venous thromboembolism prophylaxis for the hospitalized medical patients madel sadili, md, fccp,...

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

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

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

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

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%


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%

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

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

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.


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


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.



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


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


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


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


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

venous thromboembolism prophylaxis for the hospitalized medical patients madel sadili, md, fccp,...

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