TERAPIA DEL TROMBOEMBOLISMO VENOSO IN PAZIENTI ONCOEMATOLOGICI AD ALTO RISCHIO EMORRAGICO

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1 TERAPIA DEL TROMBOEMBOLISMO VENOSO IN PAZIENTI ONCOEMATOLOGICI AD ALTO RISCHIO EMORRAGICO Valerio De Stefano, Istituto di Ematologia, Università Cattolica, Roma 43 Congresso Società Italiana di Ematologia, Napoli 2011

2 DICHIARAZIONE Relatore: Valerio De Stefano Come da nuova regolamentazione della Commissione Nazionale per la Formazione Continua del Ministero della Salute, è richiesta la trasparenza delle fonti di finanziamento e dei rapporti con soggetti portatori di interessi commerciali in campo sanitario. Posizione di dipendente in aziende con interessi commerciali in campo sanitario: no Consulenza ad aziende con interessi commerciali in campo sanitario : no Fondi per la ricerca da aziende con interessi commerciali in campo sanitario : Shire Partecipazione ad Advisory Board : Amgen, Celgene, Janssen-Cilag Titolarietà di brevetti in compartecipazione ad aziende con interessi commerciali in campo sanitario : no Partecipazioni azionarie in aziende con interessi commerciali in campo sanitario : no Altro : no Napoli, Mostra d Oltremare, ottobre 2011

3 OUTLINES Guidelines for treatment of VTE, with emphasis on cancer patients Incidence of VTE in patients with leukemia and in patients who have undergone HSCT Overall analysis of the published case reports, with emphasis on the use of LMWH Use of inferior vena cava filters

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5 2008 ACCP Antithrombotic Therapy for VTE Disease Practice Guidelines Initial management of VTE Short-term treatment with SC LMWH, IV UFH, or SC fondaparinux (Grade 1A) LMWH SC once or twice daily over UFH as an outpatient if possible (Grade 1C) and as an inpatient if necessary (Grade 1A), unless renal failure (Grade 2C) IV UFH: continuous infusion with aptt monitoring (Grade 1C) If clinical suspicion of DVT is high, treatment should be initiated while awaiting results of diagnostic tests (Grade 1C) Treat for at least 5 d with LMWH, UFH, or fondaparinux until the INR 2.0 for 24 h (Grade 1C) Start warfarin on first treatment day together with LMWH, UFH, or fondaparinux (Grade 1A) Kearon C, et al. Chest. 2008;133(6 suppl):454s-545s.

6 Treatment with LMWH vs UFH LMWH vs UFH 1 (based on a meta-analysis) LMWH is more effective than UFH for initial treatment of VTE LMWH significantly reduces the occurrence of major hemorrhage during initial treatment and overall mortality at follow up LMWH use is amenable to home therapy 2 (based on a meta-analysis) Lower VTE recurrence rate than hospital treatment Lower mortality Lower major bleeding rate 1. van Dongen CJ, et al. Cochrane Database Syst Rev Oct 18;(4):CD Othieno R, et al. Cochrane Database Syst Rev Jul 18;(3):CD

7 2008 ACCP Antithrombotic Therapy for VTE Disease Practice Guidelines Anticoagulant Therapy Initial Treatment of PE For objectively confirmed PE, short-term treatment with SC LMWH, IV UFH, or SC fondaparinux (Grade 1A) For acute nonmassive PE, LMWH recommended over IV UFH (Grade 1A) If clinical suspicion of PE is high, treatment should be initiated while awaiting outcome of diagnostic tests (Grade 1C) Treat for at least 5 d with LMWH, UFH, or fondaparinux and until the INR is 2.0 for at least 24 h (Grade 1C) Start warfarin on first treatment day together with LMWH, UFH, or fondaparinux (Grade 1A) Kearon C, et al. Chest. 2008;133(6 suppl):454s-545s.

8 2008 ACCP Antithrombotic Therapy for VTE Disease Practice Guidelines Thrombolytic Therapy Initial Treatment of PE (cont) All PE patients should undergo rapid risk stratification (Grade 1C) When evidence of hemodynamic compromise, use thrombolytic therapy unless there are major contraindications owing to bleeding risk (Grade 1B) In selected high-risk patients without hypotension judged to have a low risk of bleeding, use of thrombolytic therapy is recommended (Grade 2B) The decision to use thrombolytic therapy depends on the clinician s assessment of PE severity, prognosis, and risk of bleeding For the majority of patients with PE, thrombolytic therapy is not recommended (Grade 1B) Kearon C, et al. Chest. 2008;133(6 suppl):454s-545s.

9 Outpatient VTE Protocol Clinical Exclusionary Criteria Based on compendium of RCTs and observational studies Absolute Active bleeding or positive stool guiac Thrombocytopenia <100K Major surgery/trauma or CVA <2 weeks Phlegmasia Symptomatic PE Severe renal dysfunction Recent GI bleeding Hypertensive emergency History of heparin sensitivity or HIT Active or major comorbid illness Relative History of familial bleeding disorder Morbid obesity Iliofemoral DVT Pregnancy Underlying liver disorder Aged >75 y Acquired or congenital hypercoagulable state CVA, cerebrovascular accident; HIT, heparin-induced thrombocytopenia. Spyropoulos AC. Am J Manag Care. 2000;6(20 suppl):s1034-s1044.

10 Kearon et al, N. Engl. J. Med % pt-years major bleeding during the extended period of AVK

11 Bleeding complications of AVK Palareti et al, Lancet pts on AVK followed for total 2011 pt-years bleeding complications 7.6% pt-years: 0.25 fatal, 1.1 major, 6.2 minor

12 Kearon et al, N. Engl. J. Med. 2003

13 Agnelli et al, WODIT trial, N. Engl. J. Med % major bleeding during the extended period of AVK

14 For patients with idiopathic DVT, the benefit of extended treatment is partially offset during therapy by the risk of bleeding, particularly major bleeding, and the benefit is lost when treatment is withdrawn (Buller et al, Chest 2004; 126: 401S)

15 ACCP 2008: duration of warfarin in VTE treatment FIRST EPISODE Transient risk factor Unprovoked Unprovoked/proximal/low bleed risk Cancer SECOND EPISODE Unprovoked 3 months (1A) At least 3 months (1A) -Re-evaluated risk:benefit at 3 mos. (1C) Chronic (1A) LMWH x 3-6 mos. (1A) -Indefinite or until CA resolved (1C) Indefinite (2A) Kearon C et al. Chest 2008; 133:454S 545

16 LMWH vs AVK Recurrent VTE Iorio et al, J. Thromb. Haemostas. 2003

17 LMWH versus AVK Bleeding events Iorio et al, J. Thromb. Haemostas. 2003

18 Lyman et al, JCO 2007

19 Figure 1. hazard ratio 3.2 (95% CI ) Prandoni, P. et al. Blood 2002;100: Copyright 2002 American Society of Hematology. Copyright restrictions may apply.

20 Figure 2. hazard ratio 2.2 (95% CI ) Prandoni, P. et al. Blood 2002;100: Copyright 2002 American Society of Hematology. Copyright restrictions may apply.

21 Lee et al, N. Engl. J. Med. 2003

22 Carrier & Lee, Nature Clin Pract Oncol 2009

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24 ASCO 2007 Recommendations for VTE secondary prophylaxis in patients with cancer Preventing recurrence in patients with cancer with established VTE 1. LMWH is the preferred approach for the initial 5 to 10 days of anticoagulant treatment of the patient with cancer with established VTE. 2. LMWH given for at least 6 months is also the preferred approach for long-term anticoagulant therapy. Vitamin K antagonists with a targeted INR of 2-3 are acceptable for long-term therapy when LMWH is not available. 3. After 6 months, indefinite anticoagulant therapy should be considered for patients with active cancer. 4. The insertion of a vena cava filter is only indicated for patients with contraindications to anticoagulant therapy and in those with recurrent VTE despite adequate long-term therapy with LMWH.

25 ASCO 2007 Recommendations for VTE secondary prophylaxis in patients with cancer, continued Preventing recurrence in patients with cancer with established VTE, continued 5. In patients with central nervous system malignancies and in the elderly, anticoagulation is recommended for established VTE as described for other patients with cancer. 6. Careful monitoring of anticoagulation is necessary to limit the risk of hemorrhagic complications. 7. Anticoagulation should be avoided in the presence of active intracranial bleeding or preexisting bleeding diathesis such as thrombocytopenia (platelets < 50,000/mm 3 ) or coagulopathy.

26 ACCP 2008: duration of warfarin in VTE treatment FIRST EPISODE Transient risk factor Unprovoked Unprovoked/proximal/low bleed risk Cancer SECOND EPISODE Unprovoked 3 months (1A) At least 3 months (1A) -Re-evaluated risk-benefit at 3 mos. (1C) Chronic (1A) LMWH x 3-6 mos. (1A) Indefinite or until cancer resolved (1C) Indefinite (2A) Kearon C et al. Chest 2008; 133:454S 545

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28 VENOUS THROMBOEMBOLISM AND HEMATOLOGICAL MALIGNANCIES

29 Blom et al, JAMA 2005

30 The prevalence of VTE among patients with acute leukemia was 2.7%, and 1.5% for those with stomach cancer, 2.2% for those with pancreatic cancer, and 3.2% for those with ovary cancer. Cronin-Fenton et al, Br J Cancer 2010

31 Falanga & Marchetti, J Clin Oncol 2009

32 De Stefano et al, J Thromb Haemost 2005

33 Pihusch et al, Transplantation 2002 At the time of hemorrhage, 87.3% of the patients had a platelet count below 50,000. At the time of thrombosis 44.2% of the patients had a platelet count below 50,000 (p<0.05 vs. bleeding).

34 Pihusch et al, Transplantation 2002

35 Of 1514 pts, VTE included 55 cathete associated DVT (3.6%), 11 non cathete associated DVT of the leg (0.7%) and pulmonary emboli (0.6%). The platelet count at the VTE event wa <100,000/mmc in 31 cases (60% <50,000/ mmc in 17 (34%), and < mmc in 7 cases (13%). Patients without VTE not receivin anticoagulation had major bleeding 14.3%, fatal in 3.6%. Patients receivin anticoagulation had a 3.1-fold increase risk of bleeding. Gerber et al, Blood 2008

36 Gerber et al, Blood 2008

37 Gonsalves et al, J Thromb Haemost 2008

38 CASE-REPORTS 1. Drakos et al, Cancer 1992 (n= 4) 2. Herishanu et al, Leuk Lymphoma 2004 (n= 5) 3. Imberti, Tumori 2004 (n= 4) 4. Tousovska et al, Blood Coagul Fibrinol 2009 (n= 17) 5. Stine et al, Clin Appl Thromb Hemost 2007 (n= 2) 6. De Stefano et al, J Thromb Haemost 2005 (n= 24) 7. Schimmer et al, Bone Marrow Transplant 1998 (n= 10) 8. Ibrahim et al, Bone Marrow Transplant 2005 (n= 25) 9. Boeras et al, Blood Coagul Fibrinolys 2008 (n= 1) 10. Uderzo et al, J Clin Oncol 1995 (n= 17)

39 Ref. Age Sex Diagnosis VTE Plat. x10 9 /L nadir Treatment [1] 41 F NHL (ABMT) UDVT (CVC) 19 Enoxaparin 4,000 U bid. for 14 days and then 4,000 U qd for two months 41 M NHL (ABMT) UDVT (CVC) 15 As above 21 M AML (ABMT) UDVT (CVC) 22 As above 22 M HD (ABMT) UDVT (CVC) 16 UFH 1000 U/h i.v. for 10 days, followed by enoxaparin as above [2] 20 F HD (auto-pbsct)) UDVT (CVC) 10 Between 80 and 40 U/kg bid # 62 F MM (allo-pbsct) UDVT (CVC) U/Kg qd. 65 M AML (allo-pbsct) UDVT (CVC) U/Kg qd. 56 M NHL UDVT (CVC) 22 Between 90 and 65 U/kg bid 62 M MM (auto-pbsct) UDVT (CVC) 14 Between 50 U/kg bid and 50 U/kg qd

40 [4] 15 ALL LDVT (CVC) <40 Enoxaparin or dalteparin U/Kg bid for 14 days, and then 150 U/kg qd for three months; platelet transfusion for a count <40x10 9 /L if LMWH was U/Kg bid, or <20x10 9 /L if LMWH was 150 U/Kg qd 4 ALL (FVL) UDVT (CVC) 29 As above 4 NHL UDVT (CVC) <40 As above 13 NHL UVDT (CVC) <40 As above 3 ALL UDVT (CVC) <40 As above 5 ALL (FVL) UDVT (CVC) <40 As above 9 ALL UDVT (CVC) <40 As above 16 NHL UDVT (CVC) <40 As above 17 F HD (FVL) LDVT (CVC) <40 As above 13 ALL UDVT (CVC) <40 As above 15 ALL (FVL) UDVT (CVC) <40 As above 15 ALL UDVT (CVC) <40 As above 2 ALL UDVT (CVC) <40 As above

41 Ref. Age Sex Diagnosis VTE Platelets x10 9 /L nadir Treatment [3] 27 M AML LDVT + PE <20 Enoxaparin 100 U/kg bid for one month, then 150 U/Kg qd for five months. Half dose of enoxaparin and platelelet transfusion for a count <20x10 9 /L 77 F AML LDVT 12 As above 67 M ALL LDVT 46 As above 46 M ALL LDVT 17 As above [5] 17 M ALL UDVT 10 Enoxaparin to maintain anti-xa U/ml; platelet transfusion for a count <20x10 9 /L 4 M ALL LDVT 45 As above [4] 4 ALL UDVT <40 Enoxaparin or dalteparin U/Kg bid for 14 days, and then 150 U/kg qd for three months; platelet transfusion for a count <40x10 9 /L if LMWH was U/Kg bid, or <20x10 9 /L if LMWH was 150 U/Kg qd 16 F AML (FVL) UDVT <40 As above 17 ALL LDVT <40 As above 16 NHL UDVT <40 As above

42 Out of 22 patients with CVC-related DVT described in detail, all had a platelet count < 40,000 /mmc. No patient had major bleeding. Two patients had rethrombosis, in one case after withdrawal of heparin, in another during LMWH 150 U/kg qd. Out of 10 patients with DVT not CVC-related described in detail, all had a platelet count < 50,000 /mmc. No patient had major bleeding. One patient had rethrombosis (during LMWH 150 U/kg qd)

43 In a series of 379 patients with acute leukaemia, treatment for 20 patients who had one (n=16) or two (n= 4) VTE events was enoxaparin 100 U/kg bid; in the case of a platelet count <50,000 /mmc or in the clinical suspicion of bleeding risk the dose was reduced to 100 U/kg qd or 50 U/kg bid. Alternatively, the patients received a continuous i.v. infusion of UFH to obtain aptts in the lower therapeutic range (1.5 times greater than the basal value). Secondary prophylaxis was based on the administration of enoxaparin 100 U/kg qd in the case of ongoing chemotherapy or VKA (INR between 2 and 3) otherwise. In general, the length of secondary prophylaxis was not longer than six months. De Stefano et al, J Thromb Haemost 2005

44 In 10 patients with MM who received autologous HSCT, anticoagulation was required following pre-transplant CVC-related DVT (n= 8), PE two months prior to transplant (n= 1), or a history of acute intermittent atrial fibrillation complicated by an arterial embolus to the leg (n= 1). Beginning on the first day of high-dose chemotherapy, the patients received UFH (a 5000 U i.v. bolus followed by 1000 U per h) to maintain aptts between 50 and 70 seconds and were switched to VKA treatment when their conditions stabilised. UFH treatment was interrupted once the VKA administration produced a therapeutic INR >2 for two consecutive days. Heparinised patients received platelet transfusions to maintain counts >30,000 / mmc. Three patients developed bleeding (haematuria, haematemesis, mucosal bleeding) that did not not require transfusion, and no thrombotic events occurred. Schimmer et al, Bone Marrow Transplant 1998

45 In a series of 26 patients with HSCT who were given enoxaparin for VTE, 21 patients had haematologic malignancies. There were 25 VTE events recorded (four patients had two events at different sites) and 11 cases had upper extremity CVC-related deep venous thrombosis. During thrombocytopenia (<55,000/mmc), enoxaparin was reduced to a median value of 49 U/kg/day (range 34-75) and was withdrawn in some instances when the platelet count was <20,000/mmc. Two major bleeding events (8%) occurred, in one case fatal. Ibrahim et al, Bone Marrow Transplant 2005

46 In a series of 452 children with haematological malignancies, 12 patients who received chemotherapy or bone marrow transplantation had pulmonary embolisms (recurrent events for three of the cases), and 14 of 17 events occurred in patients with CVC. Thrombolytic treatment was most often performed with urokinase at a loading dose of 2,000 to 4,560 U/kg as single bolus followed by 2,000 to 4,530 U/kg/h for 12 to 42 hours. Before the thrombolytic therapy was discontinued, UFH was initiated at a daily dose of 100 to 500 U/kg as a continuous infusion and was continued for 6 to 26 days. This treatment was effective for 15 of the 17 events, and there was no major bleeding in any of the cases. A detailed platelet count was only available from one patient, and this patient s count was <20,000 /mmc at the time of the embolic event and fibrinolysis. Uderzo et al, J Clin Oncol 1995

47 EXPERTS OPINION Experts and the AIEOP suggested that: 1) the first two weeks of treatment should consist of the administration of full- dose LMWH (anti-factor Xa level U/ml), maintaining the platelet count > 50,000/mmc. 2) After the first two weeks, halving the dose is recommended if the platelet count is between 20 and 50,000 /mmc. 3) If the platelet count is <20,000 /mmc, it is advised that the LMWH therapy be discontinued until the platelet count recovers. Bajzar et al, Curr Opin Pediatr 2006 Giordano et al, Recent Pat Cardiovasc Drug Discov 2007 Falanga & Rickles, Hematology ASH Educ Program 2007

48 CVC-related UDVT - ACCP 2008 Recommendations For patients with acute UEDVT, we recommend initial treatment with therapeutic doses of LMWH, UFH, or fondaparinux as described for leg DVT (see Section 1) [Grade 1C] For patients with acute UEDVT, we recommend treatment with a VKA for > 3 months (Grade 1C) For most patients with UEDVT in association with an indwelling central venous catheter, we suggest that the catheter not be removed if it is functional and there is an ongoing need for the catheter (Grade 2C) For patients who have UEDVT in association with an indwelling central venous catheter that is removed, we do not recommend that the duration of long-term anticoagulant treatment be shortened to < 3 months (Grade 2C).

49 British Committee for Standards in Haematology: Guidelines on use of vena cava filters. Br J Haematol 2006; 134: 590 Vena cava filters are indicated to prevent PE in patients with VTE who have a contraindication to anticoagulation (grade B, level III).

50 Inferior vena cava filters ACCP 2008 Recommendations For most patients with PE, we recommend against the routine use of a vena caval filter in addition to anticoagulants (Grade 1A) In patients with acute PE, if anticoagulant therapy is not possible because of risk of bleeding, we recommend placement of an IVC filter (Grade 1C) For patients with acute PE who have an IVC filter inserted as an alternative to anticoagulation, we recommend that they should subsequently receive a conventional course of anticoagulant therapy if their risk of bleeding resolves (Grade 1C).

51 IVC History Closing off IVC to prevent PE suggested by Trousseau in 1868 Performed by Bottini in Moretz externally clipped IVC to create a slitlike channel Serrated Mile, Adams, Deweese devices created four channels within the IVC soon followed using general anesthesia and laparotomy 1967 transvenous approach with Mobin-Uddin filter high occlusion rates Soon replaced by Kimray-Greenfield filter 50,000 placed in the United States in 1999

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53 Indications Protection against PE in following patients: Patients with acute DVT in whom conventional anticoagulation is contraindicated (recent surgery, hemorrhagic stroke, active bleeding). Patients with acute DVT in whom conventional anticoagulation has proven ineffective. Patients with a pulmonary vascular bed that is already significantly compromised (eg, because of massive pulmonary embolism or chronic thromboembolic pulmonary hypertension)

54 Indications Placement when patient has massive PE Evidence of residual thrombotic material in the LE veins. IVC placement in a patient who has experienced complete embolization of lower extremity thrombus exposes the patient to risk without expectation of benefit. Site of origin of embolic event must be such that filter will benefit patient. Infrarenal IVC placement will not provide prophylactic benefit if emboli originated in renal veins, a cardiac chamber, or upper extremity veins. Anticipated additional therapy should be considered prior to placing the filter. The filter insertion site may serve as a potential source of bleeding, which can interfere with primary anticoagulant or thrombolytic therapy.

55 Ingberg & Geerts, Curr Opin Hematol 2009

56 COMPLICATIONS Mortality Rate 0.3% Complications related to the insertion process (bleeding, pain etc.) Venous thrombosis at the site of insertion (Up to 40%) Filter migration Filter erosion through the IVC wall IVC obstruction (5-18%)

57 Temporary IVC filters Miyahara et al, J Vasc Surg 2006

58 Temporary filters remain attached to a wire or catheter that can be removed through the skin, and the advantage of these filters is their ease of insertion and removal. However, the external fixation is a potential pathway for infection, which would render such devices highly inappropriate for neutropaenic patients. Furthermore, temporary filters are often difficult to manage and present frequent complications such as thrombosis or migration. In addition, the limited duration of use that can be achieved with temporary filters is insufficient to recover the platelet count after high-dose chemotherapy. If needed, they could be replaced by another temporary filter or a retrievable filter, but this procedure is susceptible to increase the risks for the patient.

59 The guidelines for the use of retrievable filters recommends that "the decision to use an optional filter rather than a permanent filter should be based on the anticipated required duration of protection against clinically significant PE and/or risk of pharmacologic therapy. When the indication for caval filtration is no longer present in a patient or the risk of PE is acceptably low because of a change in clinical status or because prophylactic therapy was successful, these patients can be considered for filter retrieval.

60 When there is a need for continuous caval filtration, optional filters can be left in situ as a permanent device. In some cases, these filters are not removed or their retrieval may be deferred for various reasons, such as poor clinical status, short lifespan, significant amount of clot trapped within the filter, IVC thrombosis, or technical difficulties that prevent safe retrieval. In younger patients who have a longer life expectancy, use of a retrievable filter is a more valid option for physicians and patients than the use of a permanent device. These optional filters have gained popularity over the years. More and more of these devices are being left as permanent filters. Although the percentage of successful retrieval varies, some series quote retrieval rates of up to 100% technical success for the selected patients

61 Gunther-Tulip filter

62 Berczi et al, Cardiovasc Intervent Radiol 2007

63 In some cases retrievable filters cannot be removed for technical reasons, including if the filter is severely angled, if a thrombus is trapped in the filter or if the filter struts substantially penetrate the IVC wall. There are very limited data describing the long-term safety of these devices when they are not removed. Finally, their use in patients with haematologic malignancies has not been specifically addressed, so special caution should be used when deciding to use a retrievable filter in this setting due to the risk of haematoma and infection at the insertion site.

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66 CONCLUSIONS VTE complications are not uncommon for patients with haematologic malignancies. Concomitant prolonged thrombocytopaenia challenges the use of anticoagulants for the prevention of thrombus extension and recurrence. There are limited published data concerning the management of VTE in this setting, although the use of LMWH appears to be safe and effective even for patients with severe thrombocytopaenia.

67 CONCLUSIONS A careful treatment approach for either platelet transfusion or LMWH dose modulation should aim to obtain a satisfactory balance between antithrombotic potential and haemorrhagic risk. Although the reported results are encouraging, special caution should be adopted for treatment of severely thrombocytopenic patients, and the judicious use of retrievable IVC filters may be an important and helpful tool.