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					Low Molecular Weight Heparin
and the Treatment of Pulmonary
           Embolus



                  John Powers
                November 14, 2000
                 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?
                     Issue
• LMW Heparins are
  well accepted for
  treatment of DVT
• LMWH are not well
  accepted for PE
• Manifestations of the
  same disease (venous
  thromboembolism).
     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?
                  Outline
•   Introduction
•   LMWH vs UFH in DVT
•   LMWH vs UFH in PE
•   Home treatment/When to discharge
•   Cost
•   Summary
                  History
•   1916 - Heparin discovered
•   1940s - Standard for VTE
•   1972 - UFH for DVT prophylaxis
•   1980s - LMW heparin
     Venous Thromboembolic
       Disease - Incidence

• Venous Thromboembolic Disease affects 1
  in 1000

• 50 % incidence of silent PE in patients with
  proximal DVT
    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%
       Mechanism of Action


• LMWH is formed through the
  depolymerization of UFH producing
  molecules of smaller size
  – Heparin MW - 15,000
  – LMW MW - 5,000
         Mechanism of Action
• Both inhibit thrombin
  and Factor Xa

• LMWH preferentially
  inhibits Factor Xa
  (less ability to bind
  thrombin)
• Inhibiting a
  single molecule
  of Xa prevents
  the formation
  of hundreds of
  thrombin
  molecules
       Advantages of LMWH
• Reduced binding to   – More predictable dose
  plasma proteins        response
                       – Decreased need for
                         laboratory monitoring

• Reduced binding to   – Longer half life
  macrophages          – Subcutaneous
                         administration

• Reduced binding to
                       – Less thrombocytopenia
  platelets
 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
               Monitoring
• Lab monitoring required with:
  – Weight extremes - >80 or <30 kg
  – Renal insufficiency


• Monitor Plasma anti-factor Xa levels
                    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
                       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
     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
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
                                     Results
             25
                                                     p=0.049
                                                                    UFH     LMWH
             20                                                Event 6.9%   2.8%
                       p=0.07
                                                               Bleed 5.0%   0.5%
Event rate




             15
                                       p=0.006                 Death 9.6%   4.7%

             10

             5

             0                                                 UFH(219)
                  Recurrent event Major bleeding   Death       LMW(213)
    American-Canadian Study

• Conclusion:
  – LMWH at least as effective as UFH in hospital
    for treatment of DVT and could allow for
    outpatient treatment
               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
                          Koopman, et al
             18                                    p=ns
             16         p=ns                                    UFH LMWH
             14
                                                          Event 9.0%    7.0%
             12
Event rate




                                                          PE     2.5%   1.8%
             10
              8                                           Bleed 2.0%    0.5%
                                p=ns
              6                          p=ns             Death 8.0%    6.9%
              4
              2
              0
                  Recurrent    PE       Major     Death        UFH(198)
                    event              bleeding                LMW(202)
              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
               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
                               Levine Results
             18
             16
                        p=0.57                                              UFH LMWH
             14
                                                                       Event 6.0%   5.0%
             12
Event rate




                                                                       Bleed 1.2% 2.0%
             10
              8                                                        Death 6.7% 4.4%
                               p=0.50
              6
              4
              2
              0
                  Recurrent    Major     Death                UFH(253))
                    event     bleeding                        LMW(247)


                      Hospital stay reduced - (6.5 days vs.1.1 days)
                 Levine
• Conclusion
  LMW Heparin Is safe and effective for
  home treatment of proximal DVT
               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
                 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 (RR=0.76)
    favoring LMWH
                  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)
       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
       Columbus Investigators
• Evaluated:      • 1021 randomized to LMWH
                    (reviparin) or UFH. Patients
                    had PE(1/3), DVT, or both



                  •   Thrombolytics planned - 12
• Exclusion:      •   Contraindication - 68
                  •   Anticoag w/in 24 hrs - 200
                  •   Difficult followup - 59
                  Columbus Investigators
             40                              p=ns
             35                                                    UFH   LMWH
             30      p=ns
                                                               Event 4.9% 5.3%
Event rate




             25
                                                               Bleed 2.3% 3.1%
             20                  p=ns
                                                               Death 7.6% 7.1%
             15
             10
             5
             0
                  Recurrent    Major     Death      UFH(511)
                    event     bleeding              LMW(510)
  Columbus Investigators

Conclusion:

  “LMW Heparin is as effective and safe
  as UFH for initial management of VTE
  regardless of PE or previous VTE
  event.”
              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
                    THESEE trial
• Evaluated combined              UFH    LMWH
  endpoint of recurrent
  event, major bleed,
  and death               Day 8   3.0%   2.9%   P=ns


                          Day 90 7.1%    5.9%   P=ns
                              THESEE trial
             14
                        p=ns                  p=ns
             12                                                     UFH   LMWH
             10                                                 Event 4.5% 3.9%
Event rate




             8                                                  Bleed 1.9% 1.6%
                                  p=ns
             6                                                  Death 4.5% 3.9%
             4
             2
             0
                  Recurrent     Major     Death      UFH(308)
                    event      bleeding              LMW(304)
        THESEE trial


Conclusion:
  “LMW Heparin is as effective and as
  safe as UFH in patients with acute PE.”
 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
   American-Canadian Results

             9
             8                                                   UFH   LMWH
                   p=0.009
             7                             p=ns              Event 6.8% 0%
             6
Event rate




                                                             Bleed 1.9% 1.0%
             5
             4                                               Death 8.7% 6.2%
             3                  p=ns
             2
             1
             0
                 Recurrent    Major     Death     UFH(103)
                   event     bleeding             LMW(97)
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.”
      Causes of Death
              UFH   LMWH

PE              1       0

Metastatic      8       5
cancer

ALS             0       1
           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)
            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.”
          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
            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
   Columbus vs. Wells


                       8
                                                                      Columbus Wells
                       7
Percentage of events




                       6                                      Event    5.3%     3.6%
                       5                                      Bleed    3.1%     2.0%
                       4                                      Death    7.1%     7.0%
                       3
                       2
                       1
                       0
                           Recurrent    Major     Death   Columbus
                             event     bleeding           Wells
           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
               Summary
• LMW Heparins are well established for
  treating DVT

• Three RCTs have shown LMW heparin to
  be as effective as UFH in treating PE
                 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
                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
           Further Questions
• Are all LMW heparin products equivalent?

• Is once daily dosing equivalent to twice
  daily dosing?

• Is home treatment / early discharge
  appropriate?
          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
          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
           Cases Revisited
84 wf with known DVT, suspected PE
  transferred to renal service

  ? UFH or LMWH in hospital?


  UFH and LMWH are equivalent
           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
           Cases Revisited
43 wm s/p craniotomy, now with saddle
    embolus
    ? UFH or LMWH?

  Treat with unfractionated heparin
   (massive PE)
Thanks for your help
            • Dr. Dunagan

            • Amanda Ebright

            • Anne Powers

				
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posted:8/21/2012
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