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Chest 2008; 133 (suppl). Primary prevention of VTE. RATIONALE FOR THROMBOPROPHYLAXIS IN HOSPITALIZED PATIENTS - 1. High prevalence of VTE Almost all hospitalized patients have one or more risk factors for VTE The incidence of DVT is as high as 80% in some hospitalized patient groups

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Rationale for thromboprophylaxis in hospitalized patients 1
RATIONALE FOR THROMBOPROPHYLAXIS IN HOSPITALIZED PATIENTS - 1

  • High prevalence of VTE

    • Almost all hospitalized patients have one or more risk factors for VTE

    • The incidence of DVT is as high as 80% in some hospitalized patient groups

    • Hospital-acquired DVT and PE are usually clinically silent

    • It is difficult to predict which at-risk patients will develop symptomatic thromboembolic complications

    • Screening at-risk patients using physical examination or noninvasive testing is neither cost-effective nor effective


Rationale for thromboprophylaxis in hospitalized patients 2
RATIONALE FOR THROMBOPROPHYLAXIS IN HOSPITALIZED PATIENTS - 2

  • Adverse consequences of unprevented VTE

    • Symptomatic DVT and PE: postop VTE second most common medical complication

    • Fatal PE: PE is the most common cause of preventable hospital death

    • Costs of investigating symptomatic patients

    • Risks and costs of treating unprevented VTE

    • Increased future risk of recurrent VTE

    • Chronic postthrombotic syndrome


Rationale for thromboprophylaxis in hospitalized patients 3
RATIONALE FOR THROMBOPROPHYLAXIS IN HOSPITALIZED PATIENTS - 3

  • Efficacy of thromboprophylaxis

    • Thromboprophylaxis is highly efficacious at preventing DVT and proximal DVT

    • Thromboprophylaxis is highly effective at preventing symptomatic VTE and fatal PE

    • The prevention of DVT also prevents PE

    • Cost-effectiveness of thromboprophylaxis has repeatedly been demonstrated


Risk factors for vte
RISK FACTORS FOR VTE 3

  • Surgery

  • Trauma (major trauma or lower-extremity injury)

  • Immobility, lower-extremity paresis

  • Obesity

  • Increasing age

  • Cancer (active or occult)

  • Cancer therapy (hormonal, chemotherapy, angiogenesis inhibitors, radiotherapy)

  • Venous compression (tumor, hematoma, arterial abnormality)

  • Previous VTE

  • Pregnancy and the postpartum period

  • Estrogen-containing oral contraceptives or hormone replacement therapy

  • Selective estrogen receptor modulators

  • Erythropoiesis-stimulating agents

  • Acute medical illness

  • Inflammatory bowel disease

  • Nephrotic syndrome

  • Myeloproliferative disorders

  • Paroxysmal nocturnal hemoglobinuria

  • Central venous catheterization

  • Inherited or acquired thrombophilia


Thrombophilia
THROMBOPHILIA 3

  • Inherited

    • Antithrombin deficiency

    • Protein C deficiency

    • Protein S deficiency

    • Factor V Leiden (heterozygous or homozygous)

    • Prothrombin G20210A gene mutation

  • Acquired

    • Antiphospholipid syndrome

  • Highest risk: Antithrombin deficiency, homozygous Factor V Leiden or compound heterozygotes, antiphospholipid syndrome


Risk of dvt in hospitalized patients not receiving prophylaxis
RISK OF DVT IN HOSPITALIZED PATIENTS NOT RECEIVING PROPHYLAXIS

Most thrombotic events occur after hospital discharge


Regimens to prevent vte
REGIMENS TO PREVENT VTE PROPHYLAXIS

  • Low dose unfractionated heparin (5000 U q 8-12h)

  • Low molecular weight heparin (dalteparin 2500 U q 12-24h; enoxaparin 30 mg q 12h or 40 mg daily)

  • Fondaparinux (2.5 mg sq once daily)

  • Warfarin: Adjust to target INR 2-3

  • Mechanical methods: graded compression stockings, intermittent pneumatic compression, venous foot pump

  • Aspirin appears to be less effective, not recommended as sole method of prophylaxis


Relative efficacy of various thromboprophylactic regimens following thr meta analysis
Relative efficacy of various thromboprophylactic regimens following THR: meta-analysis

JAMA 1994;271:22


Thromboprophylactic drugs
THROMBOPROPHYLACTIC DRUGS following THR: meta-analysis


Unfractionated heparin in general surgery
Unfractionated heparin in general surgery following THR: meta-analysis

  • Meta-analysis of 46 RCTs comparing UFH and placebo or no treatment

  • UFH reduced DVT rate from 22% to 9%

  • Reduced symptomatic PE rate from 2.0% to 1.3%

  • Reduced fatal PE rate from 0.8% to 0.3%

  • Reduced all cause mortality from 4.2% to 3.2% (one less death per 97 patients treated)

  • Increased bleeding rate from 3.8% to 5.9% (most bleeds minor)

N Engl J Med 1988; 318:1162


Lmwh in surgery
LMWH in surgery following THR: meta-analysis

  • General surgery:

    • LMWH reduces risk of asymptomatic DVT and symptomatic VTE by over 70% vs no treatment

    • Roughly equivalent to UFH in terms of efficacy and safety

  • LMWH appears superior to UFH in high-risk orthopedic surgery

  • No study has shown clear superiority of one form of LMWH over another

2008 ACCP guidelines


Fondaparinux
FONDAPARINUX following THR: meta-analysis

  • Selective Xa inhibitor (does not inhibit thrombin)

  • Long half-life (once daily dosing), no antidote

  • Equivalent or slightly superior to LMWH for prevention of postoperative VTE

    • Slightly higher bleeding risk


Fondaparinux vs enoxaparin in orthopedic surgery pooled results from four pivotal trials
FONDAPARINUX VS ENOXAPARIN IN ORTHOPEDIC SURGERY following THR: meta-analysisPooled results from four pivotal trials

Lancet 2002;359:1710


Mechanical thromboprophylaxis
Mechanical thromboprophylaxis following THR: meta-analysis

  • Advantages

    • No bleeding risk

    • Demonstrated efficacy (but limited evidence)

    • Enhance efficacy of anticoagulant prophylaxis

    • Reduce leg swelling

  • Disadvantages

    • Less well-studied than anticoagulants

    • Less well-standardized

    • Not all devices have been evaluated in trials

    • Less effective in high-risk groups

    • Less effective in preventing proximal DVT

    • Not shown to prevent PE or death

    • Compliance issues


Risk adapted vte prophylaxis 1
Risk-adapted VTE prophylaxis - 1 following THR: meta-analysis


Risk adapted vte prophylaxis 2
Risk-adapted VTE prophylaxis - 2 following THR: meta-analysis

LDUH, low-dose unfractionated heparin; LMWH, low molecular weight heparin

*Mechanical prophylaxis = graduated compression stockings, intermittent pneumatic compression or venous foot pump


Risk adapted vte prophylaxis 3
Risk-adapted VTE prophylaxis - 3 following THR: meta-analysis

LMWH, low molecular weight heparin

*Mechanical prophylaxis = graduated compression stockings, intermittent pneumatic compression or venous foot pump


Knee arthroscopy
KNEE ARTHROSCOPY following THR: meta-analysis

  • Symptomatic DVT rate < 1% without prophylaxis

    • Asymptomatic DVT more common (up to 18%)

  • Therapeutic (vs diagnostic) procedure, longer tourniquet time associated with higher DVT rates

  • Routine thromboprophylaxis not recommended

  • LMWH recommended for patients with additional risk factors, or after prolonged/complicated procedures

2008 ACCP guidelines


Spinal or epidural anesthesia
SPINAL OR EPIDURAL ANESTHESIA following THR: meta-analysis

  • Reports of perispinal hematomas in patients receiving LMWH

    • Exact prevalence unknown

    • Few reports with low dose UFH as well

  • Risk factors:

    • coagulopathy

    • anatomic spine abnormalities

    • difficult insertion/repeated attempts

    • higher doses of anticoagulant

    • continuous epidural catheter

    • older age


Spinal or epidural anesthesia recommendations
SPINAL OR EPIDURAL ANESTHESIA following THR: meta-analysisRECOMMENDATIONS

  • Avoid in patients with known coagulopathy

  • D/C clopidogrel (Plavix) at least 5 days before

    • ASA safer?

  • Needle insertion and epidural catheter removal at least 8 hours after last dose of LMWH if twice daily, or 18 h after last dose if once daily

  • Wait at least 2h before restarting LMWH, longer if CSF bloody

  • Do not use continuous epidural anesthesia for more than 2 days if pt taking warfarin; INR should be < 1.5 when catheter removed

  • Fondaparinux not recommended (long half-life, little data)

  • Monitor for signs of cord compression

2008 ACCP guidelines


Timing of thromboprophylaxis
TIMING OF THROMBOPROPHYLAXIS following THR: meta-analysis

  • Starting LMWH just before or within 6 hours after high-risk surgery most effective

    • “appears to be little or no advantage” to starting pre-op

    • Delay until 12-24 hours postop for patients with high bleeding risk

  • Start fondaparinux 6-8 h postop, or next day

2008 ACCP guidelines


Duration of thromboprophylaxis
DURATION OF THROMBOPROPHYLAXIS following THR: meta-analysis

  • Most symptomatic VTE events occur after discharge

  • Risk of VTE increased for 2-3 months after hip replacement

  • Extended prophylaxis (up to 35 days) reduces VTE risk, but bleeding rate higher

  • Patients should receive prophylaxis for at least 10 days after high-risk orthopedic surgery, and for 25-30 days if there are additional risk factors for VTE (LMWH, warfarin or fondaparinux)

2008 ACCP guidelines


Thromboprophylaxis in pregnancy

Thromboprophylaxis in pregnancy following THR: meta-analysis


Low molecular weight heparin is safe and effective in pregnancy
LOW MOLECULAR WEIGHT HEPARIN IS SAFE AND EFFECTIVE IN PREGNANCY

  • Data from 64 studies, 2777 pregnancies

  • Main indication was thromboprophylaxis

  • No maternal deaths

  • 0.86% incidence of thrombosis

  • 1.98% incidence of significant bleeding

  • No cases of HIT

  • 0.04% incidence of osteoporotic fracture

  • 94.7% live birth rate

Blood 2005;106:401


Vte prophylaxis in pregnancy recommendations 1
VTE PROPHYLAXIS IN PREGNANCY PREGNANCYRECOMMENDATIONS - 1

For women with history of:

  • VTE associated with estrogen use or pregnancy

  • VTE and thrombophilia

  • Idiopathic VTE, no long-term anticoagulation

    Treat with prophylactic or intermediate-dose* LMWH (preferred) or UFH, or close clinical surveillance, plus anticoagulant (eg warfarin) for six weeks postpartum

    *Dalteparin 5000 U q 12h or enoxaparin 40 mg q 12h

2008 ACCP guidelines


Vte prophylaxis in pregnancy recommendations 2
VTE PROPHYLAXIS IN PREGNANCY PREGNANCYRECOMMENDATIONS - 2

For women with:

  • Hx of VTE and “high risk” thrombophilia

  • Recurrent VTE

  • Hx of VTE on long-term anticoagulant Rx

    Treat with prophylactic, intermediate-, or adjusted-dose LMWH or UFH, plus anticoagulant for six weeks postpartum

2008 ACCP guidelines


Vte prophylaxis in pregnancy recommendations 3
VTE PROPHYLAXIS IN PREGNANCY PREGNANCYRECOMMENDATIONS - 3

  • Patient preference must be taken into account (avoiding “medicalization” of pregnancy vs avoiding fetal risk)

  • LMWH is preferred to UFH during pregnancy

  • All pregnant women with a history of VTE should use graduated elastic compression stockings during and for six weeks after pregnancy

  • There is no contraindication to using LMWH, UFH or warfarin while nursing

  • Fondaparinux should be avoided during pregnancy unless there is a history of HIT

2008 ACCP guidelines


Inferior vena cava filters

Definite indications PREGNANCY

Anticoagulation failure after proximal DVT or PE

Anticoagulation contraindicated, recent proximal DVT or PE

Life-threatening hemorrhage on anticoagulation for recent VTE

Possible indication

Prophylaxis in patients at high risk for both bleeding and VTE

INFERIOR VENA CAVA FILTERS


Inferior vena cava filters1

Complications and disadvantages PREGNANCY

Thrombosis at access site (23-36%)

Most asymptomatic

Leg swelling/ulceration (13-41%)

Occlusion of filter/IVC obstruction (4-11%)

Recurrent pulmonary embolism (2.6-3.8%)

Tilting of filter (decreased efficacy) (5%)

Filter migration (5%)

Misplacement of filter

Perforation of vena cava, viscera, aorta

Most filters difficult to remove

Removable filters available, but successful removal more difficult after 2-3 mo

INFERIOR VENA CAVA FILTERS


PROPHYLACTIC VENA CAVA FILTERS PREVENT PE BUT DO NOT REDUCE MORTALITYRESULTS OF A RANDOMIZED CLINICAL TRIAL

Outcome at 12 days

Outcome at 2 years

Pulmonary Embolism

Major Bleeding

Pulmonary embolism

Recurrent DVT

Major Bleeding

GROUP

Death

Death

Filter

1.1%

2.5%

4.5%

3.4%

20.8%

21.6%

8.8%

No Filter

4.8%

2.5%

3.0%

6.3%

11.6%

20.1%

11.8%

N Engl J Med 1998;338:409


Ivc filters increase vte recurrence rate in cancer patients

% Without Recurrence MORTALITY

IVC FILTERS INCREASE VTE RECURRENCE RATE IN CANCER PATIENTS

Arch Intern Med. 2004;164:1653-1661


Vena cava filters

Conclusions MORTALITY

In patients with DVT, IVC filters:

Reduce the incidence of pulmonary embolism

Increase the incidence of recurrent DVT

Do not improve survival

No controlled trials to support routine use of IVC filters for thromboprophylaxis in “high risk” patients without DVT

VENA CAVA FILTERS



Principles of vte treatment
Principles of VTE Treatment MORTALITY

  • Adequate treatment of VTE requires administration of a rapid-acting anticoagulant

  • This drug should be given in doses sufficient to achieve a systemic anticoagulant effect, eg:

    • UFH: 70-80 U/kg loading dose, 15-18 U/kg/h infusion with aPTT monitoring

    • Enoxaparin: 1 mg/kg sq twice daily

    • Dalteparin: 100 U/kg sq twice daily

    • Fondaparinux: 7.5 mg sq daily

  • Initial treatment should be given for a minimum of 5 days

  • Failure to administer sufficient doses of a rapid-acting anticoagulant may increase risk of recurrent VTE for up to three months

No routine monitoring


Heparin is superior to a vitamin k antagonist for initial treatment of acute dvt
Heparin is superior to a vitamin K antagonist for initial treatment of acute DVT

14

Heparin + acenocoumarol

12

Acenocoumarol alone

10

8

Cumulative failures

6

4

2

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

Weeks

Brandjes et al, NEJM 1992;327:1485


Heparin should be dosed according to body weight
HEPARIN SHOULD BE DOSED ACCORDING TO BODY WEIGHT treatment of acute DVT

A randomized, controlled trial in 115 patients with thromboembolism or unstable angina (Ann Intern Med 1993;119:874)

Weight-based starting dose: 80 U/kg bolus, 18 U/kg/hr

Standard starting dose: 5000 U bolus, 1000 U/hr

Standard dose

Weight-based dose

Outcome

P value

First aPTT > 1.5 x control, %

32

86

<0.001

aPTT > 1.5 x control within 24 hours, %

77

97

0.002

Minor bleeding, %

3.8

3.2

NS

Major bleeding, %

1.9

0

NS

Recurrent DVT/PE, %

25

5

0.02


Heparin resistance

Causes and solutions treatment of acute DVT

Inadequate dose (large patient)

Solution: weight-based dosing

aPTT prolongation less than usual despite therapeutic heparin level (base aPTT short)

Solution: monitor heparin level (anti-Xa activity)

Heparin neutralized by PF4 released during clot formation

Solution: LMWH

Low plasma antithrombin level (very rarely a cause)

Solution: antithrombin concentrate or FFP infusion

Heparin antibodies (may cause thrombocytopenia and thrombosis)

Solution: alternative thrombin inhibitor (lepirudin, etc); limit heparin exposure by starting warfarin early

HEPARIN "RESISTANCE"


Low molecular weight heparin
LOW MOLECULAR WEIGHT HEPARIN treatment of acute DVT

Advantages over standard heparin

  • Better bioavailability

  • Longer half-life allows once or twice daily dosing

    • Facilitates outpatient treatment

  • Most patients do not need monitoring

  • Less likely than to cause HIT

  • Less bone mineral loss, lower fracture risk

  • Disadvantages

    • Accumulates in renal failure

    • Not well-neutralized by protamine


ENOXAPARIN LEVEL VS CREATININE CLEARANCE treatment of acute DVT

J Clin Pharmacol 2003;43:586-590

Patients treated with enoxaparin 1 mg/kg q12h

Conclusion: monitoring warranted when CrCl < 30


Standard vs lmw heparin for treatment of dvt

% Risk reduction with LMWH treatment of acute DVT

Outcome

95% CI

Symptomatic thromboembolism

53

18-73

Clinically important bleeding

68

31-85

Mortality

47

10-69

STANDARD VS LMW HEPARIN FOR TREATMENT OF DVT

meta-analysis of 10 published trials

Arch Intern Med 1995;155:601-7


Lmwh vs ufh
LMWH vs UFH treatment of acute DVT

  • Low molecular weight heparin is at least as effective as unfractionated heparin in the treatment of acute VTE

  • Low molecular weight heparin has significant practical advantages over unfractionated heparin


Initial treatment of vte accp recommendations
INITIAL TREATMENT OF VTE treatment of acute DVTACCP recommendations

  • Initial treatment:

    • LMWH once or twice daily

    • UFH IV or sq (weight-based dosing preferred)

    • Fondaparinux (7.5 mg/day)

  • LMWH preferred for DVT (outpatient) or non-massive PE

  • UFH preferred in patients receiving thrombolytic drugs or who have severe renal failure

  • Begin warfarin on day 1

  • Early ambulation preferred to bed rest

  • Continue initial treatment at least 5 days, and until INR > 2.0 for at least 24 hours

2008 ACCP guidelines


Prevention of recurrent vte

Prevention of recurrent VTE treatment of acute DVT


Prevention of recurrent vte1
PREVENTION OF RECURRENT VTE treatment of acute DVT

Hull et al, JAMA 1984;252:235

Three month followup


Warfarin for prevention of recurrent vte
Warfarin for prevention of recurrent VTE treatment of acute DVT

  • Loading dose not necessary or beneficial

  • Takes minimum of 4-5 days to establish anticoagulant effect

  • INR does not reflect anticoagulant effect for first 2-3 days

  • Target INR 2-3


It takes at least 4-5 days for warfarin to achieve an adequate anticoagulant effect

Clotting factor levels after starting warfarin


What is the optimal intensity of warfarin treatment for prevention of recurrent vte
WHAT IS THE OPTIMAL INTENSITY OF WARFARIN TREATMENT FOR PREVENTION OF RECURRENT VTE?

  • An INR between 2 and 3 is optimal for secondary prevention of VTE

  • Less intense anticoagulation (INR 1.5-2) is better than placebo, but does not significantly lower bleeding risk and is associated with a higher risk of recurrent VTE

    • Consider for patients who strongly prefer less frequent monitoring, as opposed to stopping Rx early

  • There are very few (if any) situations if any in which an INR > 3.0 is necessary or beneficial

2008 ACCP guidelines


Warfarin failure causes and solutions 1
WARFARIN "FAILURE“ PREVENTION OF RECURRENT VTE?Causes and solutions - 1

  • Inadequate initial treatment (increases recurrence rate for up to 3 months)

    • Adequate dose and duration of initial anticoagulant Rx (UFH or LMWH)

  • Overdiagnosis of recurrent DVT (vs postphlebitic syndrome)

    • Venography or MR venography if recurrence suspected in area of prior DVT

  • Poor compliance

    • Patient education

  • Poor anticoagulant control

    • Careful monitoring


Warfarin failure causes and solutions 2
WARFARIN "FAILURE“ PREVENTION OF RECURRENT VTE?Causes and solutions - 2

  • Underlying malignancy (warfarin less effective)

    • Evaluate for occult CA

    • LMWH if known CA

  • Antiphospholipid syndrome (uncommon)

    • Consider LMWH long-term

  • Delayed onset HIT with thrombosis (rare; can occur up to a month after stopping heparin)

    • Check for heparin antibodies



LMWH IS SUPERIOR TO WARFARIN FOR PREVENTION OF RECURRENT VTE IN CANCER

Lee et al, N Engl J Med 2003;349:146-53


LMW Heparin vs oral anticoagulants for prevention of recurrent VTE: a meta-analysis

J Thromb Haemost 2003;1:1906

VTE events

Bleeding

LMWH better

OAC better


Duration of anticoagulation

Duration of anticoagulation recurrent VTE: a meta-analysis


Vte recurrence risk vs time highest risk in first 3 months
VTE Recurrence Risk vs Time recurrent VTE: a meta-analysisHighest risk in first 3 months

Kaplan-Meier estimates of cumulative incidence of first overall venous thromboembolism (VTE) recurrence and hazard of first overall recurrence per 1000 person-days among Olmsted County, Minnesota, residents with a first life-time VTE diagnosed from 1966 through 1990

Heit et al. Arch Intern Med 2000;160:761-768


Idiopathic VTE recurrent VTE: a meta-analysis

Other risk factor

Postop VTE

Idiopathic VTE has a high recurrence rate

Lancet 2003; 362: 523–26


Inherited thrombophilia is a weak predictor of VTE recurrence

Lancet 2003; 362: 523–26

Hazard ratio 1.50

(95% CI = 0.82-2.77)

p=0.187


Risk factors for recurrent vte
RISK FACTORS FOR RECURRENT VTE recurrence

  • Idiopathic (unprovoked) VTE

  • Proximal DVT

  • Persistent DVT/postphlebitic syndrome

  • Male gender

  • Persistent right ventricular dysfunction

  • Active cancer

  • Antiphospholipid syndrome

  • Poor anticoagulant control (also risk for bleeding)


Duration of therapy in vte
DURATION OF THERAPY IN VTE recurrence

Summary

  • Distal DVT, or VTE with reversible risk factor: 3 months

  • First unprovoked VTE (or no reversible risk factor): 3 months, then re-evaluate for long-term treatment

    • If low bleeding risk: long-term treatment recommended

  • Second unprovoked VTE: Long-term treatment

  • VTE and cancer: LMWH for 3-6 mo, then warfarin or LMWH until cancer resolved

  • Re-assess risk:benefit ratio periodically for patients on long-term treatment

2008 ACCP guidelines


New anticoagulant drugs
New anticoagulant drugs recurrence

  • Dabigatran (Pradaxa™) (FDA approved Oct 2010)

    • Oral direct thrombin inhibitor

    • Twice daily dosing

    • Rapid onset of action

    • Monitoring not necessary

    • Renal clearance – use with caution in renal disease

    • FDA approved for stroke prevention in atrial fibrillation, not presently for VTE treatment

    • Comparable efficacy to warfarin in VTE treatment (NEJM 2009;361:2342)

  • Rivaroxaban (not yet approved)

    • Oral direct Xa inhibitor

    • Effective for VTE treatment (NEJM 2010;363:2499)

  • Apixaban (not yet approved)

    • Oral direct Xa inhibitor

    • Safer than LMWH for VTE prevention? (Thromb Haemost 2011;105: 245)


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