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?

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Cases l.jpg
Cases Embolus

  • 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 l.jpg
Issue Embolus

  • 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 l.jpg

Clinical Questions Embolus

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 l.jpg
Outline Embolus

  • Introduction

  • LMWH vs UFH in DVT

  • LMWH vs UFH in PE

  • Home treatment/When to discharge

  • Cost

  • Summary


History l.jpg
History Embolus

  • 1916 - Heparin discovered

  • 1940s - Standard for VTE

  • 1972 - UFH for DVT prophylaxis

  • 1980s - LMW heparin


Venous thromboembolic disease incidence l.jpg
Venous Thromboembolic Disease - Incidence Embolus

  • Venous Thromboembolic Disease affects 1 in 1000

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


Venous thromboembolic disease incidence8 l.jpg
Venous Thromboembolic Disease - Incidence Embolus

  • PE - 200,000 deaths/year

  • Mortality

    • untreated 23 - 87%

    • treated (heparin) 8%

  • Recurrent events

    • Oral anticoagulant alone 20%

    • Heparin + Oral 8%


Mechanism of action l.jpg
Mechanism of Action Embolus

  • LMWH is formed through the depolymerization of UFH producing molecules of smaller size

    • Heparin MW - 15,000

    • LMW MW - 5,000


Mechanism of action10 l.jpg
Mechanism of Action Embolus

  • Both inhibit thrombin and Factor Xa

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



Advantages of lmwh l.jpg

Reduced binding to plasma proteins hundreds of thrombin molecules

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 l.jpg
Approved LMWH Indications: hundreds of thrombin molecules

  • 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 l.jpg
Monitoring hundreds of thrombin molecules

  • Lab monitoring required with:

    • Weight extremes - >80 or <30 kg

    • Renal insufficiency

  • Monitor Plasma anti-factor Xa levels


Trials l.jpg
Trials hundreds of thrombin molecules

  • 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


Trials16 l.jpg
Trials hundreds of thrombin molecules

  • 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 l.jpg
LMW Heparin and DVT hundreds of thrombin molecules

  • 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 l.jpg
American-Canadian Thrombosis Study, 1992 hundreds of thrombin molecules

  • 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


Slide19 l.jpg

Results hundreds of thrombin molecules

UFH LMWH

Event 6.9% 2.8%

Bleed 5.0% 0.5%

Death 9.6% 4.7%


American canadian study l.jpg
American-Canadian Study hundreds of thrombin molecules

  • Conclusion:

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


Koopman et al l.jpg
Koopman, et al. hundreds of thrombin molecules

  • Evaluated:

    • UFH in hospital vs LMWH at home/early discharge using nadroparin in DVT

  • Exclusion

    • Suspected PE, DVT within 2 years

  • Not Blinded


Slide22 l.jpg

Koopman, et al hundreds of thrombin molecules

UFH LMWH

Event 9.0% 7.0%

PE 2.5% 1.8%

Bleed 2.0% 0.5%

Death 8.0% 6.9%


Koopman et al23 l.jpg
Koopman, et al. hundreds of thrombin molecules

  • 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 l.jpg
Levine, et al. hundreds of thrombin molecules

  • 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


Slide25 l.jpg

Levine Results hundreds of thrombin molecules

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 l.jpg
Levine hundreds of thrombin molecules

  • Conclusion

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


Harrison 1998 l.jpg
Harrison, 1998 hundreds of thrombin molecules

  • 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 l.jpg
Dolovich hundreds of thrombin molecules

  • 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


Dolovich29 l.jpg
Dolovich hundreds of thrombin molecules

  • 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 l.jpg
LMW Heparin and PE hundreds of thrombin molecules

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


Columbus investigators l.jpg

Evaluated: hundreds of thrombin molecules

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 investigators32 l.jpg
Columbus Investigators hundreds of thrombin molecules

UFH LMWH

Event 4.9% 5.3%

Bleed 2.3% 3.1%

Death 7.6% 7.1%


Columbus investigators33 l.jpg

Columbus Investigators hundreds of thrombin molecules

Conclusion:

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


Thesee trial l.jpg
THESEE trial hundreds of thrombin molecules

  • 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 trial36 l.jpg
THESEE trial and death

UFH LMWH

Event 4.5% 3.9%

Bleed 1.9% 1.6%

Death 4.5% 3.9%


Thesee trial37 l.jpg

THESEE trial and death

Conclusion:

“LMW Heparin is as effective and as safe as UFH in patients with acute PE.”


American canadian thrombosis study l.jpg
American-Canadian Thrombosis Study and death

  • Evaluated:

    • 200 patients with high probability lung scan randomized to LMW heparin (tinzaparin) or UFH

  • Exclusions:

    • Recent anticoagulation

    • Active bleeding

    • Renal/Hepatic failure


Slide39 l.jpg

American-Canadian Results and death

UFH LMWH

Event 6.8% 0%

Bleed 1.9% 1.0%

Death 8.7% 6.2%


American canadian thrombosis study40 l.jpg

American-Canadian Thrombosis Study and death

Conclusion:

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


Causes of death l.jpg
Causes of Death and death


Expert opinions l.jpg
Expert Opinions and death

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 opinions43 l.jpg
Expert Opinions and death

  • 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 l.jpg
What about home? and deathWells, 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 l.jpg
Home treatment and death

  • 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


Slide46 l.jpg

Columbus vs. Wells and death

Columbus Wells

Event 5.3% 3.6%

Bleed 3.1% 2.0%

Death 7.1% 7.0%


What about cost l.jpg
What about cost? and death

  • 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 l.jpg
Summary and death

  • LMW Heparins are well established for treating DVT

  • Three RCTs have shown LMW heparin to be as effective as UFH in treating PE


Summary49 l.jpg
Summary and death

  • 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


Summary50 l.jpg
Summary and death

  • 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 l.jpg
Further Questions and death

  • Are all LMW heparin products equivalent?

  • Is once daily dosing equivalent to twice daily dosing?

  • Is home treatment / early discharge appropriate?


Accp consensus recommendations l.jpg
ACCP Consensus Recommendations and death

  • 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 l.jpg
Cases Revisited and death

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 revisited54 l.jpg
Cases Revisited and death

84 wf with known DVT, suspected PE transferred to renal service

? UFH or LMWH in hospital?

  • UFH and LMWH are equivalent


Cases revisited55 l.jpg
Cases Revisited and death

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 revisited56 l.jpg
Cases Revisited and death

43 wm s/p craniotomy, now with saddle embolus ? UFH or LMWH?

  • Treat with unfractionated heparin (massive PE)


Thanks for your help l.jpg
Thanks for your help and death

  • Dr. Dunagan

  • Amanda Ebright

  • Anne Powers


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