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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
Risk factors for VTE
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
Leizorovicz A, Mismetti P. Circulation 2004
Risk factors for VTE
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
Leizorovicz A, Mismetti P. Circulation 2004
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
Mechanical methods if OACsare contraindicated
LMWH, followed by LMWH or
OAC
Mechanical methods if OACsare contraindicated
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