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Cancer-Associated Thrombosis: What you need to know

Cancer-Associated Thrombosis: What you need to know. Anne McLeod. Objectives. To discuss the risk of thrombosis in cancer patients To discuss signs and symptoms of thrombosis To discuss treatment of thrombosis in cancer pts. Why should you care about CAT?.

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Cancer-Associated Thrombosis: What you need to know

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  1. Cancer-Associated Thrombosis: What you need to know Anne McLeod

  2. Objectives • To discuss the risk of thrombosis in cancer patients • To discuss signs and symptoms of thrombosis • To discuss treatment of thrombosis in cancer pts

  3. Why should you care about CAT? • Cancer increases the risk of VTE ~4-7x • Diagnosis of venous thromboembolism (VTE) is associated with worsened mortality and morbidity in patients with cancer • Active cancer accounts for 20% of new VTEs

  4. VTE in Cancer patients • VTE is a major complication of cancer affecting 5-20% of pts • Second leading cause of death • Autopsy rates of VTE in cancer patients~ 50%

  5. National Hospital Discharge Survey 827,000 of 40, 787,000 cancer pts also had a diagnostic code for VTE Stein AJM 2006 119,60-68

  6. Consequences of VTE in cancer pts • Hospitalized cancer pts with VTE have greater inpatient mortality and longer admissions • Risk of fatal PE in cancer surgery is 3X greater than similar noncancer surgery Khorana JCO 24:484, 2006 Gallus ThrombHaemost 78:126, 1997

  7. Consequences of VTE in cancer pts • Cancer patients with VTE have increased risk of recurrent VTE, bleeding complications, morbidity and utilization of health care resources • Newer anticancer drugs particularly antiangiogenic drugs more thrombogenic Khorana JCO 27: 4919 2009

  8. Fatal PE, Deaths and Bleeding after Cancer Surgery • double-blind RCT of LDH TID vs certoparin QD Non-cancer Cancer Outcome (N=16,954) (N=6,124) RR P Fatal PE* 0.09 % 0.33 % 3.7 0.0001 Death 0.7 % 3.1 % 4.5 0.0001 Abn bleeding 0.04 % 0.29% 7.3 0.0001 * autopsy-proven Haas – ThrombHaemost 2005;94:814

  9. VTE, Cancer and Survival 100 1- yr survival Cancer at time of VTE 12% Cancer without VTE 36% 80 60 Survival, % of patients 40 p< .001 20 0 5 10 15 20 Years after Diagnosis Sorensen - NEJM 2000;343:1846

  10. Risk Factors for VTE in Cancer Pts • Patient-related factors • Older Age • Race (> African Americans) • Comorbid conditions (obesity, medical illness) • Prior VTE • Elevated prechemotherapy plt count • Inherited thrombophilia

  11. Risk Factors for VTE in Cancer Pts • Cancer-related factors- tumours can produce procoagulants • Type of cancer • Initial 3-6 mons after diagnosis • Metastatic disease

  12. Cancer and VTEMetastatic Disease and VTE Metastatic Disease increases VTE risk 4-13X Incidence of VTE / 100 pt-yr Pancreas 20.0 Stomach 10.7 Bladder 7.9 Renal 6.0 Lung 5.0 Chew et al. Arch Int Med. 2006;166: 458-64

  13. Levitan Medicine 1999 78:295

  14. Risk Factors for VTE in Cancer Pts • Treatment-related factors • Current hospitalization- lines procedures immobility • Active chemotherapy • Active hormonal therapy • Antiangiogenic therapy (thalidomide, lenolidomide, becacizumab) • Erythropoietin stimulating agents

  15. Volume 25 Number 34 December 1 2007

  16. ASCO Recommendations #1 • Should hospitalized pts with cancer receive anticoagulation for VTE prophylaxis? • YES • 3 large RCTs in “acute medical pts” ~15% cancer pts • Bleeding complication rate was low

  17. Are guidelines being used? • ACCP guidelines recommend prophylaxis for acutely ill hospitalized medical and surgical cancer pts • FRONTLINE Survey in Oncologist 2003 found >50% of oncology surgeons but only 5% of medical oncologists reported use of primary prophylaxis for high risk pts

  18. Medical Inpatients Kakkar, A. K. et al. Oncologist 2003;8:381-388

  19. Table 3: Appropriate Thromboprophylaxis by Clinical Service 1 = includes patients on therapeutic anticoagulants and those for whom thromboprophylaxis was not indicated

  20. Where is the lesion? • Under recognition of risk factors? • Because many pts are elderly? • Because of the risk of bleeding? • Because of the risk of HIT?

  21. ASCO Recommendations #2 • Should ambulatory pts with cancer receive anticoagulation for VTE prophylaxis during systemic chemotherapy? • NO

  22. Prevention of Thromboembolism in CancerMedical Oncology Pts • Levine 1994 Stage IV Breast – RRR 85% • Hass 2005 TOPIC Breast/Lung -NS • Perry 2007 PRODIGE – Gliomas - NS • Agnelli 2008 PROTECHT Metastatic Ca- RRR 47%

  23. Prevention of Thromboembolism in Cancer • Stage IV breast cancer patients receiving CTX • Double-blind RCT • Very low-dose warfarin: 1 mg x 6 wks  INR 1.3-1.9 Placebo Warfarin No. 159 152 Thromboembolism 4.4 % 0.6 %p = 0.03 Major bleeding 1.3 % 0.6 % NS All bleeding 3.1 % 5.3 % NS Levine - Lancet (1994)

  24. Prevention of Thromboembolism in CancerTOPIC studies Advanced Cancer on ChemoRx LMWH vs. placebo x 6 months Dopplers q 4 weeks TOPIC 1- Breast CaPlacebo LMWHp VTE 3.9% 4% Bleeding 0% 1.7% TOPIC 2 - Lung Ca Overall VTE 8.3% 4.5% .07 Stage IV VTE 10.1% 3.5% .03 Bleeding 2.2% 3.7% Haas et al J Throm Haemos 2005; 3 (suppl) OR 059

  25. Prevention of Thromboembolism in CancerPROTECHT study 2009 Oct;10(10):943-9 • Metastatic or locally advanced Ca (lung, gastrointestinal, pancreatic, breast, ovarian, or head and neck) on ChemoRx • RCT double-blind clinical outcome • LMWH vs placebo 2:1 randomization while on ChemoRx  maximum 4 months 1,150 pts LMWH 769: Placebo 381 • Primary Efficacy Endpoint: Composite of Venous/Arterial Thromboembolic events- 2% treated vs 3.9% untreated • Safety: Major Bleeding –NS difference Lancet Oncol. 2009 Oct;10(10):943-9

  26. ASCO Recommendations #2 • Except pts receiving thalidomide or lenolidamide with chemo or dexamethasoneshould • Studies to identify better markers of increased risk ambulatory pts needed

  27. ASCO Recommendations #3 • Should pts with cancer undergoing surgery receive perioperative VTE prophylaxis? • YES • All pts undergoing major surgical intervention for malignant disease should be considered for prophylaxis • Patients undergoing laporotomy, laparoscopy or thoracotomy lasting greater the 30 mins

  28. ASCO Recommendations #3 3) Prophylaxis should be commenced preoperatively, or as early as possible in the postoperative period 4) Mechanical methods may be added to pharmacologic methods, but should not be used as monotherapy for VTE prevention unless contraindicated because of active bleeding

  29. ASCO Recommendations #3 5) A combined regimen of pharmacologic and mechanical prophylaxis may improve efficacy 6) Prophylaxis should be continued for at least 7-10 days postop. Consider up to 4 wks in major abdo or pelvic surgery in pts with high-risk features such as residual disease, obese or previous VTE

  30. ASCO recommendation # 4 • What is the best treatment for patinets with cancer and with established VTE to prevent recurrent VTE? • In general LMWH

  31. ASCO Recommendation #5 • Should patients with cancer receiveanticoagulants in the absence of established VTE to improve survival?

  32. Cochrane Database Systematic Review July 2007 • Five RCTs (UFH or LMWH) • Heparin associated with a statistically and clinically significant survival benefit (HR=0.77 CI 0.65 to 0.91) • Subgroup analyses: limited small cell lung CA had a clear survival benefit (HR=0.56 CI 0.65 to 0.83)

  33. ASCO Recommendation #5 • Should patients with cancer receiveanticoagulants in the absence of established VTE to improve survival? • Recommendations: • 1) NO • 2) Pts should be encouraged to participate in trials

  34. Why treat? • To prevent fatal PE • To prevent recurrence • To prevent post-thrombotic syndrome

  35. Treating patients with VTE • Does the patient need treatment? • Small subsegmental PE? • PICC line clots? • Is it real? VOMIT • Is patient symptomatic- then treat • Lovenox 1.5 mg/kg od or 1 mg/kg bid • Check plt count and creatinine clearance may need dose adjustment in renal dysfunction • Weight based dosing even in obese pts • If can’t anticoagulate use TEDS stockings and TE service should assess role of IVC filter

  36. Incidence of CVC-Related DVT • Rate of thrombosis requiring PICC removal – 3.4% 1.1/1,000 catheter days - no prophylaxis (n=351) Walshe – J ClinOnc 2002; 20:3276 • Symptomatic thrombosis - 4%0.3 /1,000 device days PICCs, Porta- caths, Hickman catheters – 444 pts A. Lee - J ClinOnc 2006; 24:1404 Clinically Important CVC-related DVT 2 - 4%

  37. Preventing Central Venous Catheter Thrombosis in Cancer (RCTs) Warfarin 1 mg/day DVT symptDVT Study Endpoint No. control warf control warf Bern, 1990 venogram D90 82 38 % * 10 % 25 % 10 % Couban, 2002 sympt. DVT 255 NR NR 4 % 5 % Heaton, 2002 sympt. thromb 88 NR NR 12 % 18 %

  38. Preventing Central Venous Catheter Thrombosis in Cancer (RCTs) LMWH DVT Study Endpoint No. control LMWHP Monreal, 1996 venogram Day 90 29 62 % * 6 % 0.002 Reichardt, 2002 clinical 425 3.4 % 3.7 % 0.9

  39. CVC-related Thrombosis in Cancer Pts • Rate of clinically-important symptomatic DVT appears • to have decreased ~ 4% • Rate of thrombosis requiring PICC removal – 3.4% • Primary prophylaxis with Minidose warfarin or LMWH • appear to NOT be effective nor necessary in general

  40. Apixaban Idraparinux Rivaroxaban Dabigatran

  41. Questions?

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