Venous Thromboembolism (DVT and PE) Overview

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Venous Thromboembolism (DVT and PE) Overview

Venous Thromboembolism

(DVT and PE) Overview

Rob Lavender MD

Professor of Medicine

Division of General Internal Medicine

University of Arkansas Medical Sciences

Little Rock, Arkansas

Why is Prophylaxis so

Important?

Pulmonary Embolism is

not a Disease

It is a Complication of

Deep Venous Thrombosis

Question #1

1. Which of the following causes the most deaths in the

United States every year?

A. Breast cancer

B. Pulmonary embolism

C. Highway fatalities

D. AIDS

VTE Mortality in Perspective

Causes of Death in U.S.

AMI

Pulmonary Embolism

Accidents

Highway Fatalities

Breast Cancer

AIDS

Deaths/Yr

215,000

200,000

97,835

41,800

40,200

13,426

Total

< PE

Previous VTE

Malignancy

Advancing age

Obesity

Prolonged bed rest

Trauma

Surgery

Pregnancy /

postpartum

VTE Risk Stratification:

Patient Factors: Clinical

Stroke

Medical Illness

– MI

– CHF

– Pneumonia

– COPD

– Infections

Oral contraceptives

Varicose veins

2002 AHA Heart and Stroke Update.

Page 1

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Inherited

VTE Risk Stratification:

Patient Factors: Molecular

Antithrombin III deficiency

Protein C deficiency

Protein S deficiency

Factor V Leiden

Prothrombin G20210A

mutation

Hyperhomocysteinemia

Elevated factor XI levels

Elevated factor VIII levels

Acquired

Myeloproliferative disease

Hyperhomocysteinemia

Antiphospholipid antibodies

– Lupus anticoagulant

– Anticardiolipin antibodies

8 th ACCP Consensus Conference

2008

Pathogenesis of Venous Thrombosis

Venous stasis

Activation of blood coagulation

Vascular endothelial damage

Aspirin

Prophylaxis of DVT

Graduated compression

stockings

Dextran

Low dose heparin

Adjusted dose

subcutaneous heparin

Venous foot pump

Intermittent pneumatic

compression

Warfarin

Low molecular weight

heparins

Fondaparinux

Desirudin

New Agents

Advantages of LMWHs and

Fondaparinux

Good bioavailability

– no binding to proteins or endothelial cells

Stable dose response

– no monitoring required

Longer plasma half-life

Resistance not encountered

Less thrombocytopenia

Less osteoporosis

Low Molecular Weight Heparins

Enoxaparin (Lovenox)

Dalteparin (Fragmin)

Tinzaparin (Innohep)

Ardeparin

Nadroparin

Reviparin

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Fondaparinux (Arixtra)

FDA Indications

TKA

THA

Hip Fracture

Extended Prophylaxis after Hip Fracture

Abdominal Surgery

Treatment of DVT or PE

8 th ACCP Consensus Conference

General Surgery

RISK GROUP

Low risk

General surgery patients who

are undergoing minor

procedures and have no

additional thromboembolic

risk factors

Moderate risk

For moderate-risk general

surgery patients who are

undergoing a major

procedure for benign disease

RECOMMENDED PROPHYLAXIS

We recommend against the use of

specific thromboprophylaxis other

than early and frequent

ambulation(Grade 1A).

We recommend

thromboprophylaxis with LMWH,

LDUH, or fondaparinux(each grade

1A).

8 th ACCP Consensus Conference

General Surgery

RISK GROUP

Higher risk

For higher-risk general surgery

patients who are undergoing a

major procedure for cancer

High risk, multiple risk factors

General surgery patients with

multiple risk factors for VTE who

are thought to be at particularly

high risk

RECOMMENDED PROPHYLAXIS

We recommend

thromboprophylaxis with

LMWH, LDUH three times

daily, or fondaparinux (each

Grade 1A).

We recommend that a

pharmacologic method (ie,

LMWH,LDUH three times

daily, or fondaparinux) be

combined with the optimal

use of a mechanical method

(ie, graduated compression

stockings [GCS] and/or IPC)

[Grade 1C].

8 th ACCP Consensus Conference

General Surgery

RISK GROUP

Selected high risk

For selected high-risk general

surgery patients, including

some of those who have

undergone major cancer

surgery or have previously

had VTE

RECOMMENDED PROPHYLAXIS

We suggest that continuing

thromboprophylaxis after hospital

discharge with LMWH for up to 28

days be considered (Grade 2A).

8 th ACCP Consensus Conference

General Surgery

RISK GROUP

Selected high risk

For general surgery patients

with a high risk of bleeding

RECOMMENDED PROPHYLAXIS

We recommend the optimal use of

mechanical thromboprophylaxis

with properly fitted GCS or IPC

(Grade 1A). When the high

bleeding risk decreases, we

recommend that pharmacologic

thromboprophylaxis be substituted

for or added to the mechanical

thromboprophylaxis (Grade 1C).

A 52 yo man fell out of his deer stand

and is admitted with multiple

fractures including his hip and pelvis.

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Thromboembolism Prophylaxis in

Trauma Patients

Mechanical

Heparin

LMWH

Screening Duplex Scans

IVC filter

8 th ACCP Conference: Trauma

For major trauma patients, in the absence of a major

contraindication, we recommend that clinicians use

LMWH thromboprophylaxis starting as soon as it is

considered safe to do so (Grade 1A). An acceptable

alternative is the combination of LMWH and the optimal

use of a mechanical method of thromboprophylaxis

(Grade 1B).

For major trauma patients, if LMWH

thromboprophylaxis is contraindicated due to active

bleeding or high risk for clinically important bleeding,

we recommend that mechanical thromboprophylaxis

with IPC or possibly with GCS alone be used (Grade

1B).

A 67 year old white female is

scheduled for a right THA.

What is the best DVT prophylaxis

and how long should it be

continued?

What if she had a TKA?

FDA ADVISORY in 1997 on spinal

hematoma and LMWH with

neuraxial anesthesia

Incidence without pharmacologic intervention

– spinal >1/220,000

– epidural >1/150,000

60 spinal hematomas reported between 1993 –1998

1998- ASRA first consensus conference

8 spinal hematomas reported between 1998-2003

2002- ASRA second consensus conference

2010- ASRA third consensus conference

*Tryba. Anasthesiol Intensivmed Notfallmed Schmerzther 1993;28:179.

The second (2002)ASRA consensus

conference on neuraxial anesthesia and

anticoagulation

Indwelling Epidural Catheters

Twice daily dosing of LMWH: Indwelling catheters should be

removed prior to initiation of LMWH. If a continuous technique

is selected, the epidural catheter may be left indwelling

overnight and removed the following day, with the first dose of

LMWH administered at least 2 hours after catheter removal.

Single daily dosing of LMWH: Indwelling neuraxial catheters may

be safely maintained. However, the catheter should be removed

a minimum of 10-12 hours after the last dose of LMWH.

2010 ASRA Third Consensus Conference

Regional Anesthesia in the Patient Receiving

Antithrombotic or Thrombolytic Therapy: American

Society of Regional Anesthesia and Pain Medicine

Evidence-Based Guidelines (Third Edition)

What’s New?

Horlocker,et.al. Regional Anesthesia and Pain Medicine:

January/February 2010 - Volume 35 - Issue 1 - pp 64-101

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Background

A 74 year old man is admitted with

pneumonia and an exacerbation

of COPD.

Number of patients recruited in trials on

VTE prophylaxis using a systematic

search for DVT

Surgical patients > 100,000

Medical patients < 20,000

VTE in Hospitalized Patients



Causes 10% of hospital deaths

True prevalence ~ 600,000 cases per year

In-hospital VTE: ~ 70% in medical patients

~ 30% in surgical patients

Primary Efficacy Endpoints Implications

for Clinical Practice

Trial VTE RRR NNT

MEDENOX 1 Distal and proximal 63%

(N=1102) venographic DVT

+ symptomatic VTE

+ fatal PE

PREVENT 2 Compression 45%

(N=3706) ultrasonographic DVT

+ symptomatic VTE

+ fatal PE

ARTEMIS 3 Distal and proximal 47%

(N=~800) venographic DVT

+ symptomatic VTE

+ fatal PE

1 Samama MM, et al. N Engl J Med 1999;341:793-800.

2 Leizorovicz A, et al. J Thromb Haemost 2003;1 Suppl 1:OC396.

3 Cohen AT, et al. J Thromb Haemost 2003;1 Suppl 1:P2046.

NNT – justifies

thromboprophylaxis

10

45

20

NNT = number needed to treat

8 th

th ACCP Recommendations

At-Risk Medical Patients

ACCP grade 1A options for DVT

prophylaxis in “acutely ill medical

patients who have been admitted

to the hospital with CHF or severe

respiratory disease, or who are

confined to bed and have one or

more additional risk factors,

including active cancer, previous

VTE, sepsis, acute neurologic

disease or inflammatory bowel

disease”.

– Low-molecular-weight heparin

– Low dose UFH

– Fondaparinux

Thromboprophylaxis in Medical

Patients

LMWH vs UFH

DVT

PE

Death

Major

hemorrhage

LMWH better

UFH better

RR=0.48 (0.23–1.0)

P=NS

P=NS

P=NS

P=0.049

0 0.5 1 2

RR

Mismetti P, et al. Thromb Haemost 2000;83:14-19.

Meta-analysis N=4,469

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Medical Prophylaxis

LMWH vs. UFH Meta-Analysis

VTE Prophylaxis Rates in Medical

Patients

Outcome

# Patients

analyzed

RR

95% CI

SOLUCIENT 01 (1)

26

DVT

4,421

0.68

0.52-0.88

DVT FREE 01-02 (2)

42

PE

Major bleeding

Minor Bleeding

4,231

4,497

3,538

0.57

0.77

0.61

0.25-1.34

0.50-1.20

0.34-1.10

HealthFacts 01-05 (3)

PREMIER 02 (4)

IMPROVE* 02-03 (5)

IMPROVE 02-06 (6)

15.3

29

39

54

Total bleeding

4,715

0.83

0.60-1.14

SOLUCIENT 04 (1)

33

Injection site hematoma

Mortality

2,002

4,881

0.47

1.16

0.36-0.62

0.85-1.59

PREMIER 05 (4)

37

ENDORSE* 06-07 (7)

40

0 10 20 30 40 50 60 70

percentage (%)

Wein L, et al. Arch Intern Med 2007;167:1476-86.

Why is Prophylaxis Underused in

At-Risk Medical Patients?

Potential Reasons

Clinicians unaware of the level of VTE risk

Not a ‘one specialty’ responsibility

Heterogeneous population

Perceived difficulties in risk assessment

Few studies of prophylaxis

8 th ACCP Conference

For every general hospital, we recommend

that a formal, active strategy that addresses

the prevention of VTE be developed (Grade

1A).

We recommend that the local

thromboprophylaxis strategy be in the form of

a written, institution-wide thromboprophylaxis

policy.

Gee WH, et al. CHEST 2001;119:132S-175S.

2008

Joint Commission on Accreditation of

Healthcare Organizations

Collaboration with NQF to develop standardized performance

measures for DVT prevention

The Joint Commission Benchmark states

– “DVT is one of the most common preventable causes of

deaths in hospitals”

– “Only 30% to 40% of patients who should be treated to prevent DVT

actually receive such treatment”

– “The use of proven and effective DVT prevention…methods

could save the lives of many patients”

NATIONAL QUALITY FORUM ENDORSES CONSENSUS

STANDARDS FOR QUALITY OF HOSPITAL CARE

Joint Commission Core Measures as of

Oct. 1, 2009

Venous Thromboembolism

VTE prophylaxis

Intensive Care Unit (ICU) VTE Prophylaxis

VTE Patients with Anticoagulation Overlap Therapy

VTE Patients Unfractionated Heparin (UFH)

Dosages/Platelet Count Monitoring by Protocol (or

Nomogram)

VTE Discharge Instructions

Incidence of Potentially Preventable VTE

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SCIP

Surgical Care Improvement Project

SCIP VTE-1

SCIP VTE-2

www.qualitynet.org

What Happens if You Don’t

Comply With Quality Measures?

Loss of hospital accreditation

Medicare payment cuts

Relegation to less-favored HMO tiers

Poor showing on quality measurement web sites

Lower income, fewer patients

DVT and PE: Laboratory Tests

A 56 year old man presents to

clinic with a 3 day history of left

leg swelling.

D-dimer

• Numerous assays available

• Very sensitive for DVT/ PE

• ELISA most sensitive

• Very nonspecific!!! (Major limitation!!)

A 66 year old man has acute onset of

SOB and CP 4 days after being

admitted for pneumonia and an

exacerbation of CHF.

VQ versus CT for Suspected

Acute PE: The Great Debate…

What’s wrong with the VQ scan?……..

Even when PE is present, the VQ scan is

usually….

NONDIAGNOSTIC!!

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Treatment of VTE

Diagnosis of VTE

Initial treatment

UFH or LMWH or Fondaparinux

Long-term treatment

Vitamin K antagonist (INR 2.0 to 3.0)

5 to 7 days

> 3 months




8 th ACCP Recommendations

VTE Treatment

For patients with objectively confirmed DVT, we

recommend short-term treatment with SC LMWH , IV

UFH , monitored SC UFH , fixed- dose SC UFH , or SC

fondaparinux (all Grade 1A) rather than no such shortterm

treatment.

In patients with acute DVT, we recommend initial

treatment with LMWH SC once or twice daily, as an

outpatient if possible (Grade 1C), or as an inpatient if

necessary (Grade 1A), rather than treatment with IV

UFH.

In patients with acute nonmassive PE, we recommend

initial treatment with LMWH over IV UFH (Grade 1A).

2008

Initial Treatment of DVT

Enoxaparin 1 mg/kg SQ q 12 hrs or 1.5 mg/kg q 24 hrs

Dalteparin 100 U/kg SQ q 12 hrs or 200 U/kg SQ q 24 hrs

Tinzaparin 175 u/kg q SQ 24 hrs

Fondaparinux SQ q 24 hrs (< 50 kg=5 mg, 50-100 kg=7.5

mg, >100mg=10 mg)

No PTT monitoring

Special Populations

Renal Insufficiency

Obesity

Pregnancy

Start warfarin on Day 1 and D/C LMWH or Fondaparinux

when INR > 2.0 for two consecutive days

A 52 year old man with CRI (baseline Cr. 3.5)

is admitted with acute DVT of the right leg and

found to have a platelet count of 56. He was

admitted 2 weeks earlier for pneumonia and

did receive 5000 units of heparin every 8 hours

for DVT prophylaxis. His platelet count then

was 196. How would you manage his DVT?

Anticoagulation Agents For HIT

Characteristic

FDA approval

Molecular wt

HIT Crossantigenicity

Direct

antithrombin

Elimination

Danaparoid

No

6000 Da

10-12%

No

Renal

Lepirudin

Yes

6979 Da

No

Yes

Renal

Argatroban

Yes

526 Da

No

Yes

Hepatic

Bivalirudin

No

2180 Da

No

Yes

Renal

Half-life

19-24 h

1.3 h

39-51 min

10-24 min

Monitoring

Anti-XA

PTT

PTT

PTT

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Long Term Treatment

RCTs of LMWH vs warfarin in cancer

A 68 year old man with lung cancer

develops acute proximal DVT in his

right leg.

CLOT

CANTHANOX

LMWH

dalteparin

enoxaparin

Patients, N

676

147

ONCENOX

enoxaparin

101

Subgroup LITE

tinzaparin

167

CLOT Recurrent VTE

Probability of Recurrent VTE, %

25

20

15

10

5

0

risk reduction = 52%

HR 0.48 (95% CI 0.30, 0.77)

log-rank p = 0.002

VKA, 17%

dalteparin, 9%

0 30 60 90 120 150 180 210

Days Post Randomization

VTE Patients with Cancer



8 th ACCP Conference

For patients with DVT and cancer, we recommend LMWH for

the first 3 to 6 months of long-term anticoagulant therapy

(Grade 1A).

For these patients, we recommend subsequent

anticoagulant therapy with VKA or LMWH indefinitely

or until the cancer is resolved (Grade 1C).

Lee et al. New Engl J Med 2003;349:146-153.

Warfarin Therapy

When?

How Much?

How Long?

Follow Up

8 th ACCP Recommendations

VTE Treatment

For patients with DVT secondary to

a transient (reversible) risk factor,

we recommend treatment with a

VKA for 3 months over treatment

for shorter periods (Grade 1A).

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8 th ACCP Recommendations

VTE Treatment

For patients with unprovoked DVT, we

recommend treatment with a VKA for at

least 3 months (Grade 1A).

For patients with a first unprovoked VTE

that is a proximal DVT, and in whom

risk factors for bleeding are absent and

for whom good anticoagulant

monitoring is achievable, we

recommend long-term treatment (Grade

1A).

There is increasing evidence that a normal D-D

dimer level and the absence of residual

thrombus after discontinuation of oral

anticoagulation are associated with a lower risk

of recurrent VTE events.

Zhu, et. al. Venous Thromboembolism: Risk Factors for Recurrence;

Arteriosler Thromb Vasc Biol.2009;29:298-310.

75 yo WF with h/o HTN, MI and CRI is

seen in clinic for her routine INR. She

is on warfarin for recurrent DVT. Her

INR today is 6.0. She denies any

bleeding or bruising or use of OTC

meds.

What are her risk factors for bleeding

on warfarin?

How do you want to manage her?

8 th ACCP Conference: Managing

VKA Dosing

For patients with INRs of > 5.0 but < 9.0 and no significant

bleeding, we recommend omitting the next one or two doses,

monitoring more frequently, and resuming therapy at an

appropriately adjusted dose when the INR is at a therapeutic

level (Grade 1C).

Alternatively, we suggest omitting a dose and administering

vitamin K (1 to 2.5 mg) orally, particularly if the patient is at

increased risk of bleeding (Grade 2A).

High INR Management

Question: does vitamin K decrease bleeding in high INR?

Design: RCT, double blinded (INR 4.5-10.0)

Patients: 724 Canadian, American and Italian patients

Intervention: vitamin K 1.25 mg po

Comparison: placebo

Outcome:major bleeding, any bleeding, thromboembolism and

death

Timeframe: 7, 30 and 90 outcomes

High INR Management

Crowthers MA. Ann Intern Med. . 2009 Mar 3;150(5):293-300. 300. PMID: 19258557

Crowthers MA. Ann Intern Med. . 2009 Mar 3;150(5):293-300. 300. PMID: 19258557

Page 10

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8 th ACCP Conference: Managing

VKA Dosing

In patients with mild to moderately elevated

INRs without major bleeding, we recommend

that when vitamin K is to be given, it be

administered orally rather than subcutaneously

(Grade 1A).

A 56 year old woman with an acute left

popliteal DVT develops a GI bleed.

IVC Filters in the Prevention of

Pulmonary Embolism in Patients with

Proximal DVT

No Odds Ratio P

End Point at Day 12 Filter Filter (99% CI)* Value

(N=200) (N=200)

Pulmonary embolism 2 (1.1) 9 (4.8) 0.22 0.03

(0.05-0.90)

Major bleeding 9 (4.5) 6 (3.0) 1.49 0.44

(0.53-4.20)

Death 5 (2.5) 5 (2.5) 0.99 0.99

(0.29-3.42)

Decousus et al. NEJM 1998;338:409

IVC Filters in the Prevention of Pulmonary

Embolism in Patients with Proximal DVT

No Odds Ratio P

Events at 2 years Filter Filter (99% CI)* Value

(N=200) (N=200)

Symptomatic PE 6 (3.4) 12 (6.3) 0.50 0.16

(0.19-1.33)

Recurrent DVT 37 (20.8) 21 (11.6) 1.87 0.02

(1.10-3.20)

Major bleeding 17 (8.8) 22 (11.8) 0.77 0.41

(0.41-1.45)

Death 43 (21.6) 40 (20.1) 1.10 0.65

(0.72-1.70)

Decousus et al. NEJM 1998;338:409

New anticoagulants and their

targets in the coagulation cascade

Intrinsic or Extrinsic Activation

DX-9065

Rivaroxaban

Apixaban

LY 517717

Otamixaban

Factor IX

Factor X

Factor II

(Prothrombin)

Factor Xa

Factor VII

Factor IIa

(Thrombin)

Dabigatran

Fibrinogen

Fibrin

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