肺栓塞诊断和治疗策略ppt课件

Pulmonary Embolism: Latest Diagnostic 28% in 5 years17% in 1 year; 28% in 5 years See also See also KearonKearon ClCl: Natural History of Venous : Natural History of Venous Thromboembolism; Circulation 2003;107:I-22 - I-30Thromboembolism; Circulation 2003;107:I-22 - I-30 Venous Thromboembolism: PE - The Scope of the Problem (2004) 30% mortality if untreated (vs 2-8%) 10 -15% of deaths in acute care hospitals 100 - 200,000 deaths yearly (US) 50% are undiagnosed 1000X Coumarins Reduce Vitamin K dependent thrombin substrates, e.g. prothrombin “Direct thrombin inhibitor” Treatment of VTE Low Molecular Weight Heparins Generally as effective as heparin Less protein and endothelial binding More predictable, longer half-life Less bleeding One/day dose without lab monitoring Types Enoxaparin (Lovenox) Dalteparin (Fragmin) Ardeparin (Normiflo) Nadroparin (Fraxiparin) Tinzaparin (Innohep) Reviparin (Clivarine) Treatment of VTE Factor X Inhibitors Fondaparinux (Arixtra) Synthetic heparin pentasaccharide Low risk of bleeding and HIT =LMWH in DVT Buller: AIM 140:867;2004 = UFH in PE Matisse Inv: NEJM 349:1695;2003 FDA approved: prevention of DVT after hip fx (more effective than LMWH), knee/hip replacement Treatment of VTE Direct Thrombin Inhibitors Hirudin (lepirudin), Argatroban, Bivalirudin Independent of antithrombin For use in patients with heparin-induced thrombocytopenia Ximelagatran (Exanta) Oral, with rapid onset of action = LMWH + warf after DVT JACC 2000;36:1336 (THRIVE) Reduces recurrent VTE when used for 18 months after 6 months warfarin NEJM 349;1713,2003 (THRIVE III) Risk of liver toxicity (4-10%) Treatment of VTE Pharmacologic Prophylaxis Post-operative patients Fondaparinux (ortho) LMWH low dose UFH Medical patients (acutely ill or long hospitalization) LMWH reduces risk for DVT or PE at 14, 21 and 110 days Samama et al: NEJM 1999;341:793-800 (MEDENOX Study) Leizorovicz et al: Circulation 2004;110:874- 9 (PREVENT Study) Treatment of VTE 2004 Anticoagulation contraindicated?Anticoagulation contraindicated?IVC FilterIVC Filter HxHx of HIT? of HIT? DTI (lepirudin) Factor X Inhib (Fondaparinux) Hospitalize for DVT?Hospitalize for DVT? Extensive iliofemoral DVT Risk of bleeding AdmitAdmit Heparin/LMWH or Heparin/LMWH or DTI, and DTI, and warfarinwarfarin Long-term anticoagulationLong-term anticoagulation SuspectSuspect PE?PE? High Risk High Risk PE?PE? ThrombolysisThrombolysis or or EmbolectomyEmbolectomy yesyes nono yesyes nono yesyes nono yesyes End Recent Useful Reviews Circulation, vol 109, 12 (supplement); March 30, 2004 Diagnosis of VTE Circulation, vol 110, 9 (supplement); August 31, 2004 Treatment of VTE CHEST, vol 126, 3 (supplement); September 2004 Antithrombotic and Thrombolytic Therapy Evidence-based Guidelines Treatment of VTE IVC Filter Indications When anticoagulation cannot be used or doesnt work With surgical embolectomy or pulmonary endarterectomy 14% of DVTs receive filter in US Goldhaber et al, AJC 2004;93:259 5% Risk of PE; RR 2.6 rehospitalization for DVT recurrence Consider retrievable filter for temporary need Treatment of VTE Thrombolytic Treatment Indications Massive PE/hemodynamic instability Free-floating RV thrombus or PFO Limb-threatening DVT More rapid thrombolysis than heparin alone Reduces need to escalate therapy No proven mortality benefit except in highest risk 1-3% risk of intracranial bleed Treatment of VTE Pulmonary Embolectomy Indications Massive PE/Hemodynamic instability Failure or contraindication for thrombolysis Experienced cardiac surgical team available Asian/Pacific Islanders (12.1M) Venous Thromboembolism: Demographics of Risk 450 - 600,000 episodes/year in US Stein et al: Stein et al: Regional Differences in Rates of Regional Differences in Rates of Diagnosis and Mortality of Pulmonary Diagnosis and Mortality of Pulmonary ThromboembolismThromboembolism; AJC 2004;93:1194-1197; AJC 2004;93:1194-1197 Pulmonary Embolism Presentation Asymptomatic (5%) About 50% of DVT patients with PE - asymptomatic 70-90% of post-op patients with PE - asymptomatic No symptoms of VTE in 1/2 of pts with chronic thromboembolic pulmonary hypertension Syndrome of “uncomplicated” PE (22%) Often atypical, subtle presentations - usually dyspnea Pulmonary infarction syndrome (65%) Hemoptysis and/or pleuritic chest pain Circulatory collapse (8%) Treatment of VTE Heparin Dosing Nomogram aPTTBolus (U)Hold (min)Rate Chg (ml/h) Repeat aPTT 120060-46h 20,000 U UFH in 500 ml NS (1 ml/h = 40 u/hr Begin 32 ml/hr after 5000 U bolus Cruickshank et al. Arch Int Med 1991;151:333 Treatment of VTE LMWH Dosing AgentSC treatment dose for VTE Enoxaparin100 anti-Xa U/kg q 12 h or 150 anti- Xa U/kg q 24 h Dalteparin100 anti-Xa U/kg bid or 200 anti-Xa U/kg qd Tinzaparin175 anti-Xa U/kg qd For enoxaparin 100 anti-Xa U/kg = 100 mg/kg From MacRae and Ginsberg: Circulation 2004;100, I-2 Treatment of VTE Direct Thrombin Inhibitor Dosing AgentDosing Regimen LepirudinBolus 0.4 mg/kg, then 0.15 mg/kg per hr (target aPTT 1.5-2.5X baseline). Reduce in Renal failure. ArgatrobanNo bollus; 2 microgm/kg per min (target aPTT 1.5-3.0X baseline). Reduce in hepatic failure. Based on Warkentin: Br J Haematol 2003;121, 535 Treatment of VTE Thrombolytic Dosing AgentTreatment Protocol (FDA approved) Streptokinase250,000 U over 30 min, then 100,000 U/hr for 24 hr Urokinase4400 mg/kg in 10 min; 4400 mg/kg/hr x 12 hr peripheral i.v. Alteplase100 mg over 2 hrs peripheral i.v. Venous Thromboembolism Diagnosis - The Role of D-dimer Fibrin-specific degradation product Elevated in many conditions 11 of 103 neg in hosp patients with neg CT or VQ Rathbun, CHEST, 2004 Various assay methods ELISA - expensive, batch-tested, inefficient sensitivity 96%, NPV 99.6% Dunn KL et al, JACC 2002 Latex agglutination - quick, easy, available DVT: sensitivity 82.6%, specificity 70% (compression US) Anderson et al (the EDITED study): J Thromb Haemost 2002 PE: sensitivity 73-100%, specificity 24-77% Not 100% sensitive: neg does 100% rule out VTE Deep Vein Thrombosis Evaluation of Suspected DVT Ultrasonography Compression Applied to common femoral, femoral, popliteal Failure of proximal vein to compress with US probe Duplex/Color Doppler Iliac and calf vein interrogation Complete color flow duplex exam is standard of care Zierler BK: Circulation 2004;109: I-9 Sensitivity 97%, Specificity 94% Venography Invasive, technically demanding, expensive, higher risk Deep Vein Thrombosis Evaluation of Suspected DVT CT venography Sensitivity 89-100% and specificity 94-100% Overall detection rate of DVT in patients with PE is 32-89% (mean 59%) Can be performed without additional contrast after chest CT angio Pelvic and abdominal vein imaging, other diagnoses Able to use with leg casts MR venography Sensitivity 100%, Specificity 97% (pelvic, common femoral) KanneKanne JP: Circulation 2004, 109, I-15 JP: Circulation 2004, 109, I-15 Deep Vein Thrombosis Evaluation of Suspected DVT Clinical ProbabilityClinical ProbabilityLowLowHighHigh D-dimer Return in Return in morning for morning for DuplexDuplex DVTDVT Circulation 2004, 109, I-4Circulation 2004, 109, I-4 posposnegneg posposnegneg LMWHLMWH No No DVTDVT The Midnight Strategy Faster, cheaper, less invasive, more widely available than pulmonary angio Accurate to the segmental level (comparable to angiography) 90% 53-100% sensitive, 90% 80-100% specific Identifies PE in 14 - 44% of indeterminate VQ scans Can diagnose other intrathoracic diseases; can be combined with leg CT venography RyuRyu JH et al, Diagnosis JH et al, Diagnosis of Pulmonary embolism of Pulmonary embolism with Use of Computed with Use of Computed Tomographic Tomographic Angiography.Angiography. Mayo Mayo Clinic Proceedings 76:59Clinic Proceedings 76:59 -65, 2001-65, 2001 Pulmonary Embolism Diagnosis - CT Angiography Venous Thromboembolism: Risk Factors (Relative Risk) Environmental Long-haul air travel Obesity (3) Smoking (2) Hypertension (2) Immobility Natural Age 50 (5) Age 70 (10) Gender-related Oral contraceptives (5) Pregnancy Hormone replacement (2) Estrogen receptor modulators (3 -5) Medical Prior VTE (50) Cancer (5) Major medical illness requiring hospital (5) Surgical (5-200) Trauma Ortho, Gyn, General, Neuro Thrombophilia Factor V Leiden mutation heterozygous (4 - 7) homozygous (80) Prothrombin gene mutation (2.5) Hyperhomocysteinemia Antiphospholipid antibody syndrome AT III (5 - 50) Prot C defic het (3.4 - 7.8) Prot S defic het (2.4 - 20) High factor VIII or XI Increased lipoprotein (a) RosendaalRosendaal FR. Lancet 362:523-6; 1999 FR. Lancet 362:523-6; 1999 KearonKearon C. C. SeminSemin VascVasc Med 1:7-26; 2001 Med 1:7-26; 2001 GoldhaberGoldhaber SZ, Lancet 363:1295-305, 2004 SZ, Lancet 363:1295-305, 2004 Reich LM, Genetics in Medicine 3: 133-143, 2003Reich LM, Genetics in Medicine 3: 133-143, 2003 Treatment of VTE IVC Filter Increasing frequency of use: 14% of DVTs Goldhaber et al, AJC 2004;93:259 Outcomes post filter: 2 5% prevalence of significant PE (4% fatal) Increased relative risk of rehospitalization for venous thrombosis following PE (RR= 2.62) Decreased chance of PE at 8 338:409 Retrievable filters (3 models) Treatment of VTE Efficacy of Thrombolytic Treatment More rapid thrombolysis than UFH (equivalent at Day 5-7) PVR decrement 35% after 24 hr vs 4% (UFH) Reduces need to escalate therapy in hospital - i.e pressors, mechanical ventilation But no proven mortality benefit Reduced recurrent PE or death in studies enrolling high risk patients (meta-analysis) No proven benefit of catheter-directed thrombolysis 1-3% risk of intracranial hemorrhage Treatment of VTE Pharmacologic Prophylaxis Post-operative Factor X Inhibitor (ortho) LMWH low dose UH Ximelagatran warfarin (7-12 days after TKA) Francis et al: NEJM 349:1703;2003 LMWH in severely ill medical patients 0.80.60.40.21.01.21.4Relative risk * *SamamaSamama et al: NEJM 1999;341:793-800 et al: NEJM 1999;341:793-800 Day 14:DVT or PE Day 110:DVT or PE * Multinational study MEDENOX 1102 patients 866 assessed 291 enoxaperin 288 placebo Day 21:DVT, PE or SD Day 90:Sx VTE or SD Day 90:All-cause mortality Multinational study PREVENT 3706 patients * *LeizoroviczLeizorovicz et al: Circulation 2004;110:874-9 et al: Circulation 2004;110:874-9 Pulmonary Embolism Diagnosis - CT Angiography Less accurate for peripheral (subsegmental) PE Sensitivity 71-84% with faster, higher resolution scanners SchoepfSchoepf UJ et al, UJ et al, Spiral Computed Spiral Computed Tomography for Acute Pulmonary Tomography for Acute Pulmonary Embolism.Embolism. Circulation 109:2160-7, Circulation 109:2160-7, 20042004 Treatment of VTE Duration of Anticoagulation Major Transient Risk FactorMajor Transient Risk Factor Patient CharacteristicsPatient CharacteristicsRisk of Recurrence (%)Risk of Recurrence (%)Treatment DurationTreatment Duration 3 3 3 months3 months Minor Risk Factor w/o Minor Risk Factor w/o thrombophiliathrombophilia 10 if persistent 6 months6 months Until factor resolvesUntil factor resolves Idiopathic w/o Idiopathic w/o thrombophiliathrombophilia 1010Recurrent idiopathic eventRecurrent idiopathic event Cancer or high risk factorCancer or high risk factor Based on Bates: NEJM 2043;351, 268 See also Kearon: Circulation 2004; 110; I-10 Heparin Treatment of VTE Anticoagulants Unfractionated Heparin Indirect thrombin inhibitor Accelerates inhibition of factor Xa and thrombin 1000 - 4000 times Monitor with aPTT AT - - - - Coumarins “Direct thrombin inhibitor” Reduce Vitamin K dependent thrombin substrates, e.g. prothrombin IX IX TF, VIIaTF, VIIa X X Xa Xa II (PT) II (PT) IIaIIa ( (ThrThr) ) fibrinogen fibrinogen fibrin fibrin IX aIX a LMWH Treatment of VTE Anticoagulants AT - - - - Types Enoxaparin (Lovenox) Dalteparin (Fragmin) Ardeparin (Normiflo) Nadroparin (Fraxiparin) Tinzaparin (Innohep) Reviparin (Clivarine) Low Molecular Weight Heparins Advantages less protein and endothelial binding more predictable, longer half-life less bleeding one/day dose without lab monitoring IX IX TF, VIIaTF, VIIa X X Xa Xa II (PT) II (PT) IIaIIa ( (ThrThr) ) fibrinogen fibrinogen fibrin fibrin IX aIX a Treatment of VTE Anticoagulants AT - - Factor X Inhibitors Fondaparinux (Arixtra) Synthetic heparin pentasaccharide Given SQ, once-daily (T1/2=17h) - renal Very limited effect on PT, APTT Low risk of bleeding and HIT =LMWH in DVT Buller: AIM 140:867;2004 = UFH in PE Matisse Inv: NEJM 349:1695;2003 FDA approved: prevention of DVT after hip fx (more effective than LMWH), knee/hip replacement IX IX TF, VIIaTF, VIIa X X Xa Xa II (PT) II (PT) IIaIIa ( (ThrThr) ) fibrinogen fibrinogen fibrin fibrin IX aIX a Treatment of VTE Anticoagulants Direct Thrombin Inhibitors Hirudin (lepirudin), argatroban, bivalirudin AT independent Can inhibit clot-bound thrombin DTI - - Ximelagatran (Exanta) Oral, with rapid onset of action Prodrug of melagatran renal elimination Reduces recurrent VTE when used for 18 months after 6 months warfarin (Hazard ratio 0.16) NEJM 349;1713,2003 Risk of liver toxicity (4-10%) IX IX TF, VIIaTF, VIIa X X Xa Xa II (PT) II (PT) IIaIIa ( (ThrThr) ) fibrinogen fibrinogen fibrin fibrin IX