Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Cancer-Associated Thrombosis Guidelines for Treatment Professor Mark Levine, MD, MSc McMaster University Juravinski Cancer Centre Hamilton, Ontario, Canada Why do we treat proximal DVT? – To improve symptoms – To prevent progression and recurrence – To prevent pulmonary embolism – To prevent post-phlebitic syndrome Why do we treat pulmonary embolism? – To improve symptoms – To prevent pulmonary hypertension – To prevent death • Patients with pulmonary embolism diagnosed clinically. • Randomized to heparin 10,000 units Q6H x 6 doses plus concurrent nicoumalone for 14 days (target PT 2-3x control) or no treatment. Adapted from Barritt and Jordan Lancet 1960. • In the 1st 35 patients, 0 of 16 anticoagulant patients died compared to 5 of 19 control patients, P=0.036 and 5 additional control patients had recurrent PE based on clinical diagnosis. • 3 minor bleeds on anticoagulant therapy. • Randomization was discontinued and then 38 additional patients were treated with anticoagulants with no adverse outcomes. Adapted from Barritt and Jordan Lancet 1960. Initial Therapy: Unfractionated or Low Molecular Weight Heparin? Depolymerisation of UFH UFH Molecular weight = 16,000 Da DEPOLYMERISATION LMWH Molecular weight = 4,500-5,000 Da High affinity for AT III Advantages of LMWH over UFH • Binds less avidly to plasma proteins, platelets, and cells • Dose-independent renal clearance • Good bioavailability after sc injection • Experimentally less bleeding • Once-daily sc injection • Weight-adjusted dosing • No laboratory monitoring • Less HIT • Outpatient therapy HIT = heparin-induced thrombocytopenia; sc = subcutaneous Initial treatment of VTE LMWH vs UFH Primary studies Major bleeding (n=3,674) Recurrent thromboembolism (n=3,566) Duroux (1991) Hull (1992) Prandoni (1992) Lopaciuk (1992) Simonneau (1993) Lindmarker (1994) Levine (1996) Koopman (1996) Fiessinger (1996) Luomanmaki (1996) Columbus (1997) All studies (FEM) OR 0.57 (P=0.047) All studies (REM) OR 0.71 (P=0.25) 0.01 0.1 Favours LMWH 1 Odds ratio 10 100 Favours UFH Adapted from Gould et al., Ann Intern Med 1999;130:800-9. OR 0.85 (P=0.28) OR 0.87 (P=0.40) 0.01 0.1 Favours LMWH 1 Odds ratio 100 10 Favours UFH Initial treatment of VTE Outpatient LMWH vs inpatient UFH Levine1 Columbus2 Koopman3 UFH n=253 Enoxap n=247 UFH n=511 Reviparin n=510 UFH n=198 Nadroparin n=202 Recurrent VTE (%) 6.7 5.3 4.9 5.3 8.6 6.9 Major bleeding (%) 1.2 2.0 2.3 3.1 2.0 0.5 Adapted from: 1. Levine et al., N Engl J Med 1996;334:677-81. 2. The Columbus Investigators. N Engl J Med 1997;337:657-62. 3. Koopman et al., N Engl J Med 1996;334:682-87. Initial treatment of VTE Outpatient LMWH vs inpatient UFH (cont’d) Levine1 UFH n=253 Enoxap n=247 Hospital days (mean) 6.5 1.1† Entirely outpatient treatment 0.0 49% † Columbus2 Koopman3 UFH Reviparin UFH n=511 n=510 n=198 Nadroparin n=202 9.4 6.4† 8.1 2.7† 0.0 27% 0.0 36% Significantly fewer hospital days in LMWH group. Adapted from 1. Levine et al., N Engl J Med 1996;334:677-81. 2. The Columbus Investigators. N Engl J Med 1997;337:657-62. 3. Koopman et al. N Engl J Med 1996;334:682-87. Cumulative Incidence of Recurrent VTE During Anticoagulant Therapy 30 Hazard ratio 3.2 20 Cancer 10 No cancer 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Time (months) 181 661 160 631 129 602 Adapted from Prandoni et al., Blood 2002;100:3484-8. 92 161 73 120 64 115 Cancer No cancer Cumulative Incidence of Clinically Important Bleeding During Anticoagulant Therapy Cumulative proportion major bleeding (%) 30 Hazard ratio 2.2 20 Cancer 10 No cancer 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Time (months) 181 661 170 636 141 615 Adapted from Prandoni et al., Blood 2002;100:3484-8. 102 170 81 127 68 124 Cancer No cancer Oral Anticoagulant Therapy in Cancer Patients • Warfarin therapy is complicated: – difficult to maintain tight therapeutic control (anorexia, vomiting, drug interactions). – frequent interruptions for thrombocytopenia and procedures. – venous access difficult. – increased risk of recurrence and bleeding. Long-term Anticoagulant Therapy with LMWH • Does not require laboratory monitoring • Once- or twice-daily subcutaneous injection • Effective in warfarin resistance • Potentially less bleeding CANTHANOX Trial • Cancer patients with proximal DVT and/ or PE received initial enoxaparin 1.5 mg/kg subcu daily for at least four days. • Randomized to continue enoxaparin at same dose or warfarin. • Duration of therapy was three months. Adapted from Meyer et al., Arch Intern Med 2002;162,1729. CANTHANOX Treatment Outcome (recurrent VTE and/or major bleeding LMWH (n=71) 7 (9%) Warfarin (n=75) 15 (20%) P=0.09 5 bleeds in LMWH and 12 in Warfarin CLOT Trial Cancer patients with acute DVT and/or PE Dalteparin Dalteparin Dalteparin Oral anticoagulant R DVT, deep vein thrombosis; PE, pulmonary embolism. Adapted from Lee et al., NEJM 2003;349:146-53. CLOT Trial Group Initial treatment (5–7 days) Long-term therapy (6 months) OAC Dalteparin 200 IU/kg sc once daily Warfarin or acenocoumarol (target INR 2.5) LMWH Dalteparin 200 IU/kg sc once daily OAC, oral anticoagulant. Adapted from Lee et al. CLOT Trial 2003 Month 1: dalteparin 200 IU/kg Month 2–6: 75–80% of full dose Baseline Characteristics LMWH N = 338 OAC N = 338 Female gender 179 169 Age, mean (years) 62 63 Outpatient 169 156 DVT only 235 230 PE ± DVT 103 108 0 80 63 1 135 150 2 118 122 Qualifying VTE ECOG score Baseline Characteristics LMWH N = 338 OAC N = 338 Extent of solid tumour no evidence localised metastatic 298 36 39 223 308 33 43 232 Haematological malignancy Cancer treatment 40 266 30 259 Central venous catheter Previous VTE 46 39 40 36 Probability of recurrent VTE (%) Recurrent VTE Risk reduction = 52% P=0.0017 25 20 OAC 15 Dalteparin 10 5 0 0 30 60 90 120 150 Days post-randomization Adapted from Lee et al., NEJM 2003;349:146-53. 180 210 Bleeding Events Major bleed Any bleed * Fisher’s exact test LMWH N = 336 OAC N = 336 19 (5.6%) 46 (13.6%) 12 (3.6%) 62 (18.5%) P* 0.27 0.093 Treatment of VTE: Long-term • Long-term LMWH “simplifies” treatment. • In the CLOT trial each patient who received oral anticoagulants had on average 23 INRs performed (maximum 83). American Society of Clinical Oncology Guidelines: Treatment of VTE • What is the best treatment for patients with cancer with established VTE to prevent recurrent VTE Adapted from JCO 2007;25,5490-505. • LMWH is the preferred choice for the initial treatment. • LMWH given for at least six months is preferred for long term. • Vitamin K antagonist INR (2-3) when LMWH not available. Treatment: ASCO • What is the best treatment for patients with cancer with established VTE to prevent recurrent VTE. Adapted from JCO 2007;25,5490-505. • After six months, indefinite anticoagulant therapy for selected patients with active cancer e.g. metastases. • IVC Filter only in patients with contraindications to anticoagulant therapy and in those with recurrent VTE despite LMWH therapy. Treatment: ASCO 2007 • What is the best treatment for patients with cancer with established VTE to prevent recurrent VTE. Adapted from JCO 2007;25,5490-505. • For CNS malignancy, same therapy as for other cancers. However avoid anticoagulants if active intracranial bleeding, low platelets, etc. • For elderly patient with cancer and VTE same approach as for other age groups. ESMO Guidelines Initial Therapy dalteparin 200 IU/kg daily or enoxaparin 100 IU/kg BID daily or UFH by IV continuous infusion If severe renal failure (creatinine clearance < 30), IV UFH or LMWH monitored by anti Xa monitoring Thrombolytic therapy in selected patients Adapted from Ann Oncol 2008. ESMO Guidelines Long Term long-term treatment for 6 months with 75–80% of the initial dose of LMWH IVC filter in recurrent PE despite adequate anticoagulant Rx or with a contraindication to anticoagulants Adapted from Ann Oncol 2008. Consensus Statement: International Union of Angiology and Union Internationale de Phlebologie Initial Therapy Secondary Prevention Weight adjusted LMWH or IV UFH dalteparin LMWH 200 IU/kg subcu for four weeks followed by five months of 75% of dose Adapted from Int Angiol 2006;25,101-61. So Where are We in 2008? Has there been much research progress since 2003 in terms of treatment of VTE in Cancer? Probability of recurrent VTE (%) Recurrent VTE Risk reduction = 52% P = 0.0017 25 20 OAC 15 Dalteparin 10 5 0 0 30 60 90 120 150 Days post-randomization Adapted from Lee et al., NEJM 2003;349:146-53. 180 210 Progress in Treatment? • Can we do better than 8% recurrence at six months? • Has long term LMWH been adopted? • What is the duration of long term treatment? • How should a patient who develops recurrent VTE on LMWH be treated?