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

Adapted from Barritt and Jordan Lancet 1960. 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.

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 Molecular weight = 16,000 Da DEPOLYMERISATION LMWH Molecular weight = 4,500-5,000 Da High affinity for AT III

Advantages of LMWH over UFH Once-daily sc injection Weight-adjusted dosing No laboratory monitoring Less HIT Outpatient therapy Binds less avidly to plasma proteins, platelets, and cells Dose-independent renal clearance Good bioavailability after sc injection Experimentally less bleeding HIT = heparin-induced thrombocytopenia; sc = subcutaneous

Initial treatment of VTE LMWH vs UFH Major bleeding (n=3,674) Recurrent thromboembolism (n=3,566) Primary studies 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) OR 0.85 (P=0.28) All studies (REM) OR 0.71 (P=0.25) OR 0.87 (P=0.40) 0.01 0.1 1 10 100 0.01 0.1 1 10 100 Favours LMWH Odds ratio Favours UFH Favours LMWH Odds ratio Favours UFH Adapted from Gould et al., Ann Intern Med 1999;130:800-9.

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 8.6 6.9 Major bleeding (%) 1.2 2.0 2.3 3.1 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 Columbus2 Koopman3 UFH n=253 Enoxap n=247 UFH n=511 Reviparin n=510 UFH n=198 Nadroparin n=202 Hospital days (mean) 6.5 1.1† 9.4 6.4† 8.1 2.7† Entirely outpatient treatment 0.0 49% 27% 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 181 661 1 160 631 2 3 129 602 4 5 6 92 161 7 8 9 73 120 10 11 12 64 115 20 30 Cumulative proportion recurrent thromboembolism (%) Hazard ratio 3.2 Cancer No cancer Time (months) Adapted from Prandoni et al., Blood 2002;100:3484-8.

Cumulative proportion major bleeding (%) Cumulative Incidence of Clinically Important Bleeding During Anticoagulant Therapy 181 661 1 170 636 2 3 141 615 4 5 6 102 7 8 9 81 127 10 11 12 68 124 Cancer No cancer 20 30 Cumulative proportion major bleeding (%) Hazard ratio 2.2 Time (months) Adapted from Prandoni et al., Blood 2002;100:3484-8.

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.

Outcome (recurrent VTE and/or major bleeding 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 R Cancer patients with acute DVT and/or PE Dalteparin Oral anticoagulant DVT, deep vein thrombosis; PE, pulmonary embolism. Adapted from Lee et al., NEJM 2003;349:146-53.

Adapted from Lee et al. CLOT Trial 2003 Group Initial treatment Long-term therapy (5–7 days) (6 months) OAC Dalteparin 200 IU/kg Warfarin or acenocoumarol sc once daily (target INR 2.5) LMWH Dalteparin 200 IU/kg Month 1: dalteparin 200 IU/kg sc once daily Month 2–6: 75–80% of full dose OAC, oral anticoagulant. Adapted from Lee et al. CLOT Trial 2003

Baseline Characteristics LMWH OAC N = 338 N = 338 Female gender 179 169 Age, mean (years) 62 63 Outpatient 169 156 Qualifying VTE DVT only 235 230 PE ± DVT 103 108 ECOG score 0 80 63 1 135 150 2 118 122

Baseline Characteristics LMWH OAC N = 338 N = 338 Extent of solid tumour 298 308 no evidence 36 33 localised 39 43 metastatic 223 232 Haematological malignancy 40 30 Cancer treatment 266 259 Central venous catheter 46 40 Previous VTE 39 36

Days post-randomization Probability of recurrent VTE (%) 5 10 15 20 25 Days post-randomization 30 60 90 120 150 180 210 Probability of recurrent VTE (%) Risk reduction = 52% P=0.0017 Dalteparin OAC Adapted from Lee et al., NEJM 2003;349:146-53.

Bleeding Events LMWH OAC P* N = 336 N = 336 Major bleed 19 (5.6%) 12 (3.6%) 0.27 Any bleed 46 (13.6%) 62 (18.5%) 0.093 * Fisher’s exact test

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 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. Adapted from JCO 2007;25,5490-505.

Treatment: ASCO What is the best treatment for patients with cancer with established VTE to prevent recurrent VTE. 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. Adapted from JCO 2007;25,5490-505.

Treatment: ASCO 2007 What is the best treatment for patients with cancer with established VTE to prevent recurrent VTE. 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. Adapted from JCO 2007;25,5490-505.

Thrombolytic therapy in selected patients 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.

Weight adjusted LMWH or IV UFH 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?

Recurrent VTE Risk reduction = 52% P = 0.0017 5 10 15 20 25 Days post-randomization 30 60 90 120 150 180 210 Probability of recurrent VTE (%) Risk reduction = 52% P = 0.0017 Dalteparin OAC Adapted from Lee et al., NEJM 2003;349:146-53.

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?