Prophylaxis of Venous Thromboembolism in the Medical Patient

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Prophylaxis of Venous Thromboembolism in the
Medical Patient

• Low Molecular Weight Heparin vs. Standard Heparin
• Melissa Zorn M.D.

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The Case

• In general medical patients we frequently employ
  VTE prophylaxis in the form of heparin or
  intermittent pneumatic compression hose. The
  orthopedic population utilizes LMWH for its hip
  fracture patients. If LMWH is better for hip
  fx patients why not use it in general medical
  patients?

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QUESTIONS

• How does LMWH differ from UFH?
• Is LMWH superior to standard UFH in the
  prevention of DVT/PE in the general medical
  patient?
• Does LMWH have a better side effect profile?
• Is it cost effective?

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Risk Factors For VTE

• Age gt 40
• Immobility
• H/O VTE
• Malignancy
• Major surgery
• Hypercoagulable state
• Obesity
• Femoral line

• Varicose veins
• CHF
• MI
• CVA
• LE fractures
• Nephrotic syndrome
• Estrogen use
• Inflammatory bowel dz

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LMWH Preparations

• Name Molecular Weight AntiXaIIa
• Ardeparin 6000 1.9
• Dalteparin 6000 2.7
• Enoxaparin 4200 3.8
• Nadroparin 4500 3.6
• Reviparin 4000 3.5
• Tinzaparin 4500 1.9

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LMWH vs. UFH

• More predictable anticoagulant response
• Better bioavailability at low doses
• Dose-independent clearance mechanism
• Longer half life
• No lab monitoring necessary

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Dahan 1986

• RCT, double blind
• 263 elderly medical patients randomized to
  placebo vs. LMWH (enoxaparin 60mg qd)
• Groups equal at baseline except slightly higher
  rbc count in placebo, and more malignancy in LMWH
  group
• 10 day trial, all patients screened routinely
  with 125 I fibrinogen scan

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Dahan 1986 (cont)

• RESULTS
• DVT diagnosed in 12 of 131 (9.1) of placebo and
  4 of 132 (3) of LMWH
• p0.03
• Immobilized patients had an incidence of DVT of
  19.5 in subgroup analysis
• Six patients in each group died

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Dahan 1986 (cont)

• Autopsy revealed 3 fatal PE in the control group
• One patient in LMWH group died of MI and also had
  PE on autopsy
• One diffuse hemorrhage in LMWH group
  (DIC/malignancy) and two in control
• Injection site hematomas greater in LMWH group

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Dahan 1986 (cont)Conclusions

• LMWH was more effective than placebo in reducing
  DVT in general medical elderly patients.
• LMWH did not increase the risk of hemorrhage
• Study size was small
• Use of 125 I fibrinogen scan to dx DVT

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Harenberg 1990

• Randomized, double blind study
• LMWH (? Sandoparin) qd versus UFH 5,000 units tid
• 166 General medical patients on bedrest x 1 week,
  study duration 10 days
• Groups equal except previous VTE, smoking, and
  malignancy higher in LMWH group

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Harenberg 1990 (cont)Results

• DVT screened with doppler U/S
• UFH developed DVT in 4.5 of patients
• LMWH developed DVT in 3.6
• p not significant
• Incidence of hematomas lower in the LMWH group

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Harenberg 1990 (cont)Conclusions

• LMWH was equivalent to UFH for the prevention of
  DVT in medical patients
• PE not addressed
• Small study size
• Groups not equal with respect to baseline
  characteristics (LMWH more risk)
• One death in UFH, three in LMWH

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Harenberg (hes back) 1996

• Randomized trial of LMWH (fraxiparine) qd versus
  UFH tid
• 1590 patients, multicenter trial
• General medical patients bedridden x 10 days with
  increased risk DVT

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Harenberg 1996 (cont)

• PE evaluated if clinically indicated with Q scan
  /- V scan or angiography
• Baseline groups equal
• All pts screened with LE dopplers (for proximal
  clots only) on day 1 and 9

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Harenberg 1996 (cont)Results

• 4 patients in UFH group developed DVT
• 6 patients in LMWH group developed DVT (p not
  significant)
• 23 deaths in LMWH
• 9 deaths in UFH group (p0.02)
• Increased death in LMWH not 2ndary to VTE

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Harenberg 1996 (cont)Results

• Increased death attributed to poorer prognosis,
  longer bed rest and increased clinical risk
• Adverse events such as hematomas, erythema, and
  thrombocytopenia higher in UFH group

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Harenberg 1996 (cont)Conclusions

• LMWH was as effective as UFH for the prevention
  of DVT in bedridden medical patients
• LMWH does NOT offer any mortality benefit and may
  present increased mortality
• Less adverse effects with LMWH
• Lower incidence DVT ? Only looked at proximal
  disease?

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Bergmann 1996

• Multicenter randomized double blind
• Compared enoxaparin 20 mg qd to UFH bid
• 423 elderly medical patients evaluated for
  endpoints of DVT and PE
• DVT screened by 125 I fibrinogen scan

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Bergmann 1996 (cont)

• Incidence of VTE in LMWH group was 10/207 (4.8)
  and 10/216 (4.6) in UFH
• p not significant
• Adverse events small and similar between groups

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Bergmann 1996 (cont) Conclusions

• Enoxaparin was as effective as UFH to prevent VTE
  in bedridden elderly patients
• Small study
• No placebo group
• No mortality benefit seen with use of LMWH
• Low dose of enoxaparin used (20 qd)

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Lechler 1996

• Multicenter randomized double blind trial
• 959 immobilized medical patients with one or more
  risk factors
• Enoxaparin 40 mg qd versus UFH tid
• DVT screened with duplex U/S on days 1 and 7
• PE confirmed by perfusion scan, angiography or
  autopsy

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Lechler 1996 (cont)

• Incidence of VTE in LMWH group was 0.2 and in
  UFH group was 1.4
• p not significant
• Two episodes of PE in UFH group and none in LMWH
  group
• Seven deaths in LMWH group and eleven in UFH group

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Lechler 1996 (cont) Conclusions

• LMWH was as effective as UFH for DVT prophylaxis
  in medical patients
• Trend towards less adverse events in LMWH group
• Problem low incidence of VTE and PE
• ? Sensitivity of U/S in asymptomatic patients

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Kleber 1998

• Randomized, multicenter open study with blinded
  central reading
• 451 patients evaluated
• Enoxaparin 40 mg qd versus UFH tid
• Published in abstract form only

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Kleber 1998 (cont) Results

• 20/239 (8.4) of LMWH group experienced VTE while
  22/212 (10.4) of UFH had VTE
• Subgroup analysis of CHF patients had a more
  dramatic difference (9.7 in LMWH group and 16.1
  in UFH)
• Adverse events (bleeding, hematoma, etc) higher
  in UFH group

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Kleber 1998 (cont) Conclusions

• Enoxaparin was not inferior to UFH in the
  prevention of VTE in medical patients
• Published in abstract form only

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Samama 2000

• Randomized controlled double blind trial
  comparing enoxaparin 40 mg qd, 20 mg qd, and
  placebo
• Goals were to determine the incidence of VTE in
  this population of medical patients and to
  distinguish efficacy of different doses versus
  placebo

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Samama 2000 (cont)

• Duration of treatment six to fourteen days
• DVT evaluated by venography or ultrasound, PE by
  lung scan, angio, or CT
• Primary outcomes assessed in 866 patients
• Patients evaluated between days one to fourteen
  then reevaluated at day 110

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Samama 2000 (cont) Results

• Incidence of VTE in 40 mg group was 5.5
• In 20 mg group was 15
• In placebo group was 14.9
• No significant difference in adverse events or
  deaths in 3 groups
• Benefit in 40 mg group remained present at day
  110 (prophylaxis ceased)

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Samama 2000 (cont) Conclusions

• Enoxaparin 40 mg qd significantly reduced the
  incidence of VTE in medical patients compared to
  20 mg qd or placebo
• Large numbers of drop outs (21 in all)
• Drop out rate was similar across all 3 groups

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Conclusions

• The incidence of VTE in general medical patients
  varies with different prophylaxis but averages
  9-19 when no prophylaxis is used
• Heparins in any form reduce the incidence of DVT
• Low molecular weight heparin is as effective as
  UFH for DVT prophylaxis

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Conclusions

• LMWH was NOT proven to be superior to UFH in any
  of the studies
• LMWH was NOT proven to decrease mortality

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More Questions

• Are all the LMWH agents equivalent?
• What is the appropriate dose and interval of LMWH?

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What about the hip fx protocol?

• Some data in the ortho literature suggests LMWH
  may be superior to UFH (Lancet 1992 meta
  analysis)
• Cochrane Database Systematic Review (2000)
  however stated that insufficient evidence was
  present to establish if LMWH was superior to UFH
  in hip fx

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What about the squeezers?

• Intermittent pneumatic compression hose (IPC) or
  SCDs are frequently employed in the medical
  patient population
• NO trials have been done to establish their
  efficacy in general medical patients
• Data for IPCs exist in the surgical field in the
  reduction of DVT

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What about the squeezers?

• Combined trials of IPCs in general surgery
  patients show a relative risk reduction of DVT of
  60 (25 ---gt 10)
• IPCs have not been proven to prevent PE in
  general surgery patients
• Limited data exists regarding ortho patients

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Recommended Regimens at WFUBMC
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Cost Comparison of VTE prophylaxis regimens at WFU
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Back to the case

• The evidence to date supports using standard UFH
  for DVT prophylaxis in medical patients
• MORE STUDIES are warranted regarding the use of
  LMWH (especially for medical patients with
  multiple risk factors)
• The squeezers are indicated when the patient
  cannot tolerate heparin

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• Thanks to Pam Pride for reviewing my paper
• Bill Gates for creating microsoft
• Al Gore for creating the internet

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Arriving May 2001