Low Molecular Weight Heparin and the Treatment of Pulmonary Embolus

1
Low Molecular Weight Heparin and the Treatment of
Pulmonary Embolus

• John Powers
• November 14, 2000

2
Cases

• 84 wf with known DVT, suspected PE transferred to
  renal service ? UFH or LMWH in hospital?
• 38 wm with post-op DVT and PE ? UFH or LMWH?
  Hospital or Home?
• 25 bf with PE and hypoxia (4L NC) ? UFH or
  LMWH? Discharge when?
• 43 wm s/p craniotomy, now with saddle
  embolus ? UFH or LMWH?

3
Issue

• LMW Heparins are well accepted for treatment of
  DVT
• LMWH are not well accepted for PE
• Manifestations of the same disease (venous
  thromboembolism).

4
Clinical Questions

• 1. What is the evidence for the use of LMW
  Heparin in PE?
• 2. What is the evidence for home treatment or
  early discharge in PE patients treated with LMW
  Heparin?

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Outline

• Introduction
• LMWH vs UFH in DVT
• LMWH vs UFH in PE
• Home treatment/When to discharge
• Cost
• Summary

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History

• 1916 - Heparin discovered
• 1940s - Standard for VTE
• 1972 - UFH for DVT prophylaxis
• 1980s - LMW heparin

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Venous Thromboembolic Disease - Incidence

• Venous Thromboembolic Disease affects 1 in 1000
• 50 incidence of silent PE in patients with
  proximal DVT

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Venous Thromboembolic Disease - Incidence

• PE - 200,000 deaths/year
• Mortality
• untreated 23 - 87
• treated (heparin) 8
• Recurrent events
• Oral anticoagulant alone 20
• Heparin Oral 8

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Mechanism of Action

• LMWH is formed through the depolymerization of
  UFH producing molecules of smaller size
• Heparin MW - 15,000
• LMW MW - 5,000

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Mechanism of Action

• Both inhibit thrombin and Factor Xa
• LMWH preferentially inhibits Factor Xa (less
  ability to bind thrombin)

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• Inhibiting a single molecule of Xa prevents the
  formation of hundreds of thrombin molecules

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Advantages of LMWH

• Reduced binding to plasma proteins
• Reduced binding to macrophages
• Reduced binding to platelets

• More predictable dose response
• Decreased need for laboratory monitoring
• Longer half life
• Subcutaneous administration
• Less thrombocytopenia

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Approved LMWH Indications

• DVT Prophylaxis
• Hip/knee replacement surgery
• General surgery
• Treatment of Unstable angina/NQWMI
• Treatment of DVT with or without PE
• enoxaparin 1 mg/kg q12 or 1.5 mg/kg q24

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Monitoring

• Lab monitoring required with
• Weight extremes - gt80 or lt30 kg
• Renal insufficiency
• Monitor Plasma anti-factor Xa levels

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Trials

• Goal
• Equivalence between LMW heparin and
  unfractionated heparin
• Method
• Treatment with UFH or LMWH initially
• Started on warfarin day 1 to 3
• Overlapped for 5 days
• Warfarin for 3 months with followup evaluation

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Trials

• Endpoints
• Recurrent events
• Major bleed
• Death
• Major bleeding
• Drop in hemoglobin of 2 g/dl
• Transfusion of 2 units or more
• Intracranial or retroperitoneal bleed

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LMW Heparin and DVT

• American-Canadian Thrombosis Study, NEJM 1992
• Koopman, et al. NEJM 1996
• Levine, et al. NEJM 1996
• Harrison, Archives 1998
• Dolovich, Archives 2000

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American-Canadian Thrombosis Study, 1992

• Objective
• Compared Use of UFH vs. LMWH (Logiparin) for in
  hospital treatment of DVT
• Exclusion
• Active bleeding
• Previous PE or DVT
• Thrombocytopenia
• Severe hepatic or renal failure

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Results
UFH LMWH Event 6.9 2.8 Bleed
5.0 0.5 Death 9.6 4.7
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American-Canadian Study

• Conclusion
• LMWH at least as effective as UFH in hospital for
  treatment of DVT and could allow for outpatient
  treatment

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Koopman, et al.

• Evaluated
• UFH in hospital vs LMWH at home/early discharge
  using nadroparin in DVT
• Exclusion
• Suspected PE, DVT within 2 years
• Not Blinded

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Koopman, et al
UFH LMWH Event 9.0 7.0 PE
2.5 1.8 Bleed 2.0 0.5 Death 8.0
6.9
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Koopman, et al.

• LMW heparin group
• 36 never hospitalized
• 40 early discharge
• 25 hospitalized entire time
• 67 reduction in hospital days
• Conclusions
• LMWH can be used to treat low risk DVT at home
  with similar outcomes to UFH in the hospital

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Levine, et al.

• Evaluated
• UFH in hospital with enoxaparin at home
• Exclusion Criteria
• PE, Two Previous DVTs, Active Bleeding,
  Coagulation Disorders
• Sample
• 50 of LMW group not hospitalized
• 50 hosp. for avg 2.2 days
• Not Blinded

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Levine Results
UFH LMWH Event 6.0 5.0 Bleed
1.2 2.0 Death 6.7 4.4
Hospital stay reduced - (6.5 days vs.1.1 days)
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Levine

• Conclusion
• LMW Heparin Is safe and effective for home
  treatment of proximal DVT

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Harrison, 1998

• Evaluated
• patient satisfaction with outpatient DVT
  treatment
• Results
• 92 satisfied with training and support given
  
• 91 pleased with home treatment
• 70 felt comfortable self injecting

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Dolovich

• Objective
• Meta-analysis of 13 trials comparing efficacy and
  safety of UFH vs LMWH
• Result
• No statistical significance in recurrence, PE,
  major bleeding, minor bleeding, thrombocytopenia
• Small difference in overall mortality (RR0.76)
  favoring LMWH

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Dolovich

• Results
• No apparent differences in once vs twice daily
  dosing or in brand of LMWH
• In patient setting may reduce risk of major
  bleeding (outpatient setting may need monitoring
  of patients)

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LMW Heparin and PE

• Three Randomized, Controlled Trials 1.
  Columbus Investigators 1997, NEJM 2.
  THESEE 1997, NEJM 3.
  American-Canadian Thrombosis 2000,
  Archives of Int Medicine

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Columbus Investigators

• Evaluated
• Exclusion

• 1021 randomized to LMWH (reviparin) or UFH.
  Patients had PE(1/3), DVT, or both
• Thrombolytics planned - 12
• Contraindication - 68
• Anticoag w/in 24 hrs - 200
• Difficult followup - 59

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Columbus Investigators
UFH LMWH Event 4.9 5.3 Bleed
2.3 3.1 Death 7.6 7.1
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Columbus Investigators

• Conclusion
• LMW Heparin is as effective and safe as UFH for
  initial management of VTE regardless of PE or
  previous VTE event.

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THESEE trial

• Evauated
• 612 patients with symptomatic PE randomized to
  LMWH (tinzaparin) or UFH
• Diagnosis by angiogram, high prob v/q or intermed
  prob v/q with LE dopplers
• Exclusion
• Those requiring embolectomy or thrombectomy
• Active bleeding
• Contraindication to anticoagulation

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THESEE trial

• Evaluated combined endpoint of recurrent event,
  major bleed, and death

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THESEE trial
UFH LMWH Event 4.5 3.9 Bleed
1.9 1.6 Death 4.5 3.9
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THESEE trial

• Conclusion
• LMW Heparin is as effective and as safe as UFH
  in patients with acute PE.

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American-Canadian Thrombosis Study

• Evaluated
• 200 patients with high probability lung scan
  randomized to LMW heparin (tinzaparin) or UFH
• Exclusions
• Recent anticoagulation
• Active bleeding
• Renal/Hepatic failure

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American-Canadian Results
UFH LMWH Event 6.8 0 Bleed
1.9 1.0 Death 8.7 6.2
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American-Canadian Thrombosis Study

• Conclusion
• LMWH is no less effective and probably more
  effective than UFH in the initial treatment of
  patients with submassive PE.

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Causes of Death
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Expert Opinions

• American College of Chest Physicians Consensus
  Recommendations (1998) LMW Heparin
  can be substituted for unfractionated heparin
  in the treatment of DVT and stable condition
  patients with PE.
• (Grade AI based on Level I studies)

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Expert Opinions

• Cochrane Review (1999) Since only
  approximately 25 of patients in this review had
  a diagnosis of PE, it would be prudent to await
  further results of new studies prior to adopting
  LMW heparin as standard therapy.

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What about home?Wells, et al.

• Evaluated
• expanded eligibility for outpatient treatment
  administered by home care nurse or patient
• Results
• 194/233 (83) of consecutive patients treated as
  outpatients

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Home treatment

• Treated all patients except those with massive
  PE(6), high risk bleed or active bleeding(7), or
  other reasons for hospitalization (20)
• Results Recurrence 3.6 Major bleed 2.0
  Death 7
• No difference - nurse vs. patient injection

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Columbus vs. Wells
Columbus Wells Event 5.3
3.6 Bleed 3.1 2.0 Death
7.1 7.0

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What about cost?

• Hull, et al. evaluated cost per 100 patients for
  inpatient use
• LMWH - 335,687 vs. UFH - 375,836
• Cost savings - 40,149
• Outpatient therapy augments cost savings

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Summary

• LMW Heparins are well established for treating
  DVT
• Three RCTs have shown LMW heparin to be as
  effective as UFH in treating PE

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Summary

• Enoxaparin is the only LMW heparin that is
  approved by the FDA for DVT with or without PE
• LMW heparin has been shown to be cost-effective
  for treatment both in hospital and out of hospital

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Summary

• There is no RCT data regarding home treatment for
  stable patients with PE or when to discharge from
  the hospital
• Seems reasonable to discharge when stable and not
  hypoxic
• We may be doing this already since 50 of
  patients with proximal DVT have silent PE

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Further Questions

• Are all LMW heparin products equivalent?
• Is once daily dosing equivalent to twice daily
  dosing?
• Is home treatment / early discharge appropriate?

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ACCP Consensus Recommendations

• Treat with LMWH for at least five days
  (overlapped with oral anticoagulation) until INR
  therapeutic for two days (range 2-3)
• Patients with reversible or time-limited risk
  factors treated for three to six months. Those
  with idiopathic DVT treated for six months

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Cases Revisited

• 38 wm with post-op DVT and PE
• ? UFH or LMWH? Hospital or Home?
• UFH and LMWH are equivalent
• No data for sending home

54
Cases Revisited

• 84 wf with known DVT, suspected PE transferred to
  renal service
• ? UFH or LMWH in hospital?
• UFH and LMWH are equivalent

55
Cases Revisited

• 25 bf with PE and hypoxia (4L NC) ? UFH or
  LMWH? Discharge when?
• UFH and LMWH are equivalent
• No data directing discharge but consider
  discharging when not hypoxic

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Cases Revisited

• 43 wm s/p craniotomy, now with saddle
  embolus ? UFH or LMWH?
• Treat with unfractionated heparin (massive PE)

57
Thanks for your help

• Dr. Dunagan
• Amanda Ebright
• Anne Powers