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PROPHYLAXIS OF VENOUS

THROMBOEMBOLISM IN MEDICAL

PATIENTS

Problems with VTE prophylaxis

in medical patients

• Efficacy of different VTE prevention methods in non-

surgical patients has not been so widely assessed

• From 1993 to 1998, only 9 out of 44 prophylaxis trials

published were conducted on non-surgical patients

• Clinical trials of VTE prophylaxis enrolled approximately

100,000 surgical patients, and only approximately

15,000 non-surgical patients

• Reasons explaining these facts:

VTE incidence in these patients is not exactly known

Clinical trials are more complex in non-surgical patients becauseof their difficult management

The most adequate prophylaxis schemes for this type of diseasesare not well defined

VTE incidence

in medical patients

0.05-1.50.25-317-3425-4030-75

40-1006-105-20

30-6030-5010-30

8-1010-2010-1515-20

PregnancyPostpartumMyocardial infarctionCongestive heart failureIschemic cerebral infarctionSpinal cord lesionCancerChemotherapyCentral venous catheterPolytrauma patientsPatients admitted to ICUElderly subjectsImmobilized elderly subjectsProlonged immobilization (> 3-4 days)General medical disease

DVT incidence (%)Risk factor

Risk factors for VTE

in medical patients

Acute medical conditions

• Cerebral infarction

• Myocardial infarction

• Diseases requiring ICU admission

• Other acute diseases requiring immobilization ≥ 3

days

Leizorovicz A, Mismetti P. Circulation 2004


in medical patients

Clinical risk factors

• Prior VTE

• Cancer

• Congestive heart failure

• Obstructive pulmonary disease

• Diabetes mellitus

• Inflammatory bowel disease

• Use of antipsychotic drugs

• Central venous catheter

• Permanent pacemaker

• Collagen disease

• Internal cardiac defibrillator

• Current home confinement orrepeated hospital admission

• Varicose veins

• Hormone replacement therapy

• Obesity

• Cancer chemotherapy



in medical patients

Thrombophilia

• Factor V Leiden

• Prothrombin gene mutation

• Hyperhomocysteinemia

• Antiphospholipid syndrome

• AT, protein C, or protein S deficiency

• High levels of factors VIII, IX, or X


Indications for VTE prophylaxis

with LMWHs in medical patients

• Pregnancy and postpartum

• Acute myocardial infarction

• Congestive heart failure

• Ischemic cerebralinfarction

• Spinal cord lesion

• Cancer

• Chemotherapy

• Central venous catheter

• Chronic obstructivepulmonary disease

• Acute pulmonary disease

• Acute infectious disease

• Chronic inflammatory boweldisease

• Multiple trauma

• Patients admitted to ICU

• Elderly subjects

• Prolonged immobilization fordifferent reasons

Clinical trials of LMWHs vs placebo

in various medical conditions

* Assessed PE, but not DVT, incidence** This study included a third arm with LMWH at lower doses showing no efficacy (DVT incidence = 15 %)

p valueLMWHPlacebo

DVT incidence (%)Patients enrolled(Placebo/LMWH)

ConditionAuthor

Dahan et al, 1986

Bergmann et al, 1996*

Fraisse et al, 1998

MEDENOX study, 1999

PREVENT study, 2004

Elderly

Various

Various

Various

Various

131/132

1,244/1,230

113/108

288/291**

1473/1518

9.1

1.4*

28

14.9

5.0

3

0.8*

15

5.5**

2.8

0.02

ns

0.01

0.001

0.001

Clinical trials of LMWHs vs UFH

in various medical conditions

*p = 0.002** p = 0.012

2

3.6

2

6

0.6

0

0.2

4.3

8.4

2

4.9

2

62*

0.8**

0.8

0.8

4.6

10.4

50/49

82/84

49/46

13/16

710/726

127/129

482/477

216/207

212/239

Various

Various

Various

Venous catheter

Various

Various

Various

Various

Various

Aquino et al, 1990

Harenberg et al, 1990

Forette et al, 1995

Monreal et al, 1996

Haremberg et al, 1996

APTE study, 1996

PRIME study, 1996

Bergman and Neuhart, 1996

Kleber et al, 2003

LMWHUFH

DVT incidence (%)Patients enrolled

(UFH/LMWH)PatologíaAuthor

Meta-analysis of randomized

clinical trials in medical diseases

0.48(p = 0.049)

1.07(p =0.66)

0.74(p = 0.52)

0.83(p = 0.37)

LMWH vs UFH

1.87(p = 0.08)

0.95(p = 0.40)

0.48(p < 0.001)

0.44(p < 0.001)

Heparin vs control

Majorbleeding

RR (p value)

MortalityRR (p value)

PE incidenceRR (p value)

DVT incidenceRR (p value)

Comparison

Mismetti P et al. Thromb Haemost 2000

Trials of VTE prophylaxis in

patients with ischemic stroke

Author,year Treatments used

DVT n/N (%) Mortality n/N (%)

Test

drugControl

Control

Turpie et al, 1987 Heparinoid vs Placebo 2/50 (4) 7/25 (28) 1/50 (2) 2/25 (8)

Prins et al, 1989 LMWH vs Placebo 6/30 (20) 15/30(50) 9/27 (33) 4/30 (13)

Sandset et al, 1990 LMWH vs Placebo 15/42 (36) 17/50 (34) 0/42 (0) 1/50 (2)

Turpie et al, 1992 Heparinoid vs UFH 4/45 (9) 13/42 (31) 9/45 (20) 9/42 (21)

Dumas et al, 1994 Heparinoid vs UFH 13/89 (15) 17/86 (20) 17/89 (19) 11/90 (12)

Hillbom et al, 2002 LMWH vs UFH 14/106 (13) 24/106 (23) 21/106 (20) 28/106 (26)

Test

drug

Recommendations for prophylaxis

of VTE in medical patients

Disease Recommended prophylaxis Alternative prophylaxis

Low dose LMWH or UFH Mechanical methods if OACsare contraindicated

UFH at low or therapeutic

doses

Mechanical methods if OACsare contraindicated

Low dose OACs

Low dose LMWH of UFH

Central venous catheter in cancer Low dose LMWH or OACs


LMWH, followed by LMWH or

OAC


Admitted to ICU with additional

risk factorsLow dose LMWH or UFH

Stroke with limb paralysis

Acute myocardial infacrtion

Metastasic breast cancer

Neoplasms with risk factors

Major trauma with RFs

Spinal cord lesion

LMWH

Relationship betweencancer and VTE

• Incidence of an underlying neoplasm in VTEpatients ranges from 6% and 14 % in differentstudies (mean, 10 %)

• Mean frequency of cancer in various studies inpatients with idiopathic VTE is 11 %, as comparedto 2.5 % in patients with secondary VTE

• The most common sites of occult neoplasm inpatients with VTE are colon, prostate, pancreas,lung, and stomach, in this order

Mortality in patients with cancer

and VTE treated with UFH vs LMWHs

RESULTS OF VARIOUS META-ANALYSES

RR = 0.31

RRR = 64 % (p = 0.01)

RR = 0.61

RRR = 9.75 % (p < 0.05)

13

10

9

11

Lensing et al, 1995

Siragusa et al, 1996

Hettiarachi et al, 1999

Gould et al, 1999

Increase in long-term survivalfavoring LMWHs

Trialsincluded

Authors

RR = Relative riskRRR = Relative risk reduction

Mortality in patients with cancer

and VTE treated with UFH vs LMWHs

STUDIES SHOWING INCREASED SURVIVAL IN CANCERPATIENTS TREATED WITH LMWHs

Lee et al, 2005

Authors Results

Increased survival in patients with localized small cell lung

carcinoma

Increased one-year survival in patients with solid

non-metastatic tumors

Increased survival in patients with solid tumors,

particularly when life expectation is > 6 months

Kakkar AK et al, 2004 Increased survival in a patient subgroup with solidtumors surviving > 17 months

Altinbas et al, 2004

Klerk et al, 2005

Role of LMWHs in cancer patients

LMWHs

VTEprophylaxis

and treatment

• Action upon:• Angiogenesis• Cell adhesion• Oncogene expression• Cell proliferation• Apoptosis• Other mechanisms

Antitumoral actionAnticoagulant action

Mortality reduction

Role of primary care

in VTE prophylaxis

Surgical conditions:

• Early hospital discharge in general and endoscopicsurgery (up to 7-10 days)

• Prolongation of prophylaxis after hospital discharge in:

Orthopedic surgery (up to 6 weeks)

Cancer surgery (up to 4 weeks)

Medical conditions:

• Pregnancy and postpartum

• Cardiac, neurological, and pulmonary diseases

• Acute infectious disease

• Neoplastic conditions

• Patients with central venous catheter

• Elderly patients

• Prolonged immobilization for various reasons

Stratification of VTE risk

in home patients

VTE history

Neoplasms

Fracture-immobilization

Age > 70 years

Bed confinement > 3 days

Myocardial infarction

Stroke

Heart failure

Chronic obstructive pulmonary disease

Recent surgery

Lower limb paralysis

Chronic inflammatory bowel disease

Risk factor

Low 1 point

Moderate 2-4 points

High >4 points

VTE RISK

Points

3

2

2

1

1

1

1

1

1

1

1

1

Women possibly requiring

prophylaxis of VTE during pregnancy

• VTE during pregnancy

• Primary prophylaxis of VTE in asymptomaticcarriers of thrombophilic disorders

• Secondary prophylaxis in women with prior VTEhistory, whether they have thrombophilia or not

• Patients on anticoagulants before pregnancy due torepeated VTE

• Prophylaxis of patients with history of obstetriccomplications: repeated miscarriage, preeclampsia,intrauterine death, intrauterine growth retardation

• Surgery during pregnancy

Use of LMWHs for prophylaxis

of VTE during pregnancy

• Osteoporosis in treatments longer than one month(less than with UFH)

• Exceptional cases of skin intolerance

Advantages

• Do not cross the placental barrier, thus avoiding

malformations and fetal bleeding

• Low risk of bleeding complications in pregnant women

(less than with UFH)

• Low risk of immune thrombocytopenia (HIT)

• (less than with UFH)

• Easy management

Disadvantages

Use of LMWHs for prophylaxis of

VTE during pregnancy

• In pregnant women with history of a VTE event, idiopathic or

associated to thrombophilia: administer LMWH in prophylactic

doses or UFH in moderate doses or in minidoses

• In pregnant women with history of several VTE events: use

adjusted doses of LMWH or UFH

Treatment of VTE events during pregnancy

Prophylaxis of VTE events during pregnancy

• LMWH in adjusted doses or UFH as a continuous intravenous

infusion (at least 5 days adjusting for APTT) followed by UFH

or LMWH in adjusted doses for the rest of pregnancy,

discontinuing treatment 24 hours before labor induction

Bates SM et al. Chest 2004

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