LOW MOLECULAR WEIGHT HEPARINS IN PREGNANCY A …：低分子肝素在怀孕…课件.ppt

1、Chest 2008; 133 (suppl)RATIONALE FOR THROMBOPROPHYLAXIS IN HOSPITALIZED PATIENTS - 1High 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 clinic

2、ally 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 effectiveRATIONALE FOR THROMBOPROPHYLAXIS IN HOSPITALIZED PATIENTS - 2Adverse

3、 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 V

4、TE Chronic postthrombotic syndromeRATIONALE FOR THROMBOPROPHYLAXIS IN HOSPITALIZED PATIENTS - 3Efficacy 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 o

5、f DVT also prevents PE Cost-effectiveness of thromboprophylaxis has repeatedly been demonstratedRISK FACTORS FOR VTESurgeryTrauma (major trauma or lower-extremity injury)Immobility, lower-extremity paresisObesityIncreasing ageCancer (active or occult)Cancer therapy (hormonal, chemotherapy, angiogene

6、sis inhibitors, radiotherapy)Venous compression (tumor, hematoma, arterial abnormality)Previous VTEPregnancy and the postpartum periodEstrogen-containing oral contraceptives or hormone replacement therapySelective estrogen receptor modulatorsErythropoiesis-stimulating agentsAcute medical illnessInfl

7、ammatory bowel diseaseNephrotic syndromeMyeloproliferative disordersParoxysmal nocturnal hemoglobinuriaCentral venous catheterizationInherited or acquired thrombophilia Inherited Antithrombin deficiency Protein C deficiency Protein S deficiency Factor V Leiden (heterozygous or homozygous) Prothrombi

8、n G20210A gene mutation Acquired Antiphospholipid syndrome Highest risk: Antithrombin deficiency, homozygous Factor V Leiden or compound heterozygotes, antiphospholipid syndromeMost thrombotic events occur after hospital discharge Low dose unfractionated heparin (5000 U q 8-12h) Low molecular weight

9、 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 recomme

10、nded as sole method of prophylaxisTreatmentAll DVT (%)Prox DVT (%)Bleeding (%)None47230.3Aspirin36160.4UFH24142.6LMWH1761.8Stockings18130Warfarin2451.3JAMA 1994;271:22AgentAdvantagesDisadvantagesHeparinCostHIT riskShorter half-lifeLMWHLower risk of HITOnce daily dosing optionCostIncreased blood leve

11、ls in renal failureWarfarinOral drugCostNo HIT riskVariable dose-responseDelayed onset of effectNeed for monitoringFondaparinuxEfficacy? (vs LMWH)Once daily dosingMinimal HIT riskCostIncreased bleeding?High blood levels in renal failure Meta-analysis of 46 RCTs comparing UFH and placebo or no treatm

12、ent 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; 318:116

13、2 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 another2008 AC

14、CP guidelines 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 riskOutcomeFondaparinuxEnoxaparinOdds Ratio(95% CI)All VTE6.8%13.7%0.45 (0.37-0.54)Pro

15、ximal DVT1.3%2.9%0.43(0.27-0.64)Major Bleed2.7%1.7%1.54(1.11-2.16)Lancet 2002;359:1710 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

16、 Not all devices have been evaluated in trialsLess effective in high-risk groupsLess effective in preventing proximal DVTNot shown to prevent PE or death Compliance issuesLevel of RiskApproximate VTE risk without prophylaxisSuggested thromboprophylaxis optionsLow Risk:Minor surgery in mobile patient

17、sFully mobile medical patients10%No specific prophylaxisEarly and “aggressive” ambulationLDUH, low-dose unfractionated heparin; LMWH, low molecular weight heparin*Mechanical prophylaxis = graduated compression stockings, intermittent pneumatic compression or venous foot pumpLevel of RiskApproximate

18、VTE risk without prophylaxisSuggested thromboprophylaxis optionsModerate Risk:Most general, open GYN or urologic surgeryMedical patients at bed rest or sick10-40%LMWHLDUH bid or tidFondaparinuxIf bleeding risk high: mechanical prophylaxis* LMWH, low molecular weight heparin*Mechanical prophylaxis =

19、graduated compression stockings, intermittent pneumatic compression or venous foot pumpLevel of RiskApproximate VTE risk without prophylaxisSuggested thromboprophylaxis optionsHigh Risk:Hip or knee arthroplasty, hip fracture surgery, major trauma, spinal cord injury40-80%LMWH Fondaparinux, Warfarin

20、(INR 2-3)If bleeding risk high: mechanical prophylaxis* Symptomatic DVT rate 1% without prophylaxis Asymptomatic DVT more common (up to 18%) Therapeutic (vs diagnostic) procedure, longer tourniquet time associated with higher DVT ratesRoutine thromboprophylaxis not recommendedLMWH recommended for pa

21、tients with additional risk factors, or after prolonged/complicated procedures2008 ACCP guidelines 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/rep

22、eated attempts higher doses of anticoagulant continuous epidural catheter older age 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 aft

23、er 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 x control, %3286 1.5 x control within 24 hours, %77970.002Minor bleeding, %3.83.2NSMajor bleeding, %1.90NSR

24、ecurrent DVT/PE, %2550.02A 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/hrStandard starting dose: 5000 U bolus, 1000 U/hrInadequate dose (large patient)Solution: weight-based dosin

25、gaPTT 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 formationSolution: LMWHLow plasma antithrombin level (very rarely a cause)Solution: antithrombin concentrate or FFP

26、infusionHeparin antibodies (may cause thrombocytopenia and thrombosis)Solution: alternative thrombin inhibitor (lepirudin, etc); limit heparin exposure by starting warfarin early Better bioavailability Longer half-life allows once or twice daily dosing Facilitates outpatient treatment Most patients

27、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 protamineJ Clin Pharmacol 2003;43:586-590Patients treated with enoxaparin 1 mg/kg q12hConclusion: monitoring warranted when CrCl 2.0 for

28、 at least 24 hours2008 ACCP guidelinesHull et al, JAMA 1984;252:235TreatmentRecurrence (%)Bleeding (%)Warfarin (target INR 3-6)222Warfarin (target INR about 1.8)24Low dose heparin(5000 U sq bid)470Adj dose heparin(PTT target 1.5x)42Three month followup Loading dose not necessary or beneficial Takes

29、minimum of 4-5 days to establish anticoagulant effect INR does not reflect anticoagulant effect for first 2-3 days Target INR 2-3Clotting factor levels after starting warfarin An INR between 2 and 3 is optimal for secondary prevention of VTE Less intense anticoagulation (INR 1.5-2) is better than pl

30、acebo, 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

31、2008 ACCP guidelines 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 Po

32、or compliance Patient education Poor anticoagulant control Careful monitoring Underlying malignancy (warfarin less effective) Evaluate for occult CA LMWH if known CA Antiphospholipid syndrome (uncommon) Consider LMWH long-term Delayed onset HIT with thrombosis (rare; can occur up to a month after st

33、opping heparin) Check for heparin antibodiesLee et al, N Engl J Med 2003;349:146-53VTE eventsBleedingLMWH betterOAC betterJ Thromb Haemost 2003;1:1906Kaplan-Meier estimates of cumulative incidence of first overall venous thromboembolism (VTE) recurrence and hazard of first overall recurrence per 100

34、0 person-days among Olmsted County, Minnesota, residents with a first life-time VTE diagnosed from 1966 through 1990Heit et al. Arch Intern Med 2000;160:761-768Lancet 2003; 362: 52326Idiopathic VTEPostop VTEOther risk factorLancet 2003; 362: 52326Hazard ratio 1.50(95% CI = 0.82-2.77)p=0.187 Idiopath

35、ic (unprovoked) VTE Proximal DVT Persistent DVT/postphlebitic syndrome Male gender Persistent right ventricular dysfunction Active cancer Antiphospholipid syndrome Poor anticoagulant control (also risk for bleeding) Distal DVT, or VTE with reversible risk factor: 3 months First unprovoked VTE (or no

36、 reversible risk factor): 3 months, then re-evaluate for long-term treatmentIf low bleeding risk: long-term treatment recommended Second unprovoked VTE: Long-term treatment VTE and cancer: LMWH for 3-6 mo, then warfarin or LMWH until cancer resolved Re-assess risk:benefit ratio periodically for pati

37、ents on long-term treatment2008 ACCP guidelinesDabigatran (Pradaxa) (FDA approved Oct 2010) Oral direct thrombin inhibitor Twice daily dosing Rapid onset of action Monitoring not necessary Renal clearance use with caution in renal disease FDA approved for stroke prevention in atrial fibrillation, no

38、t presently for VTE treatment Comparable efficacy to warfarin in VTE treatment (NEJM 2009;361:2342)Rivaroxaban (not yet approved) Oral direct Xa inhibitor Effective for VTE treatment (NEJM 2010;363:2499) Apixaban (not yet approved) Oral direct Xa inhibitor Safer than LMWH for VTE prevention? (Thromb Haemost 2011;105: 245)