1 / 61

Chest 2008; 133 (suppl)

Chest 2008; 133 (suppl). Primary prevention of VTE. RATIONALE FOR THROMBOPROPHYLAXIS IN HOSPITALIZED PATIENTS - 1. High prevalence of VTE Almost all hospitalized patients have one or more risk factors for VTE The incidence of DVT is as high as 80% in some hospitalized patient groups

sue
Download Presentation

Chest 2008; 133 (suppl)

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Chest 2008; 133 (suppl)

  2. Primary prevention of VTE

  3. RATIONALE FOR THROMBOPROPHYLAXIS IN HOSPITALIZED PATIENTS - 1 • High prevalence of VTE • Almost all hospitalized patients have one or more risk factors for VTE • The incidence of DVT is as high as 80% in some hospitalized patient groups • Hospital-acquired DVT and PE are usually clinically silent • It is difficult to predict which at-risk patients will develop symptomatic thromboembolic complications • Screening at-risk patients using physical examination or noninvasive testing is neither cost-effective nor effective

  4. RATIONALE FOR THROMBOPROPHYLAXIS IN HOSPITALIZED PATIENTS - 2 • Adverse consequences of unprevented VTE • Symptomatic DVT and PE: postop VTE second most common medical complication • Fatal PE: PE is the most common cause of preventable hospital death • Costs of investigating symptomatic patients • Risks and costs of treating unprevented VTE • Increased future risk of recurrent VTE • Chronic postthrombotic syndrome

  5. RATIONALE FOR THROMBOPROPHYLAXIS IN HOSPITALIZED PATIENTS - 3 • Efficacy of thromboprophylaxis • Thromboprophylaxis is highly efficacious at preventing DVT and proximal DVT • Thromboprophylaxis is highly effective at preventing symptomatic VTE and fatal PE • The prevention of DVT also prevents PE • Cost-effectiveness of thromboprophylaxis has repeatedly been demonstrated

  6. RISK FACTORS FOR VTE • Surgery • Trauma (major trauma or lower-extremity injury) • Immobility, lower-extremity paresis • Obesity • Increasing age • Cancer (active or occult) • Cancer therapy (hormonal, chemotherapy, angiogenesis inhibitors, radiotherapy) • Venous compression (tumor, hematoma, arterial abnormality) • Previous VTE • Pregnancy and the postpartum period • Estrogen-containing oral contraceptives or hormone replacement therapy • Selective estrogen receptor modulators • Erythropoiesis-stimulating agents • Acute medical illness • Inflammatory bowel disease • Nephrotic syndrome • Myeloproliferative disorders • Paroxysmal nocturnal hemoglobinuria • Central venous catheterization • Inherited or acquired thrombophilia

  7. THROMBOPHILIA • Inherited • Antithrombin deficiency • Protein C deficiency • Protein S deficiency • Factor V Leiden (heterozygous or homozygous) • Prothrombin G20210A gene mutation • Acquired • Antiphospholipid syndrome • Highest risk: Antithrombin deficiency, homozygous Factor V Leiden or compound heterozygotes, antiphospholipid syndrome

  8. RISK OF DVT IN HOSPITALIZED PATIENTS NOT RECEIVING PROPHYLAXIS Most thrombotic events occur after hospital discharge

  9. REGIMENS TO PREVENT VTE • Low dose unfractionated heparin (5000 U q 8-12h) • Low molecular weight heparin (dalteparin 2500 U q 12-24h; enoxaparin 30 mg q 12h or 40 mg daily) • Fondaparinux (2.5 mg sq once daily) • Warfarin: Adjust to target INR 2-3 • Mechanical methods: graded compression stockings, intermittent pneumatic compression, venous foot pump • Aspirin appears to be less effective, not recommended as sole method of prophylaxis

  10. Relative efficacy of various thromboprophylactic regimens following THR: meta-analysis JAMA 1994;271:22

  11. THROMBOPROPHYLACTIC DRUGS

  12. Unfractionated heparin in general surgery • Meta-analysis of 46 RCTs comparing UFH and placebo or no treatment • UFH reduced DVT rate from 22% to 9% • Reduced symptomatic PE rate from 2.0% to 1.3% • Reduced fatal PE rate from 0.8% to 0.3% • Reduced all cause mortality from 4.2% to 3.2% (one less death per 97 patients treated) • Increased bleeding rate from 3.8% to 5.9% (most bleeds minor) N Engl J Med 1988; 318:1162

  13. LMWH in surgery • General surgery: • LMWH reduces risk of asymptomatic DVT and symptomatic VTE by over 70% vs no treatment • Roughly equivalent to UFH in terms of efficacy and safety • LMWH appears superior to UFH in high-risk orthopedic surgery • No study has shown clear superiority of one form of LMWH over another 2008 ACCP guidelines

  14. FONDAPARINUX • Selective Xa inhibitor (does not inhibit thrombin) • Long half-life (once daily dosing), no antidote • Equivalent or slightly superior to LMWH for prevention of postoperative VTE • Slightly higher bleeding risk

  15. FONDAPARINUX VS ENOXAPARIN IN ORTHOPEDIC SURGERYPooled results from four pivotal trials Lancet 2002;359:1710

  16. Mechanical thromboprophylaxis • Advantages • No bleeding risk • Demonstrated efficacy (but limited evidence) • Enhance efficacy of anticoagulant prophylaxis • Reduce leg swelling • Disadvantages • Less well-studied than anticoagulants • Less well-standardized • Not all devices have been evaluated in trials • Less effective in high-risk groups • Less effective in preventing proximal DVT • Not shown to prevent PE or death • Compliance issues

  17. Risk-adapted VTE prophylaxis - 1

  18. Risk-adapted VTE prophylaxis - 2 LDUH, low-dose unfractionated heparin; LMWH, low molecular weight heparin *Mechanical prophylaxis = graduated compression stockings, intermittent pneumatic compression or venous foot pump

  19. Risk-adapted VTE prophylaxis - 3 LMWH, low molecular weight heparin *Mechanical prophylaxis = graduated compression stockings, intermittent pneumatic compression or venous foot pump

  20. KNEE ARTHROSCOPY • Symptomatic DVT rate < 1% without prophylaxis • Asymptomatic DVT more common (up to 18%) • Therapeutic (vs diagnostic) procedure, longer tourniquet time associated with higher DVT rates • Routine thromboprophylaxis not recommended • LMWH recommended for patients with additional risk factors, or after prolonged/complicated procedures 2008 ACCP guidelines

  21. SPINAL OR EPIDURAL ANESTHESIA • Reports of perispinal hematomas in patients receiving LMWH • Exact prevalence unknown • Few reports with low dose UFH as well • Risk factors: • coagulopathy • anatomic spine abnormalities • difficult insertion/repeated attempts • higher doses of anticoagulant • continuous epidural catheter • older age

  22. SPINAL OR EPIDURAL ANESTHESIARECOMMENDATIONS • Avoid in patients with known coagulopathy • D/C clopidogrel (Plavix) at least 5 days before • ASA safer? • Needle insertion and epidural catheter removal at least 8 hours after last dose of LMWH if twice daily, or 18 h after last dose if once daily • Wait at least 2h before restarting LMWH, longer if CSF bloody • Do not use continuous epidural anesthesia for more than 2 days if pt taking warfarin; INR should be < 1.5 when catheter removed • Fondaparinux not recommended (long half-life, little data) • Monitor for signs of cord compression 2008 ACCP guidelines

  23. TIMING OF THROMBOPROPHYLAXIS • Starting LMWH just before or within 6 hours after high-risk surgery most effective • “appears to be little or no advantage” to starting pre-op • Delay until 12-24 hours postop for patients with high bleeding risk • Start fondaparinux 6-8 h postop, or next day 2008 ACCP guidelines

  24. DURATION OF THROMBOPROPHYLAXIS • Most symptomatic VTE events occur after discharge • Risk of VTE increased for 2-3 months after hip replacement • Extended prophylaxis (up to 35 days) reduces VTE risk, but bleeding rate higher • Patients should receive prophylaxis for at least 10 days after high-risk orthopedic surgery, and for 25-30 days if there are additional risk factors for VTE (LMWH, warfarin or fondaparinux) 2008 ACCP guidelines

  25. Thromboprophylaxis in pregnancy

  26. LOW MOLECULAR WEIGHT HEPARIN IS SAFE AND EFFECTIVE IN PREGNANCY • Data from 64 studies, 2777 pregnancies • Main indication was thromboprophylaxis • No maternal deaths • 0.86% incidence of thrombosis • 1.98% incidence of significant bleeding • No cases of HIT • 0.04% incidence of osteoporotic fracture • 94.7% live birth rate Blood 2005;106:401

  27. VTE PROPHYLAXIS IN PREGNANCYRECOMMENDATIONS - 1 For women with history of: • VTE associated with estrogen use or pregnancy • VTE and thrombophilia • Idiopathic VTE, no long-term anticoagulation Treat with prophylactic or intermediate-dose* LMWH (preferred) or UFH, or close clinical surveillance, plus anticoagulant (eg warfarin) for six weeks postpartum *Dalteparin 5000 U q 12h or enoxaparin 40 mg q 12h 2008 ACCP guidelines

  28. VTE PROPHYLAXIS IN PREGNANCYRECOMMENDATIONS - 2 For women with: • Hx of VTE and “high risk” thrombophilia • Recurrent VTE • Hx of VTE on long-term anticoagulant Rx Treat with prophylactic, intermediate-, or adjusted-dose LMWH or UFH, plus anticoagulant for six weeks postpartum 2008 ACCP guidelines

  29. VTE PROPHYLAXIS IN PREGNANCYRECOMMENDATIONS - 3 • Patient preference must be taken into account (avoiding “medicalization” of pregnancy vs avoiding fetal risk) • LMWH is preferred to UFH during pregnancy • All pregnant women with a history of VTE should use graduated elastic compression stockings during and for six weeks after pregnancy • There is no contraindication to using LMWH, UFH or warfarin while nursing • Fondaparinux should be avoided during pregnancy unless there is a history of HIT 2008 ACCP guidelines

  30. Definite indications Anticoagulation failure after proximal DVT or PE Anticoagulation contraindicated, recent proximal DVT or PE Life-threatening hemorrhage on anticoagulation for recent VTE Possible indication Prophylaxis in patients at high risk for both bleeding and VTE INFERIOR VENA CAVA FILTERS

  31. Complications and disadvantages Thrombosis at access site (23-36%) Most asymptomatic Leg swelling/ulceration (13-41%) Occlusion of filter/IVC obstruction (4-11%) Recurrent pulmonary embolism (2.6-3.8%) Tilting of filter (decreased efficacy) (5%) Filter migration (5%) Misplacement of filter Perforation of vena cava, viscera, aorta Most filters difficult to remove Removable filters available, but successful removal more difficult after 2-3 mo INFERIOR VENA CAVA FILTERS

  32. PROPHYLACTIC VENA CAVA FILTERS PREVENT PE BUT DO NOT REDUCE MORTALITYRESULTS OF A RANDOMIZED CLINICAL TRIAL Outcome at 12 days Outcome at 2 years Pulmonary Embolism Major Bleeding Pulmonary embolism Recurrent DVT Major Bleeding GROUP Death Death Filter 1.1% 2.5% 4.5% 3.4% 20.8% 21.6% 8.8% No Filter 4.8% 2.5% 3.0% 6.3% 11.6% 20.1% 11.8% N Engl J Med 1998;338:409

  33. % Without Recurrence IVC FILTERS INCREASE VTE RECURRENCE RATE IN CANCER PATIENTS Arch Intern Med. 2004;164:1653-1661

  34. Conclusions In patients with DVT, IVC filters: Reduce the incidence of pulmonary embolism Increase the incidence of recurrent DVT Do not improve survival No controlled trials to support routine use of IVC filters for thromboprophylaxis in “high risk” patients without DVT VENA CAVA FILTERS

  35. Treatment of acute VTE

  36. Principles of VTE Treatment • Adequate treatment of VTE requires administration of a rapid-acting anticoagulant • This drug should be given in doses sufficient to achieve a systemic anticoagulant effect, eg: • UFH: 70-80 U/kg loading dose, 15-18 U/kg/h infusion with aPTT monitoring • Enoxaparin: 1 mg/kg sq twice daily • Dalteparin: 100 U/kg sq twice daily • Fondaparinux: 7.5 mg sq daily • Initial treatment should be given for a minimum of 5 days • Failure to administer sufficient doses of a rapid-acting anticoagulant may increase risk of recurrent VTE for up to three months No routine monitoring

  37. Heparin is superior to a vitamin K antagonist for initial treatment of acute DVT 14 Heparin + acenocoumarol 12 Acenocoumarol alone 10 8 Cumulative failures 6 4 2 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Weeks Brandjes et al, NEJM 1992;327:1485

  38. HEPARIN SHOULD BE DOSED ACCORDING TO BODY WEIGHT A randomized, controlled trial in 115 patients with thromboembolism or unstable angina (Ann Intern Med 1993;119:874) Weight-based starting dose: 80 U/kg bolus, 18 U/kg/hr Standard starting dose: 5000 U bolus, 1000 U/hr Standard dose Weight-based dose Outcome P value First aPTT > 1.5 x control, % 32 86 <0.001 aPTT > 1.5 x control within 24 hours, % 77 97 0.002 Minor bleeding, % 3.8 3.2 NS Major bleeding, % 1.9 0 NS Recurrent DVT/PE, % 25 5 0.02

  39. Causes and solutions Inadequate dose (large patient) Solution: weight-based dosing aPTT prolongation less than usual despite therapeutic heparin level (base aPTT short) Solution: monitor heparin level (anti-Xa activity) Heparin neutralized by PF4 released during clot formation Solution: LMWH Low plasma antithrombin level (very rarely a cause) Solution: antithrombin concentrate or FFP infusion Heparin antibodies (may cause thrombocytopenia and thrombosis) Solution: alternative thrombin inhibitor (lepirudin, etc); limit heparin exposure by starting warfarin early HEPARIN "RESISTANCE"

  40. LOW MOLECULAR WEIGHT HEPARIN Advantages over standard heparin • Better bioavailability • Longer half-life allows once or twice daily dosing • Facilitates outpatient treatment • Most patients do not need monitoring • Less likely than to cause HIT • Less bone mineral loss, lower fracture risk • Disadvantages • Accumulates in renal failure • Not well-neutralized by protamine

  41. ENOXAPARIN LEVEL VS CREATININE CLEARANCE J Clin Pharmacol 2003;43:586-590 Patients treated with enoxaparin 1 mg/kg q12h Conclusion: monitoring warranted when CrCl < 30

  42. % Risk reduction with LMWH Outcome 95% CI Symptomatic thromboembolism 53 18-73 Clinically important bleeding 68 31-85 Mortality 47 10-69 STANDARD VS LMW HEPARIN FOR TREATMENT OF DVT meta-analysis of 10 published trials Arch Intern Med 1995;155:601-7

  43. LMWH vs UFH • Low molecular weight heparin is at least as effective as unfractionated heparin in the treatment of acute VTE • Low molecular weight heparin has significant practical advantages over unfractionated heparin

  44. INITIAL TREATMENT OF VTEACCP recommendations • Initial treatment: • LMWH once or twice daily • UFH IV or sq (weight-based dosing preferred) • Fondaparinux (7.5 mg/day) • LMWH preferred for DVT (outpatient) or non-massive PE • UFH preferred in patients receiving thrombolytic drugs or who have severe renal failure • Begin warfarin on day 1 • Early ambulation preferred to bed rest • Continue initial treatment at least 5 days, and until INR > 2.0 for at least 24 hours 2008 ACCP guidelines

  45. Prevention of recurrent VTE

  46. PREVENTION OF RECURRENT VTE Hull et al, JAMA 1984;252:235 Three month followup

  47. Warfarin for prevention of recurrent VTE • Loading dose not necessary or beneficial • Takes minimum of 4-5 days to establish anticoagulant effect • INR does not reflect anticoagulant effect for first 2-3 days • Target INR 2-3

  48. It takes at least 4-5 days for warfarin to achieve an adequate anticoagulant effect Clotting factor levels after starting warfarin

  49. WHAT IS THE OPTIMAL INTENSITY OF WARFARIN TREATMENT FOR PREVENTION OF RECURRENT VTE? • An INR between 2 and 3 is optimal for secondary prevention of VTE • Less intense anticoagulation (INR 1.5-2) is better than placebo, but does not significantly lower bleeding risk and is associated with a higher risk of recurrent VTE • Consider for patients who strongly prefer less frequent monitoring, as opposed to stopping Rx early • There are very few (if any) situations if any in which an INR > 3.0 is necessary or beneficial 2008 ACCP guidelines

  50. WARFARIN "FAILURE“Causes and solutions - 1 • Inadequate initial treatment (increases recurrence rate for up to 3 months) • Adequate dose and duration of initial anticoagulant Rx (UFH or LMWH) • Overdiagnosis of recurrent DVT (vs postphlebitic syndrome) • Venography or MR venography if recurrence suspected in area of prior DVT • Poor compliance • Patient education • Poor anticoagulant control • Careful monitoring

More Related