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Low Molecular Weight Heparin and the Treatment of Pulmonary Embolus

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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  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?

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

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

  7. Venous Thromboembolic Disease - Incidence • Venous Thromboembolic Disease affects 1 in 1000 • 50 % incidence of silent PE in patients with proximal DVT

  8. 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%

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

  10. Mechanism of Action • Both inhibit thrombin and Factor Xa • LMWH preferentially inhibits Factor Xa (less ability to bind thrombin)

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

  12. 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

  13. 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

  14. Monitoring • Lab monitoring required with: • Weight extremes - >80 or <30 kg • Renal insufficiency • Monitor Plasma anti-factor Xa levels

  15. 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

  16. 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

  17. 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

  18. 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

  19. Results UFH LMWH Event 6.9% 2.8% Bleed 5.0% 0.5% Death 9.6% 4.7%

  20. American-Canadian Study • Conclusion: • LMWH at least as effective as UFH in hospital for treatment of DVT and could allow for outpatient treatment

  21. 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

  22. 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%

  23. 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

  24. 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

  25. 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)

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

  27. 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

  28. 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

  29. 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)

  30. 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

  31. 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

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

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

  34. 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

  35. Evaluated combined endpoint of recurrent event, major bleed, and death THESEE trial

  36. THESEE trial UFH LMWH Event 4.5% 3.9% Bleed 1.9% 1.6% Death 4.5% 3.9%

  37. THESEE trial Conclusion: “LMW Heparin is as effective and as safe as UFH in patients with acute PE.”

  38. 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

  39. American-Canadian Results UFH LMWH Event 6.8% 0% Bleed 1.9% 1.0% Death 8.7% 6.2%

  40. 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.”

  41. Causes of Death

  42. 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)

  43. 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.”

  44. 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

  45. 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

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

  47. 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

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

  49. 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

  50. 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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