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VENOUS THROMBOEMBOLISM PROPHYLAXIS for the Hospitalized Medical Patients. Madel Sadili, MD, FCCP, FPCCP. Lecture Outline. Arterial & Venous Thrombosis Burden Of Disease (VTE) Incidence Rationale for Thromboprophylaxis Risk Factors Grading of Recommendations Recommendations - PowerPoint PPT Presentation
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VENOUSTHROMBOEMBOLISM
PROPHYLAXISfor the
Hospitalized Medical Patients
Madel Sadili, Madel Sadili, MD, FCCP, MD, FCCP, FPCCPFPCCP
Lecture Outline Arterial & Venous Thrombosis Burden Of Disease (VTE)
Incidence Rationale for Thromboprophylaxis Risk Factors Grading of Recommendations Recommendations Drugs Summary
Lecture Outline Arterial & Venous Thrombosis Burden Of Disease (VTE)
Incidence Rationale for Thromboprophylaxis Risk Factors Grading of Recommendations Recommendations Drugs Summary
Venous Thromboembolism(VTE)
DVT : Deep-vein thrombosisPE : Pulmonary Embolism
Arterial Thrombosis
Most common cause of MI, stroke, & limb gangrene
Usually is initiated by the spontaneous or mechanical rupture of atherosclerotic plaque
Consists of platelet aggregates held together by small amounts of fibrin
Strategies to inhibit arterial thrombogenesis focus mainly on drugs that block platelet function but often include anticoagulant agents to prevent fibrin deposition
Venous thrombosis Leads to PE (can be fatal) & to postphlebitic syndrome
Occurs when procoagulant stimuli overwhelm natural protective mechanisms, ie, excessive activation of coagulation with thrombophilic abnormalities, vessel wall damage or stasis; inflammatory cytokines generated after trauma, surgery, or medical illness activate endothelial cells that express adhesion molecules that attract leukocytes which elaborate tissue factor & express receptors for factor X & fibrinogen, that promotes coagulation on their surfaces; neutrophils generate O2 free radicals & release hydrolytic enzymes, enhancing local clot formation
Venous thrombus is composed mainly of fibrin & RBCs Anticoagulants are the drugs of choice for their
prevention & treatment
Lecture Outline Arterial & Venous Thrombosis Burden Of Disease (VTE)
Incidence Rationale for Thromboprophylaxis Risk Factors Grading of Recommendations Recommendations Drugs Summary
IMPACTOF
VENOUSTHROMBOEMBOLISM
Hospitalization for an acute medical illness
Independently associated with ~8fold increase in relative risk for VTE (Heit, et al. Arch Int Med 2000;160)
10-30% of general medical patients may develop VTE (Cohen, et al. Thromb Haemost 2005; 94)
50-70% of symptomatic thromboembolic events, and 70-80% of fatal PEs occur in non-surgical patients (Goldhaber, et al. Chest 2000; 118)
¾ of VTE in hospitalized patients occur in acutely ill nonsurgical patients (Leizorovicz, et al. J Thrombosis & Hemostasis 2003)
PE (postmortem studies) is associated with up to 10% of deaths in hospitalized patients, and only ¼ of these occur following surgery
thus… ¾ of hospitalized patients who suffer a fatal
PE are in fact medical patients
Cohen et al. Thromb Haemost 2005; 94
11
Death60,000 cases
Estimated cost of VTE care = US$ 1.5 billion/year
VTE: Magnitude of the Problem
Post-thrombotic syndrome
800,000 cases
Pulmonary hypertension30,000 cases
Goldhaber SZ et al. Lancet 1999;353:1386–9
DVT2 million cases
PE600,000 cases
Therefore...
the appropriate prophylaxis of medical inpatients offers an important opportunity to significantly reduce the burden of disease due to VTE
Lecture Outline Arterial & Venous Thrombosis Burden Of Disease (VTE)
Incidence Rationale for Thromboprophylaxis Risk Factors Grading of Recommendations Recommendations Drugs Summary
Rationale for Thromboprophyl
axis in Hospitalized
Patients
RationaleHigh Prevalence of VTE
Adverse Consequences of unprevented VTE
Efficacy & Effectiveness of thromboprophylaxis
DescriptionMost hospitalized px have risk factors for VTEDVT is common in many hospitalized pxHosp-acquired DVT & PE are usually clinically silentDifficult to predict which at-risk patients will develop symptomatic thromboembolic complicationsScreening at-risk px using PE or noninvasive testing is
neither effective nor cost-effective
Symptomatic DVT & PEFatal PECosts of investigating symptomatic patientsRisks & costs of treating unprevented VTE, esp bleedingIncreased future risk of recurrent VTEChronic post-thrombotic syndrome
Thromboprophylaxis is highly efficacious at preventing DVT, proximal DVT, symptomatic VTE, & fatal PE
Prevention of DVT also prevents PECost-effectiveness of prophylaxis has repeatedly been
demonstrated
Geerts, et al. Chest 2001; Geerts, et al. Chest 2001; 119:132S-175S119:132S-175S
Lecture Outline Arterial & Venous Thrombosis Burden Of Disease (VTE)
Incidence Rationale for Thromboprophylaxis Risk Factors Grading of Recommendations Recommendations Drugs Summary
Who are at risk for
VTE?
Surgery Trauma (major or lower extremity) Immobility, paresis Malignancy Cancer therapy (hormonal, chemotx, radiotx) Previous VTE Increasing age Pregnancy & the postpartum period Estrogen-containing oral contraception or HRT Selective estrogen receptor modulators Acute medical illness Heart or respiratory failure Inflammatory bowel disease Nephrotic syndrome Myeloproliferative disease Paroxysmal nocturnal hemoglobinuria Obesity Smoking Varicose veins Central venous catheterization Inherited or acquired thrombophilia
Heit, et al. Arch Int Med 2002; Heit, et al. Arch Int Med 2002; 162:1245-1248162:1245-1248
Absolute risk of DVT in Hospitalized Patients
Medical px 10-20 %
General surgery 15-40 Major gyne surgery 15-40 Major urologic surgery 15-40 Neurosurgery 15-40 Stroke 20-50 Hip or knee arthroplasty;
hip fracture surgery 40-60 Major trauma 40-80 Spinal cord injury 60-80 Critical care patients 10-80
Geerts, et al. Chest 2001; 119:132S-Geerts, et al. Chest 2001; 119:132S-175S175S
Despite consensus-group recommendations that at-risk medical patients should receive thromboprophylaxis,
there is NO CONSENSUS as to which patients are at risk,
thus, many patients may not receive appropriate thromboprophylaxis
Cohen, et al. Thromb Haemost 2005: 94
Cohen, p 9. Fig. 2
Samama MM et al. N Engl J Med 1999;341:793–800
Thromboprophylaxis in Acutely Ill Patients
MEDENOX (1999) Prophylaxis of VTE in MEDical Patients with ENOXaparin
40mg, 20mg enoxaparin vs placebo OD x 6-14 days 866 patients with heart failure, respiratory, & infectious
disease Primary outcome – VTE between days 1-14 – DVT
detected by bilateral venography (or duplex utz) between days 6-14 (or earlier if clinically indicated) or documented PE
Duration of ff-up – 3 months
0
2
4
6
8
10
12
14
16
All VTE Proximal DVT PE
(%) Placebo
Enoxaparin 20 mg
Enoxaparin 40 mg
NS = not significant
NS
P = 0.0002
P = 0.037
RRR = -63%
RRR = -65%
Samama MM et al. N Engl J Med 1999;341:793–800
MEDENOX: Incidence of VTE at Day 14
MEDENOX
The incidence of VTE was significantly lower in the 40mg enoxaparin group (5.5%) than in the placebo (14.9%)
The benefit was maintained at 3 months
PREVENT (2003)
Prospective evaluation of Dalteparin efficacy for the prevention of VTE in immobilized patients
Largest trial (radomized, double-blind, palacebo-controlled) comparing a LMWH with placebo – Dalteparin 5000 IU OD x 14 days
3706 acutely ill medical patients – CHF, acute respiratory failure, or infectious disease
Primary endpoint – clinically important VTE defined as objectively verified symptomatic DVT, PE, sudden death, & objectively verified asymptomatic proximal DVT. Compression UTZ done in all patients who had not reached an endpoint by day 21
Leizorovicz, et al. J Thrombosis & Haemostasis. July Leizorovicz, et al. J Thrombosis & Haemostasis. July 20032003
PREVENT: Results
Medically ill patients 52% CHF 30% respiratory failure Also, infection without
septic shock, rheumatic disorders, arthritis of the legs, or inflammatory bowel disease
3.7%
0.6%
2.8%
1.8%
5.0%
0.3%
0.0%
1.0%
2.0%
3.0%
4.0%
5.0%
6.0%
Imp
ort
ant
VT
E
Asy
mp
tom
atic
Pro
xim
al D
VT
Sym
pto
mat
icD
VT
Th
rom
bo
em
bo
lic
ev
en
ts (
%)
Placebo
Dalteparin
P=0.0015
Leizorovicz A. et al J Thromb Haemost 2003; 1 (Suppl 1):)OC396
PREVENT
The incidence of the composite primary outcome was 2.77% in the dalteparin group and 4.96% in the placebo group, a risk reduction of 45%
Lecture Outline Arterial & Venous Thrombosis Burden Of Disease (VTE)
Incidence Rationale for Thromboprophylaxis Risk Factors Grading of Recommendations Recommendations Drugs Summary
Grading of Recommendati
ons
Grade Clarity of
risk/benefit
Methodological strength of supporting evidence
Implications
1A Clear RCTs w/o important limitations
Strong recommendation; can apply to most patients in most circumstances without reservation
1C+ Clear No RCTs, but strong RCT results can be unequivocally extrapolated, or overwhelming evidence from observational studies
Strong recommendation; can apply to most patients in most circumstances
1B
1C
Clear
Clear
RCTs with important limitations (inconsistent results, methodological flaws)
Observational studies
Strong recommendation; likely to apply to most patients
Intermediate-strength recommendation; may change when stronger evidence is available
Grade Clarity of risk/benefit
Methodological strength of supporting evidence
Implications
2A Unclear RCTs without important limitations
Intermediate-strength recommendation; best action may differ depending on cirumstances or patients’ or societal values
2C+ Unclear No RCTs, but strong RCT results can be unequivocally extrapolated, or overwhelming evidence from observational studies
Weak recommendation; best action may differ depending on circumstances or patients’ or societal values
2B Unclear RCTs with important limitations
Weak recommendation; alternative approaches likely to be better for some patients under some circumstances
2C Unclear Observational studies Very weak recommendation; other alternatives may be equally reasonable
Lecture Outline Arterial & Venous Thrombosis Burden Of Disease (VTE)
Incidence Rationale for Thromboprophylaxis Risk Factors Grading of Recommendations Recommendations Drugs Summary
Recommendations:
Thromboprophylaxis in the
Medically Ill
Geerts, et al. Chest Supplement. Sept Geerts, et al. Chest Supplement. Sept 2004; 126/32004; 126/3
General Recommendations
It is recommended that mechanical methods of prophylaxis be used primarily in patients who are at high risk of bleeding (Grade 1C+) or as an adjunct to anticoagulant-based prophylaxis (Grade 2A). Careful attention should be directed toward ensuring the proper use of, and optimal compliance with, the mechanical device (Grade 1C+)
We recommend against the use of aspirin alone as prophylaxis against VTE for any patient group (Grade 1A)
For each of the antithrombotic agents, it is recommended that clinicians consider the manufacturer’s suggested dosing guidelines (Grade 1C)
General Recommendations
We recommend consideration of renal impairment when deciding on doses of LMWH, fondaparinux, the direct thrombin inhibitors, & other antithrombotic drugs that are cleared by the kidneys, particularly in elderly patients and those who are at high risk for bleeding (Grade 1C+)
In all patients undergoing neuraxial anesthesia or analgesia, special caution when using anticoagulant prophylaxis is recommended (Grade 1C+)
Medical Conditions In acutely ill medical patients who
have been admitted to the hospital with CHF or severe respiratory disease, or who are confined to bed & have 1 or more additional risk factors, including active cancer , previous VTE, sepsis, acute neurologic disease, or inflammatory bowel disease, prophylaxis with LDUH or LMWH is recommended (Grade IA)
In medical patients with risk factors for VTE, & in whom there is a contraindication to anticoagulant prophylaxis, the use of mechanical prophylaxis with GCS or IPC is recommended (Grade 1C+)
Medical Condition: Acute MI
For all patients at high risk of systemic or venous thromboembolism (anterior MI, pump failure, previous embolus, atrial fibrillation, or LV thrombus), the administration of IV UFH while receiving streptokinase, is recommended (Grade 1C+)
Medical Condition: Acute Ischemic Stroke
For acute stroke patients with restricted mobility, prophylactic low-dose subcutaneous heparin or LMWH or heparinoids is recommended (Grade 1A). *Low-dose heparin should be restricted for 24h after administration of thrombolytic therapy; it may be used safely in combination with aspirin.
For patients who have contraindications to anticoagulants, it is recommended that clinicians use intermittent pneumatic compression devices or elastic stockings (Grade 1C)
Medical Conditions: Intracerebral Hemorrhage
We recommend the initial use of intermittent pnuematic compression (Grade 1C+).
In stable patients, low-dose SQ heparin may be initiated as soon as the 2nd day after the onset of the hemorrhage (Grade 2C).
Underlying values and preferences: the recommendation for SQ heparin assumes a relatively low degree of risk aversion.
Cancer Patients
6-fold increased risk of VTE compared to those without cancer More specific risk estimates of VTE by cancer type, stage, and
treatment approaches are still largely unknown High among those with malignant brain tumors and
adenocarcinoma of the ovary, pancreas, colon, stomach, lung, prostate, and kidney
Cancer patients undergoing surgery have at least 2x the risk of postoperative DVT and more than 3x the risk of fatal PE
Cancer Patients Cancer patients undergoing surgical
procedures receive prophylaxis that is appropriate for their current risk state (Grade 1A). Refer to the surgical subsections.
Hospitalized cancer patients who are bedridden with an acute medical illness should receive prophylaxis that is appropriate for their current risk state (Grade 1A). Refer to the medical subsection.
It is suggested that clinicians not routinely use prophlaxis to try to prevent thrombosis related to long-term indwelling CVCs in cancer patients (Grade 2B).
Critical Care On admission to a critical care unit, all patients
should be assessed for their risk of VTE. Accordingly, most patients should receive thromboprophylaxis (Grade 1A)
For patients who are at high risk for bleeding, mechanical prophylaxis with GCS &/or IPC is recommended, until the bleeding risk decreases (Grade 1C+)
For ICU patients who are at moderate risk for VTE (eg, medically ill or postoperative px), LDUH or LMWH prophylaxis is recommended (Grade 1A)
For patients who are at higher risk, such as that following major trauma or orthopedic surgery, LMWH prophylaxis is recommended (Grade 1A)
BURNS Burn patients with additional risk
factors for VTE, including one or more of the ff: advanced age, morbid obesity, extensive or lower extremity burns, concomitant lower extremity trauma, use of a femoral venous catheter, &/or prolonged immobility (Grade 1C+)
If there are no contraindications, the use of either LDUH or LMWH is recommended, starting as soon as it is considered safe to do so (Grade 1C+)
Increased Risk of Bleeding
Recent surgery Known bleeding disorder Impaired renal function Uncontrolled hypertension Large ischaemic cerebral infarction Active GI bleeding (peptic/bowel) Use of antiplatelet drugs or NSAIDs
Lecture Outline Arterial & Venous Thrombosis Burden Of Disease (VTE)
Incidence Rationale for Thromboprophylaxis Risk Factors Grading of Recommendations Recommendations Drugs Summary
Methods of DVT Prophylaxis
Unfractionated heparin (UFH) Low-molecular-weight heparins (LMWHs) Oral anticoagulants (warfarin) Pentasaccharides (fondaparinux) Antiplatelet therapy Mechanical compression and early
ambulation
Unfractionated Heparin
Main anticoagulant action is mediated by the heparin/AT interaction, which inactivates thrombin factor IIa & factors Xa, IXa, & XIIa
Increases vessel wall permeability, suppresses proliferation of vascular smooth muscle cells, suppresses osteoblast formation, & activates osteoclasts, promoting bone loss, & HIT
IV infusion or SC injection (reduced bioavailabiltiy, thus, 10% higher initial dose)
Dose adjustment by monitoring aPTT, or, when very high doses are given, by ACT (activated clotting time)
LMWH Polysulfated glycosaminoglycans about 1/3 the molecular weight of UFH Like heparin, major anticoagulant effect by activating AT Administered in fixed doses, for thromboprophylaxis,
or in total body weight (TBW)-adjusted doses, for therapeutic effect
LMWH Reduced binding properties to proteins & cells, explaining all of the
anticoagulant, phramacokinetic, & other biological differences between heparin & LMWH:
-reduced ability to inactivate thrombin bec the smaller
fragments cannot bind simultaneously to AT & thrombin, but,
since bridging bet AT & factor Xa is less critical
for factor Xa activity, the smaller fragments inactivate
factor Xa almost as well as larger molecules
-reduced binding to plasma proteins is responsible for the
more predictable dose-response relationship of LMWHs
-lower binding to macrophages & endothelial cells increases the
plasma half-life of LMWHs
-reduced binding to platelets & PF4 explains lower incidence of HIT
-reduced binding to osteoblasts results in lower incidence of bone loss
Fondaparinux
New parenteral indirect factor Xa inhibitor, with no activity against thrombin
Excellent bioavailability after SQ injection with a plasma half-life of 17h, thus given OD
Does not bind to platelets or PF4 (no heparin/PF4 complex), thus, no HIT
Phase III trial for thromboprophylaxis at 2.5mg OD
9.7
16.1
02468
1012141618
Enoxaparin UFH
Patients with heart failure
Pati
en
ts (
%)
Kleber FX et al. Am Heart J 2003;145:614–21
THE-PRINCE Study: Incidence of VTE with Enoxaparin and UFH
Thromboembolism Prevention in Heart Failure or Severe Respiratory Disease with Enoxaparin (THE-PRINCE)
P=0.0139
8.4 10.4
Enoxaparin UFH
Pati
en
ts (
%)
P=0.0146
All evaluable patients
02468
1012141618
VTE PreventionNon-Pharmacologic Methods
Ambulation Elastic or Graduated
compression stockings (GCS)
Intermittent pneumatic compression (IPC) devices
Arteriovenous foot pumps (VFP)
Mechanical Methods of Prophylaxis
Increase venous outflow and/or reduce stasis within the leg veins
Primary attraction is the lack of bleeding potential, therefore, are considered for patients with high bleeding risks
Must select the correct size of the device, must properly apply them, and must ensure that they are removed for only a short time each day, and that they do not impede ambulation
Recommendation: Mechanical Methods of
Prophylaxis Should be used primarily in patients who are at high risk of bleeding
(Grade 1C+), or an an adjunct to anticoagulant-based prophylaxis (Grade 2A)
Careful attention must be directed toward ensuring the proper use of, and optimal compliance with, the mechanical device (Grace 1C+)
Summary VTE is an important clinical problem worldwide
Thromboprophylaxis for the medically-ill patients who are at risk for VTE is effective & safe
The concensus recommends against the use of aspirin alone for thromoprophylaxis
LDUH, LMWH, VKA, Fondaparinux, and mechanical devices are recommended for thromboprophylaxis.
Thromboprophylaxis in Internal Medicine: a Meta-analysis
19,764 patients UFH or LMWH versus control
Thromboprophylaxis in Internal Medicine: LMWH vs. UFH
4,469 patients LMWH vs. UFH
*Includes randomized trials in which routine screening with an objective diagnostic test for DVT was used
General Medical Patients:LDUH Versus No Prophylaxis*
1.6 (1/64)
10.4 (7/67)
b.i.d.PlaceboCade 1982
4.0 (2/50)
26.0 (13/50)
t.i.d.No prophylaxis
Belch et al. 1981
2.6 (1/38)
22.5 (9/40)t.i.d.No prophylaxis
Gallus et al. 1973
LDUHControl
LDUHControl
DVT, % (n/N) Intervention
Study
b.i.d., twice a day; t.i.d., 3 times a day
Gallus AS et al. N Engl J Med 1973;288:545–51Belch JJ et al. Scott J Med 1981;26:115–7Cade JF. Crit Care Med 1982;10:448–50
Bergmann & Neuhart1996Harenberget al. 1996Lechleret al. 1996
5,000 IUb.i.d.
5,000 IUt.i.d.
5,000 IUt.i.d.
Enoxaparin20 mg o.d.
Nadroparin36 mg o.d.
Enoxaparin40 mg o.d.
4.6 (10/216)
0.5 (4/780)
1.4 (6/443)
4.8 (10/207)
0.7 (6/810)
0.2 (1/442)
*Includes randomized trials in which LDUH and LMWH were compared and routine screening with an objective diagnostic test for DVT was used
General Medical Patients:LDUH Versus LMWH* (1)
LMWHLDUHLMWHLDUH
DVT, % (n/N) Intervention
Study
Bergmann J-F & Neuhart E. Thromb Haemost 1996;76:529–34Harenberg J et al. Haemostasis 1996;26:127–39
Lechler E et al. Haemostasis 1996;26(Suppl 2):49–56
Harenberget al. 1999†
Kleberet al. 2003
5,000 IUt.i.d.
5,000 IUt.i.d.
Enoxaparin40 mg o.d.
Enoxaparin40 mg o.d.
22.1 (67/303)
10.4 (22/212)
15.6 (51/327)
8.4 (20/239)
*Includes randomized trials in which LDUH and LMWH were compared and routine screening with an objective diagnostic test for DVT was used†This study has been presented only in abstract form to date
General Medical Patients:LDUH Versus LMWH* (2)
LMWHLDUHLMWHLDUH
DVT, % (n/N) Intervention
Study
Harenberg J et al. Blood 1999;94(Suppl 1):399AKleber FX et al. Am Heart J 2003;145:614–21
RR=0.43 (95% CI, 0.37–0.50)
RR of DVT in studies comparing heparins with no treatment
Surgery
General medicine
Stroke
Acute MI
0 0.5 1 1.5
n=12,550
n=845 RR=0.44 (95% CI, 0.29–0.64)
n=791 RR=0.43 (95% CI, 0.26–0.73)
n=659 RR=0.32 (95% CI, 0.20–0.61)
CI, confidence interval; MI, myocardial infarction
Prophylaxis of VTE in Medical Patients
Heparin better Heparin worse
RR
Thromboprophylaxis in Internal Medicine: Risk:Benefit Ratio
Risk:benefit ratio of heparins vs. controls 50% reduction in risk of symptomatic PE 2-fold increase in major bleeding
Risk:benefit ratio of LMWH versus UFH Similar effect on symptomatic PE 50% reduction in risk of major bleeding
LMWHs are effective and safe
20
16
12
8
4
0MEDENOXPlacebo
(n=96)
MEDENOXEnoxaparin 40 mg o.d.
(n=98)
THE-PRINCEEnoxaparin 40 mg o.d.(n=113)
THE-PRINCE UFH
5,000 IU t.i.d.(n=93)
14.6
4.0
9.7
16.1
Inci
den
ce o
f V
TE
(%
)
UFH, unfractionated heparinKleber FX et al. Am Heart J 2003;145:614–21
Samama MM et al. N Engl J Med 1999;341:793–800
Incidence of VTE in Heart Failure Patients in
THE-PRINCE and MEDENOX studies
PREVENT: Study Design
Dalteparin vs. Placebo in medically ill patients (n=3,706) Primary endpoint: reduction in clinically important VTE
Objectively verified symptomatic DVT Objectively verified asymptomatic proximal DVT Fatal and non-fatal PE Sudden death
Selection of Patients: Day 3 Randomizations: Day 1 Bilateral ultrasonography
Treatment Period Follow-up period
PREVENT, Prospective Evaluation of Dalteparin EfficacyIn Immobilized Patients Trial
Vaitkus PT et al Vasc Med 2002;7:269-73
Leizorovicz A et al. J Thromb Haemost 2003;1(Suppl 1):OC396
P=0.0015 (Cochran-Mantel-Haenszel test)
PREVENT: Incidence of VTE on Day 21
Incidence of VTE (%) Difference in Risk
Dalteparin Placebo incidence ratio
(n=1,518) (n=1,473)
2.77 4.96 2.19 0.55 (–3.57 to –0.81) (0.38–
0.80)
EXCLAIM: Extended Clinical Prophylaxis in Acutely ill Medical
Patients
Thromboprophylaxis in Medical Patients: Real World Data
DVT Free Routine preventive efforts among inpatients are
not widely practiced, especially among acutely ill medical patients
IMPROVE2
International Medical Prevention Registry on Venous Thromboembolism
Most acutely ill medical patients do not receive thromboprophylaxis during hospitalization
Goldhaber SZ & Tapson VF. J Thromb Haemost 2003; 1 (Suppl 1):P1470 Anderson FA et al. J Thromb Haemost 2003; 1 (Suppl 1):P1438
DVT FREE Registry (1)
Of the 5,451 patients, 50% (n=2,725) were diagnosed with DVT as outpatients or in the emergency department and 50% (n=2,726) were diagnosed as inpatients
Overall, 71% (n=3,894) of patients received no prophylaxis for DVT within 30 days prior to diagnosis
Of the 29% (n=1,557) of patients who did receive prophylaxis, 30% (n=410) were diagnosed with DVT as outpatients and 70% (n=1,147) as inpatients
Goldhaber SZ & Tapson VF. J Thromb Haemost 2003;1(Suppl 1):P1470
DVT FREE Registry (2)
Surgical patients (those with a history of surgery within 3 months prior to diagnosis) were far more likely to receive DVT prophylaxis than non-surgical patients
The vast majority of non-surgical patients (80%; n=2,295) received no prophylaxis within 30 days before diagnosis
Goldhaber SZ & Tapson VF. J Thromb Haemost 2003;1(Suppl 1):P1470
IMPROVE: Prophylaxis According to
Primary-admission Category
50
45 46
24
0
20
40
60
Cardiac(n=254)
Pulmonary(n=348)
Neurological(n=208)
Cancer(n=104)
Pati
en
ts r
eceiv
ing
thro
mb
op
rop
hyla
xis
(%
)
Primary-admission category
IMPROVE: Prophylaxis According to
Number of Risk Factors
2931
51
64
0
20
40
60
80
0 (n=86)
1–2 (n=826)
3–4 (n=605)
5 (n=77)
Number of VTE risk factors
Pati
en
ts r
eceiv
ing
thro
mb
op
rop
hyla
xis
(%
)
RR=0.44 (0.29–0.64) P<0.001
RR=0.48 (0.34–0.68) P<0.001
P=NS
P=NS
Mismetti P et al. Thromb Haemost 2000;83:14–19
Thromboprophylaxis in Medical Patients:
Heparins (UFH and LMWH) versus Control
DVT
PE
Death
Major haemorrhage
Heparins better Heparins worse
10.50 1.5 2.0 2.5 3.0 3.5RR
P=NS
P=NS
P=NS
RR=0.48 (0.23–1.0)
0 0.5 1 1.5 2
Thromboprophylaxis in Medical Patients: LMWH versus UFH
Mismetti P et al. Thromb Haemost 2000;83:14–19
DVT
PE
Death
Major haemorrhag
e
LMWH better UFH better
RR
P=0.049
SAFETY of
THROMBOPROPHYLAXIS
MEDENOX: Summary of haemorrhage during the
treatment period
0.0
2.0
4.0
6.0
8.0
10.0
12.0
14.0
No.
of
patie
nts
(%)
Haematomas at injection site
Minor haemorrhage
Major haemorrhage
n = 27
n = 36n = 34
n = 5n = 4
n = 1n = 4 n = 6
NS
NS = not significant
Placebo Enoxaparin 20 mg Enoxaparin 40 mg
53.845.8
010
20
30
40
50
60
UFH
Overall adverse events Injection-site haematoma
7.2
12.6
0
5
10
15
UFH
P<0.004 P<0.027
Pati
en
ts (
%)
Pati
en
ts (
%)
THE-PRINCE Study: Adverse-event Analysis
Kleber FX et al. Am Heart J 2003;145:614–21
Enoxaparin Enoxaparin
Monreal M et al. J Thromb Haemost 2003;1(Suppl 1):P1398
RIETE: Does VTE Outcome Differ in Surgical and Medical Patients?
RIETE: computerized registry of patients with VTE Consecutive, current and symptomatic VTE 3-month outcome
Surgical Medical
(n=672) (n=1,286)
Thromboprophylaxis 454 (68%) 312 (24%)
RIETE: VTE Characteristics
Surgical Medical P value
(n=671) (n=1,286)
Distal DVT 117 (17%) 115 (9%) 0.001
Proximal DVT 295 (44%) 645 (50%) 0.009
PE 259 (39%) 526 (41%) NS
Monreal M et al. J Thromb Haemost 2003;1(Suppl 1):P1398
Death
Fatal PE
Fatal bleeding
Major bleeding
RIETE: Major Outcomes at 3 Months
Odds ratio
(95% CI)
0.36 (0.25–0.51)
0.22 (0.08–0.58)
0.11 (0.01–0.79)
0.36 (0.17–0.74)
Surgical
(n=671)
46 (7%)
5 (0.8%)
1 (0.1%)
10 (1.5%)
Medical
(n=1,286)
218 (17%)
43 (3.3%)
17 (1.3%)
52 (4.0%)
P value
0.0001
0.0004
0.0099
0.002
Monreal M et al. J Thromb Haemost 2003;1(Suppl 1):P1398
ADR, adverse drug reaction
Safety of LMWHs in Medical Patients
Hemorrhage Anecdotal reports of ADRs induced by LMWHs In 1997, two cases of fatal bleeding were
reported (cancer in one case, morbid obesity and cardiac failure in the other). Patients were over 80 years with worsening renal insufficiency (Hôtel Dieu, Paris, France)
Increased bleeding in cardiac patients in trialswith a high dose of enoxaparin
Safety of Enoxaparin
Pooled analysis of THE-PRINCE, PRIME and MEDENOX studies
Placebo
n (%)
UFH
5,000 IU TID
n(%)
Enoxaparin
40 mg OD
n (%)
Total 362 (100) 815 (100) 1,169 (100)
Major bleeding* 4 (1.1) 8 (1.0) 9 (0.8)
Minor bleeding^ 27 (7.5) 105 (12.9) 89 (7.6)
Thrombocytopenia§ 3 (0.8) 5 (0.6) 5 (0.4)
*UFH vs. placebo: RR=1.73 (95% CI, 1.15-2.59); P=0.009^Enoxaparin vs. Placebo: RR=1.02 (95% CI, 0.67-1.54); P=NS§ Enoxparin vs. UFH: RR= 0.59 (95% CI, 0.45-0.77); P=0.0001
Alikhan R. & Cohen AT. Alikhan R. & Cohen AT. Thromb HaemostThromb Haemost 2003;89:590-1 2003;89:590-1
Tolerability of LMWHs: Bleeding Events
Patients from medical departments: cardiology, geriatrics,angiology, infectious disease
More than 50% of patients received aspirin Prolonged treatment of more than 10 days in 27% of patients Bleeding events observed in 15/334 (4.7%) of patients
7 (7%) during curative treatment 8 (3.4%) during thromboprophylaxis increased bleeding risk when creatinine clearance <20 ml/min
• Digestive hemorrhage 3 Haematoma 7• Ecchymoses 2 Epistaxis 1• Gingival bleeding 2
13 cases of thrombocytosis, 4 moderate thrombocytopenia,1 hepatic cytosis (doubtful causal relationship)
Cestac P et al. Drug Saf 2003;26:197–207
LMWHs: Safe and Cost-effective
The good safety profile of LMWHs is an important characteristic of these drugs which allows wide international use and substitution for UFH in most clinical indications Success factor
Socio-economic studies have concluded that LMWHs are cost-effective1,2 MEDENOX trial: for patients in a tertiary-care setting,
incremental cost-effectiveness of enoxaparin 40 mg versus placebo was US$ 87/VTE avoided1
1Lamy A et al. Can Respir J 2002;9:169–772de Lissovoy G & Subedi P. Am J Manag Care 2002;8:1082–8
FDA Approved Indications for Currently Available LMWH
Indication Enoxaparin Dalteparin Tinzaparin
Prevention of DVT in Hip Replacement Yes Yes No
Extended Prophylaxis Yes Yes No
Prevention of DVT in Knee Replacement Yes No No
Prevention of DVT in Abdominal Surgery Yes Yes No
Inpatient treatment of DVT w/wo PE Yes No Yes
Outpatient treatment of DVT w/o PE Yes No ??
Prevention of Ischemia in UA/NSTEMI Yes Yes No
Prevention of DVT in Medically Ill Yes No No
SUMMARY andRECOMMENDATIO
NS