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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?

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Low Molecular Weight Heparin and the Treatment of Pulmonary Embolus

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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

    • untreated23 - 87%

    • treated (heparin)8%

  • Recurrent events

    • Oral anticoagulant alone20%

    • Heparin + Oral8%


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


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

Advantages of LMWH


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

UFH LMWH

Event 6.9% 2.8%

Bleed 5.0% 0.5%

Death 9.6% 4.7%


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

UFH LMWH

Event 9.0% 7.0%

PE 2.5% 1.8%

Bleed 2.0% 0.5%

Death 8.0% 6.9%


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

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)


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 supportgiven

    • 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 Trials1. Columbus Investigators 1997, NEJM2. THESEE 1997, NEJM3. American-Canadian Thrombosis 2000, Archives of Int Medicine


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

Columbus Investigators


Columbus Investigators

UFH LMWH

Event 4.9% 5.3%

Bleed 2.3% 3.1%

Death 7.6% 7.1%


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


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

THESEE trial


THESEE trial

UFH LMWH

Event 4.5% 3.9%

Bleed 1.9% 1.6%

Death 4.5% 3.9%


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

UFH LMWH

Event 6.8% 0%

Bleed 1.9% 1.0%

Death 8.7% 6.2%


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


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)

  • ResultsRecurrence3.6%Major bleed2.0% Death 7%

  • No difference - nurse vs. patient injection


Columbus vs. Wells

Columbus Wells

Event 5.3% 3.6%

Bleed 3.1% 2.0%

Death 7.1% 7.0%


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 augmentscost 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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