1. Cancer og trombose Tromboseprofylakse Morten Schnack Rasmussen Overlæge Kirurgisk Gastroenterologisk K Bispebjerg Hospital Cancer og trombose Tromboseprofylakse Morten Schnack Rasmussen Overlæge Kirurgisk Gastroenterologisk K Bispebjerg Hospital

2. DispositionDisposition  Primær profylakse  Kemoterapi og anti-hormonel behandling  Central Vene Katetre  Stråle behandling  Postoperative venøs tromboemboliske komplikationer  Sekundær profylakse  Øger LMWH overlevelsen hos cancer patienter?  Primær profylakse  Kemoterapi og anti-hormonel behandling  Central Vene Katetre  Stråle behandling  Postoperative venøs tromboemboliske komplikationer  Sekundær profylakse  Øger LMWH overlevelsen hos cancer patienter?

3. Concurrent VTE and cancer increases the risk of death Probability of death within 183 days of initial hospital admission Probability of death 1.00 0.80 0.60 0.40 0.20 0.00 04080120180 Number of days Malignant disease alone DVT/PE and malignant disease Levitan et al Medicine 1999

4. Kemoterapi og anti-hormonel behandling

5. Incidence of VTE in malignancy: Breast cancer Prevention (1) Node –ve (2) Node +ve (3) Advanced (4) 0.2%0.1% 0.2% 0.9% 1.6% 9.6% 17.6% VTE incidence 1:Fischer et al J Natl Cancer Inst 1997;89:1673; 2:Fischer et al New Eng J Med 1989; 320: 479; 3: Pritchard J Clin Oncol 1996: 14; 4:Goodnough et al Cancer; 1984: 54

6. 311 kvinder, stage 3 and 4 mamma cancer. Kemoterapi. 6 week 1mg Warfarin dagligt. INR 1.3–1.9 Median behandlingstid 181 dage Thrombosis (%) 4.4 % 0.7% p=0.03 PlaceboWarfarin 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 85% VTE reduction Levine M et al. Lancet 1994;886:886–9 LAVDOSIS Warfarin BEHANDLING ved C. MAMMAE

7. Kemo terapi og VTE komplikationer  Mangler evidensbaserede rekommandationer  Ingen fra ACCP  Kun et enkelt randomiseret studie med peroral AK behandling.  Mangler evidensbaserede rekommandationer  Ingen fra ACCP  Kun et enkelt randomiseret studie med peroral AK behandling.

8. Central venøse katetre og venøse tromboemboliske komplikationer

9. treatment n/N control n/N 5/125 8/13 VTE n.s 6/130SympCouban et al 2002 n.sSympReitchard et al 2002 1/16VenoMonreal et al. 1996 P value Author Central Venous Catheter VTE complications LMWH=low-molecular-weight heparin LMWH 0.002 15/40< 0.001 LMWH Warfarin 3.7% 3.4% 4/42 Warfarin Diagnosis Veno Bern et al. 1992

10. Stråle behandling og venøse tromboemboliske komplikationer

11. Stråle- behandling control 3.0% VTE Silvani et al 2003 13.0%Goldberg et al. 1994 Holm et al. 1996 P value Author VTE og strålebehandling <0.001 0.001 19.0% 7.5% Rectum cancer Malignt Glioma 3.6% Rectum cancer

12. Postoperative venøs tromboemboliske komplikationer

13. SurgeryRandomization Phlebography Prophylaxis 6-10 days Day 30 control prophylaxis The ENOXACAN II study design Bergqvist et al. N Engl J Med 2002;346:975-80

14. Incidence of venous thromboembolic events: The ENOXACAN II study Bergqvist et al. N Engl J Med 2002;346:975-80 p = 0.02 12 4.8 1.8 0.6 0.6 Percentage of patients ns ns

15. FAME study design Major abdominal surgery Bilateral venography (assessor-blinded) 7 days 21 days Dalteparin (5,000 IU sc od) + TED Dalteparin (5,000 IU sc od) No further prophylaxis R TED: graduated compression stockings

16. RRR: 55% (95% CI: 15% - 76%) NNT: 12 (7 – 44) Incidence of all VTE 28 days after major abdominal surgery p = 0.01

17. Incidence of proximal DVT 28 days after major abdominal surgery p = 0.009 RRR: 77% (95% CI: 22% – 93%) NNT: 17 (10 – 59)

18. ConclusionsConclusions  Cancer patients undergoing surgery: High risk patients  TP: LMWH in combination with TED.  Cancer patients undergoing surgery: High risk patients  TP: LMWH in combination with TED. In selected high risk patients, including those operated for cancer, we suggest post hospital discharge prophylaxis with LMWH The 7th ACCP Guidelines. Chest 2004; 126 (3 suppl): 410S

19. Anti-koagulations behandling hos cancer patienter

20. Øget risiko for recidiv og blødning

21. VTE recidivBlødning * * : Fatal, hjerne, retroperitoneum. ≥ 2 transfusioner, fald i Hb ≥ 2 mmol/L Hutten BA, et al. J Clin Oncol 2000; 18: 3078-83 AK-behandling: Effekt, risiko

22. Lavmolekylært heparin ved VTE Veldokumenteret til behandling og profylakse af VTE Bedre end UFH Pålidelig biotilgængelighed og kinetik, få interaktioner Vægtbaseret dosering. Ingen monitorering Bedre effekt, færre blødninger Sikkert i langtidsbehandling (HIT, osteoporose) Selvadministration, behandling i hjemmet

23. Long-term treatment of cancer patients with VTE: LMWH versus warfarin OutcomeWarfarinLMWH* 3 monthsn=71 (%)n=67 (%) Major bleed 12 (16.9)5 (7.5) VTE 3 (4.2)2 (3.0) Total15 (21.1)7 (10.5) † OutcomeWarfarinLMWH* 3 monthsn=71 (%)n=67 (%) Major bleed 12 (16.9)5 (7.5) VTE 3 (4.2)2 (3.0) Total15 (21.1)7 (10.5) † *Enoxaparin 1.5 mg/kg; † P=0.09 Meyer G et al. Arch Intern Med. 2002;162:1729–35.

24. 14 LITE trial EventTinzaparin(n=369) OAC (n=368) Recurrent VTE (%) 4.95.7 Major bleeding (%) 3.34.6 Subgruppe-analyse: Cancer n=80n=87 Recurrent VTE (%) 6.311.5 * * P =0.03 LITE trial: Hull et al. ASH 2002

25. R Dalteparin Oral anticoagulant CLOT in cancer Acute VTE 5-7 days Dalteparin 200 IU/kg Acute VTE 5-7 days Dalteparin 200 IU/kg Lee A et al. N Engl J Med 2003;349:146-153

26. CLOT trial Treatment group Initial treatment (5-7 days) Long-term therapy (180 days) OACDalteparin 200 IU/kg sc once-daily Warfarin or acenocoumarol (target INR 2.5) LMWHDalteparin 200 IU/kg sc once-daily Day 30: dalteparin 200 IU/kg Day 31 to 180: 75-80% of full dose

27. Recurrent VTE 0 5 10 15 20 25 Days post-randomisation 0306090120150180210 Probability of recurrent VTE (%) Risk reduction=52% p=0.0017 Dalteparin OAC

28. Recidiv af VTE 8,0% 15,8% Absolut risikoreduktion 7,8% 1 event sparet pr. 13 behandlede (NNT 13)

29. ”For patients with DVT and cancer, we recommend LMWH for the first 3 to 6 months of long-term anticoagulant therapy (Grade 1A)”. ”For these patients, we recommend anticoagulant therapy indefinitely or until the cancer is resolved (Grade 1C)”. The 7th ACCP Guidelines. Chest 2004; 126 (3 suppl): 410S TreatmentOutcomesResults Long-term LMWH Recurrent VTE BleedingNo increase Quality of life CLOT-studiet

30. LMWH AND SURVIVAL 385 patients with solid tumour malignancy R Dalteparin 5000 units once daily for up to 1 year Placebo Up to 1 year 84 patients with Small cell lung cancer (SCLC) Chemotherapy plus dalteparin 5000 IU od 18 weeks Chemotherapy (cyclophosphamide, epirubicin, vincristine) 18 weeks 302 patients with solid tumor malignancy Nadroparin 2 weeks therapeutic dose 4 weeks 1/2 therapeutic dose Placebo 6 weeks FAMOUS SCLC study MALT R R

31. LMWH and Survival Data YearLMWH Survival (months) Median (95% CI) Overall populationGood prognosis population FAMOUS2002DalteparinD 10.80 P 9.14 43.5 24.3 CLOT2003DalteparinD 62%* OAC 61%* (HR 1.0) 80%* 64%* (HR 0.5) SCLC study2003DalteparinD 13.0 P 8.0 16.0 10.0 MALT2003NadroparinN 8.0 P 6.6 (HR 0.75) 15.4 9.4 (HR 0.64) *% surviving at 1 year D = dalteparin; N = nadroparin; OAC = oral anticoagulant; P = placebo; HR = hazard ratio