cough• Chest pain• Tachycardia• Hypotension• Low-grade fever

1. Moll S. Arterioscler Thromb Vasc Biol. 2008;28(3):373-379.2. Pai M et al. http://www.uptodate.com/contents/deep-vein-thrombosis-dvt-beyond-the-basics Accessed September 20153. Thompson et al. http://www.uptodate.com/contents/pulmonary-embolism-beyond-the-basics Accessed September 20154. Goldhaber SZ. Pulmonary Embolism. In: Bonow RO, Mann DL, Zipes DP, Libby P, Braunwald E, eds. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 9th ed.

Philadelphia, PA: Elsevier, 2012.

16

Left image from National Blood Clot Alliance. http://www.stoptheclot.org/learn_more/learn_thrombosis.htm. Accessed September 2015.Right image from University of Maryland Medical Center. http://www.umm.edu/patiented/articles/000583.htm. Accessed September, 2015

Image from Medic Scientist. http://medicscientist.com/chest-pain-differential-diagnosis. Accessed September, 2015.

Clinical Feature ScoreActive cancer (ongoing Rx or within 6 months or palliative 1

Paralysis, paresis, or recent immobilization (cast) of lower extremity 1

Recently bedridded > 3 days or major surgery within 4 weeks 1

Localized tenderness along the distribution of the deep venous system 1

Entire swelling of the leg (thigh to foot) 1

Calf swelling > 3 cm as compared to asymptomatic leg 1

Pitting edema worse in the affected leg 1

Collateral superficial veins (non-varicose) 1

Alternative diagnosis as likely or more likely than DVT -2

Previously documented DVT 1

Modified Wells Criteria for DVT

Adapted from:Wells PS, Anderson DR, Bormanis J, et al. Value of assessment of pretest probability of deep-vein thrombosis in clinical management. Lancet 1997; 350:1795Wells PS, Anderson,DR, Rodger M, et al. Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med 2003; 349:1227

Modified Wells Scoring

• 2 or greater DVT likely

• 1 or less DVT unlikely

• Modified Wells score takes into account D-Dimer

• (eg) if DVT unlikely (score 1 or less), negative D-Dimer rules out DVT

Diagnosis

DVT1

• D-dimer measurements• Venous ultrasonography• Contrast venography

•PE2

• ECG• Chest radiograph• CT angiogram

• Ventilation-perfusion (V/Q) scan3

• Pulmonary angiogram

1. Bates SM et al. Chest. 2012;141(2 Suppl):e351S-e418S.2. Tapson VF. N Engl J Med. 2008;358:1037-1052.3. Schümichen C. Respiration. 2003;70(4):329-342.

4. Sidhu PS, et al. Br J Radiol. 2007;80(959):859-865.19

Image from Phlebologia. http://www.phlebologia.com/en/anatomie_classique_04.asp. Accessed September, 2015.

Image courtesy of RF Schneider, Pfizer

Image from Schümichen C.

Upper calf image from Sidhu PS et al.4

Phases of Anticoagulation Treatment for VTE

Vitamin K antagonist (VKA) or other agent†Parenteral

Initial1

(0 to ~7 days)Long-term

(~7 days to ~3 months)Extended

(~3 months to indefinite)

Treatment

Secondary preventionRisk

of R

ecur

rent

VTE

Time since starting treatment

Start of treatmentand secondary prevention2 Completion of treatment

1. Kearon C et al. Chest. 2012;141(2 Suppl):e419s-e494s.2. Kearon C. J Thromb Haemost. 2012;10:507-511. 20

Phases of Anticoagulation Treatment for VTE

NOAC/DOAC or Vitamin K Antagonist

Initial1

(0 to ~7 days)Long-term

(~7 days to ~3 months)Extended

(~3 months to indefinite)

Treatment

Secondary preventionRisk

of R

ecur

rent

VTE

Time since starting treatment

Start of treatmentand secondary prevention2 Completion of treatment

1. Kearon C et al. Chest. 2012;141(2 Suppl):e419s-e494s.2. Kearon C. J Thromb Haemost. 2012;10:507-511. 21

• Do not delay treatment while waiting for diagnostics

• Prevent clot extension

• Prevent the development of PE

• Reduce the risk of recurrence

• Limit the development of late complications

Treatment Rationale

High probability or

Confirmed VTE

No Treatment

Bleeding Risk2

< 2%High Risk

Clot

Severe Symptoms 1

Inpatient Treatment

Outpatient Treatment

1Severe Symptoms

• Symptomatic PE• Severe leg swelling limiting

mobility• Cerulea phlegmasia dolens

NO

YES

NOYES

NO

YES

YES

HAS-BLED Score

Courtesy of mayoclinic.org, Accessed October, 2015

• Unfractionated heparin• Fallen out of favour – reserved for patients with decreased renal function

• Low molecular weight heparin (LMWH)• Dalteparin

• Fondiparinox – synthetic Xa inhibitor• Used in patients with HIT (heparin induced thrombocytopenia)

• If using warfarin, start at the same time and overlap for 2 days of therapeutic INR (2 – 3)

Inpatient Treatment

• LMWH plus warfarin• Overlap 2 days within therapeutic INR range (2-3)

• New Oral Anticoagulants (NOAC)• Dabigatran – direct thrombin inhibitor• Rivoroxiban – Xa inhibitor• Apixiban – Xa inhibitor

• Avoid NOACs in patients with impaired renal function (eGFR < 30)

Outpatient Treatment

A Few Words About NOACs

• Advantages

• Rapid onset and offset• No monitoring• Reliable and predictable

pharmakokinetics• Less incidence of major bleeding

(compared to warfarin)• Non-inferior to warfarin

• Disadvantages

• Expensive• Can’t use in patients with poor

renal function• No “anti-dote”

Using current criteria for approval, warfarin

would NEVER be approved for use today.

• 1st provoked DVT – 3 months

• 2nd provoked DVT – 6 months

• 1st unprovoked DVT – 3-6 months (depending on risk of bleeding)

• 2nd unprovoked DVT – indefinite

• Documented PE treated for 6 months• 2nd PE – indefinite anticoagulation

Duration of Treatment

• Post-thrombotic syndrome (PTS)1

• Can occur within 1-2 years after DVT in 20% to 50% of all patients• Severe PTS occurs in 25-33% of patients with PTS

• Can lead to deep vein insufficiency and leg ulcers

• Chronic thromboembolic pulmonary hypertension (CTPH)• Can occur after PE and is associated with significant

morbidity and mortality2

• Frequency3

• 1.0% at 6 months• 3.1% at 1 year• 3.8% at 2 years

Secondary Complications of VTE

1. Kahn SR, Ginsberg JS. Arch Intern Med. 2004;164:17-26.2. McNeil K, Dunning J. Heart. 2007;93:1152-1158.3. Pengo V et al. N Engl J Med. 2004;350(22):2257-2264 29

Image from UpToDate. http://www.uptodate.com/contents/diagnostic-evaluation-of-chronic-venous-insufficiency. Accessed September 1, 2012.

Image from McNeil K. Heart. 2007;93:1152-1158.

• Age appropriate screening acceptable

• Multi-phase CT of chest, abdomen, pelvis

Malignancy Screening