LMWH (Low Molecular Weight Heparin) -vs- Warfarin in Cancer Patients with Recurrent VTE (Venous ThromboEmbolism)

1. LMWH(Low Molecular Weight Heparin) -vs-Warfarin in Cancer Patients withRecurrent VTE (Venous ThromboEmbolism) By Robert Pohlmeyer Jan 14 2003

2. Outline of talk goals • Case presentation • A description of how cancer patients differ from non-cancer patients in risk of VTE and bleeding. • Treatment options for recurrent VTE. • Advantages of LMWH-vs-other TX options. • Mechanisms of actions of UFH (unfractionated heparin), LMWH and warfarin. • Evidence demonstrating the advantages of LMWH-vs-Warfarin in cancer patients with recurrent presentation. • Summary

3. Case Presentation • 41 yo male with stage 4 Colon cancer (known liver Mets) status post resection and chemotherapy (irinotecan/5FU/leucovorin). Course has been complicated by a pulmonary embolism treated with chronic warfarin. Patient presented to the ED with complaints of left lower extremity swelling and pain. INR was 3.1 and doppler ultrasound revealed a DVT.

4. Why does this patient have a recurrent VTE? • Are cancer patients different from non-cancer patients in the development of VTE and recurrence of events? • And if so what evidence supports this and what is the proposed mechanism? • What is the best way to treat this recurrence?

5. Haemostasis 1999:29(suppl1):pages 91-97 Clinical reviews have demonstrated an increase in clinically apparent VTE in 26% of patients with cancer. Specifically, in mucinous carcinomas particularly of those in lung, pancreas, and gastrointestinal tract. Proposed etiologies of the increase in VTE is thought to be disturbances in both the haemostatic and fibrinolytic systems. Also, cancer patients have: increased immobility, increased surgical procedures, increased placement of central venous catheraters and treatment with chemo/hormonal therapies all of which may contribute to VTE formation. Also, cancer patients spent more time outside the therapeutic INR range despite weekly monitoring.

6. Management of Venous Thromboembolism in Cancer Patients. Oncology March 2000 • Cancer patients remaining on therapeutic levels of warfarin still have a two fold greater risk of VTE recurrence than non-cancer patients.

7. Incidence of RecurrentThromboembolic and Bleeding. Journal of Clinical Oncology 9/00 • Retrospective analysis of two large randomized trials. Specifically the Columbus study 97 and the Tasman Study 96. Both of which compared initial anticoagulation with either UFH or LMWH followed by oral warfarin. • This study then combined these two populations (1299) and then subdivided them into malignancy (261) and no malignancy (1038). • These groups were then examined with regards to recurrent VTE and major bleeding events (defined as an overt hemorrhage, decrease in hgb by 2 grams, requiring a PRBC transfusion, or a retroperitoneal/intracranial hemorrhage.

8. Incidence of recurrent VTE • Cancer pt’s were again noted to be outside the therapeutic INR range. They were only in the 2-3 range approximately 50% of the time. This corresponded to a risk of recurrent VTE that was three times the non-cancer patients. Most of these events occurred when the INR<2 which was consistent with the non-cancer group.

9. Incidence of Major Bleeding • The surprising finding was that the cancer group had a six fold increased risk of major bleed compared to the non-cancer patients. Here the INR was not a factor as the cancer group with the highest bleeding had an INR<2. Thus, cancer group had a predisposition to bleeding.

10. Possible treatment options in our case patient with recurrent VTE. • Placement of a Greenfield filter. • Dose adjusted UFH to keep the PTT 1.5-2.5 the normal range. • Increase the dose of warfarin for a goal INR of 3.5-4.0. • Conversion of warfarin to subcutaneous LMWH.

11. Disadvantage of a Greenfield filter • Still require anticoagulation. • Increase the risk of lower extremity deep venous thrombosis secondary to sluggish blood flow. • Over time still have a risk for PE as clot can form on the filter itself.

12. Advantages of LMWH-vs-UFH • Binds less to plasma proteins/plts/endothelial cells and thus has better bio-availability and a longer half life. • IV access not needed. • Don’t need to monitor the PTT because medicine is weight based. • May be given either once a day or twice a day with the same efficacy. • Less incidence of Heparin Induced Thrombocytopenia. • Faster regression of the thrombus.

13. Effects of LMWH on thrombus regression.NEJM March 1, 2001 • Head to Head comparisons via repeat venography demonstrated faster regression in the LMWH group. • Specifically, LMWH had a 42% reduction -vs- UFH 33% reduction at 14 days, and a 53%-vs-40% at 21 days.

14. Review of the coagulation cascade and points of inhibition.

15. Mechanism of action of UFH • Heparins are long chain molecules which can form tertiary complexes allowing them to inactivate IIa/thrombin (which is why the PTT increases) as well as factor Xa. It also accelerates the activity of antithrombin III (AT III) which aids in thrombolysis.

16. Mechanism of action of LMWH • LMWH is partial depolymerization of UFH resulting in fragments approximately 33% the size of the parent compound. • This is much more selective and works mostly on Xa and ATIII with not much effect on thrombin. Thus, it doesn’t effect the PTT. • Instead must use specific anti-factor Xa assays.

17. Mechanism of action of warfarin A vitamin K antagonist which prevents the hepatic post-translational carboxylation of factors 2, 7, 9, and 10.

18. Evidence for using LMWH in warfarin-failure thromboembolic disease. • Extended outpatient therapy with LMWH for treatment of recurrent VTE despite warfarin therapy. • American Journal of Medicine Sept 2001 • Study design: Retrospective Review • Purpose: Determine the optimal management of patients who have recurrent VTE despite treatment with warfarin. • Methods: Review of patient records in 3 tertiary hospitals in England from 6/96-8/98

19. Results continued • All 878 patients were initially treated with either LMWH or UFH and started of warfarin. The LMWH/UFH was then continued until the INR was > 2. • There were 32 patients during the 2 years reviewed with recurrent VTE. • 25 of these patients were initially treated with LMWH and 7 with UFH. • 20 of the 32 patients (63%) had known cancer at the time of recurrence and later another patient was diagnosed with cancer. • At the time of recurrence 23 (72%) of the patients had a INR>2 and all the patients INR was >1.5 • Average time to recurrence was 18 weeks with (SD=33)

20. Results: 32 of the 878 patients were found to had recurrence during the 2 years reviewed.

21. Treatments • These 32 patients were then treated with Dalteparin 200u/kg. • 7 patients were treated with this for 4-6 wks then converted back to warfarin. • 5 patients received 10-12 weeks prior to conversion back. • 16 patients received this until death <12 wks. • 1 patient received 36 weeks. • The other 3 patients developed recurrent VTE on Dalteparin and required the dose be increased. There were not any recurrences on the higher dose. • No major bleeding episodes occurred on the Dalteparin.

22. Study limitations • Retrospective study: although it would be difficult to do an Randomized Clinic Trial (RCT) on these cancer patients with recurrent VTE despite warfarin as it would require multiple centers to recruit enough patients to have enough power. (the ability to detect a difference if one does exists). • Not blinded and therefore susceptible to selection bias. • 3 patients had recurrence despite being on the lower dose of LMWH. • Patients were not standardized to how long they would receive the LMWH. • Study done outside the US.

23. Conclusions • Most of the recurrent VTE occurred in cancer patients. • Other etiologies for recurrence included: 3 Protein C def, 1 Factor V Leiden, 1 lupus anticoagulant, 3 post-op. • All patients had an INR>1.5 and 23 had an INR>2.0, and thus had “warfarin failure”. • The lower dose Dalteparin was effective in preventing recurrence in 29 patients, but did require the higher dose in 3 patients. • There were no major bleeding episodes in patients while on the Dalteparin. • Therefore, LMWH may be a more effective, safe, and convenient option in cancer patients with recurrent VTE and “warfarin resistance”.

24. Evidence for using LMWH in warfarin-failure thromboembolic disease. • Comparison of LMWH and Warfarin for the Secondary Prevention of VTE in Patients Cancer. • Arch Intern Med, Aug 2002 • Study Design: RCT • Purpose: Compare warfarin head to head with LMWH in patients with cancer and acute VTE. • Methods: 146 patients were randomized from 25 centers in France between 4/95 and 3/99. Patients were treated with the assigned therapy for 3 months. Patients assigned to the warfarin group (75 patients) had weekly INR with a goal of 2.0-3.0. The LMWH group (71 patients) were treated with 1.5mg/kg given once daily. Patients had anti-factor Xa levels checked on days 2,10,30,60, and 90, however no dose adjustments were made.

25. Some of the Exclusion Criteria • History of HIT • Pregnancy • History of iodine allergy • Fibrinolytic therapy in the last 3 days • Already on warfarin for > 5 days • Major PE with resulting Shock • Life expectance of < 3 months • Surgery planned in the next 3 months • Severe liver dysfunction with PT>17 • Renal dysfunction with CR>2

26. End Points • Primary= Treatment Failure defined as either a recurrent VTE or a major bleed. • Secondary= 3 and 6 month mortality, bleeding, HIT, recurrent VTE during the 6 month follow up. • All patients’ analysis was done using an intention-to-treat model. • 8 patients were excluded from final analysis (4 from each group): Specifically 2 were lost to follow up, 3 withdrew consent, 3 died and didn’t have autopsy.

27. Baseline Characteristics

28. Baseline Characteristics

29. Results • Patients in the warfarin group were only in the 2-3 range 41% of the time. • Major bleeding occurred in 12 (16%) of the warfarin group -vs- 5 (7%) in the LMWH group. • 6 patients (8%) in the warfarin group died secondary to bleeding –vs- 0 in the LMWH. • The 5 patients who bled in the LMWH group all had Cr>1.85

30. Charts

31. Study limitations • 66% of cancer patients who presented with VTE met exclusion criteria and thus were not eligible for the study. Therefore, it is unclear if this information can be applied to all cancer patients. • Small study population. • Open-label trial i.e. no blinding therefore can have selection bias. • Done outside the US. • This study did use weekly INR checks and adjustments by the patients primary physician but did not have a warfarin clinic.

32. Conclusions • The warfarin group 16% bleeding risk was higher than other studies which have tended to be approximately 13%. This may have been due to the fact that the patients were only in the 2-3 range 41% of the time-vs- 50% in other studies. • 8 of the 12 had INR 3 or > at the time of their bleed, 3 of 12 had INR<1.4. 6 patients died as a result of their bleed. • During the 3 month trial 15 patients (21.1%) in the warfarin group had either a major bleed or recurrent VTE-vs- 7 patients (10.5%) in the LMWH group. • This was significant with a P value=.04

33. Summary of advantages of LMWH over warfarin • Avoids “warfarin resistance” i.e.. development of recurrent VTE while on warfarin. • NO documented evidence that increasing the INR>3.5 decreases the likelihood of recurrent VTE, but does increase the risk of bleeding. • Not influenced by dietary habits. • Doesn’t have all the medical interactions (Direct displacement, increased or inhibited hepatic metabolism, antibiotics which decrease gut flora and thus vit k ). • No lag time between administration and effective levels. • Frequent lab draws not required. • No increase in vascular calcification. • Possible anti-tumor effect of heparins.

34. Case Presentation Review • 41 yo male with stage 4 Colon cancer (known liver Mets) status post resection and chemotherapy (irinotecan/5FU/leucovorin). Course has been complicated by a pulmonary embolism treated with chronic warfarin. Patient presented to the ED with complaints of left lower extremity swelling and pain. INR was 3.1 and doppler ultrasound revealed a DVT.

35. Case Conclusion • Our patient’s warfarin was discontinued and he was started on lovenox at 1.5 mg/kg sc once daily. • Annals of Internal Med in 2/2001 demonstrated that once a day and twice a day lovenox were equally effective. In the cancer patient sub-group there was a trend towards the twice a day dose, however, it wasn’t statically significant. More research is needed to look specifically at this question.

36. Duration of treatment post VTE in a cancer patient. • Overall there is not a consensus statement. • General practice is to treat these patients as long as they have persistent disease or are receiving anti-neoplastic therapies. • Once disease is non-detectable and treatment has been stopped for 3-6 months then therapy can be stopped.

37. Take Home lessons • Remember roughly 1 in 4 cancer patients will develop a VTE at some point. • Cancer patients with recurrent VTE despite warfarin treatment and normal renal function would benefit to conversion of LMWH. • Currently Lovenox 1.5 mg/kg once a day is thought to be as effective as the 1 mg/kg twice daily, but more research is needed for the cancer subgroup. • If you want to see if the patient is therapeutic on that dose check an Anti-factor Xa level. This should be between 0.5-0.8. • Remember to dose LMWH based on the patient’s ideal weight especially in the very obese patient. • For example in the infamous words of Brent Powers beware the “BIGGONS”!

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40. 14-0