Are guidelines for anticoagulation useful in cancer patients?

Session 3 Striking a Balance Between Bleeding and the Risk of Thrombosis in Cancer Patients Are guidelines for anticoagulation useful in cancer patients? Sebastian Szmit Department of Pulmonary Circulation and Thromboembolic Diseases Head of Department: Prof. Adam Torbicki Department of Oncology Head of Department: Prof. Tadeusz Pieńkowski

OnCOReview International Journal for Interdisciplinary Oncology The Official Journal of East European Branch of International CardiOncology Society

Several national and international guidelines for the prevention and treatment of VTE in cancer patients have been published in the past

The latest guidelines were recently prepared by different globally recognised societies

When may guidelines be useful and helpful in cancer patients? 1) Which anticoagulants are the best choice in cancer patients? 2) What does secondary antithrombitic prevention mean? what is the optimal dose of heparin? how long should be continued? 3) What does primary antithrombitic prevention mean? during pharmacological anticancer therapy during surgery due to cancer 4) What is recommended in special situation? bleeding thrombocytopenia severe renal failure

Which anticoagulants are the best choice for acute VTE treatment in cancer patients? Guidelines International consensus (2013) American College of Chest Physicians (2012) European Society of Medical Oncology (2011) Recommendations LMWH is recommended for the initial treatment of established VTE in cancer patients [Grade 1B]. Fondaparinux and UFH can be also used for the initial treatment of established VTE in cancer patients [Grade 2D]. In patients with DVT of the leg / PE and cancer, we suggest LMWH over VKA therapy (Grade 2B). Choice of treatment in patients with and without cancer is sensitive to the individual patient s tolerance for daily injections, need for laboratory monitoring, and treatment costs. The standard initial treatment of an acute episode of VTE in cancer and non-cancer patients consists: LMWH s.c. at a dose adjusted to body weight: (e.g. dalteparin or enoxaparin) UFH - first administered as a bolus of 5000 IU, followed by continuous infusion adjusted to achieve and maintain an activated partial thromboplastin time (aptt) prolongation of 1.5 2.5 times the basal value.

Can we use thrombolysis as effective and safety method for treatment of cancer patients with severe VTE? Guidelines International consensus (2013) American College of Chest Physicians (2012) European Society of Medical Oncology (2011) Recommendations Thrombolysis in cancer patients with established VTE may only be considered on a case-by-case basis, with specific attention paid to contraindications, especially bleeding risk (brain metastasis) [Best clinical practice] Not specified Thrombolytic treatment should be considered for specific subgroups of patients such as those with PE presenting with severe right ventricular dysfunction, and for patients with massive ilio-femoral thrombosis at risk for limb gangrene, where rapid venous decompression and flow restoration may be desirable. Urokinase, streptokinase and tissue-type plasminogen activator are able to achieve a rapid lysis of fresh pulmonary emboli [II, A].

What do guidelines say about new anticoagulant agents in cancer patients? Guidelines International consensus (2013) American College of Chest Physicians (2012) European Society of Medical Oncology (2011) Recommendations It was premature to issue recommendations on the use of new agents in this setting, because: -absence of specific data - none of the experts had enough clinical experience with their use In patients with DVT and cancer who are not treated with LMWH, we suggest VKA over dabigatran or rivaroxaban for long-term therapy (Grade 2B). In patients with PE and cancer who are not treated with LMWH, we suggest VKA over dabigatran or rivaroxaban for long-term therapy (Grade 2C). Not specified

Clinical trials with new parenteral indirect FXa anticoagulants for prophylaxis and treatment of venous thromboembolism Clinical trial Subjects (n) Cancer (%) Drug Conclusions SAVE-ONCO 3212 100% Semuloparin Prophylaxis SAVE-ABDO 4413 81% Semuloparin prophylaxis Van Gogh-DVT Van Gogh-PE Van-Gogh extension 2904 15% 2215 14% 1215 9.9% Idraparinux Idraparinux Idraparinux SEM superior to placebo Noninferiority of SEM versus ENO IDRA noninferior to heparin + VKA IDRA inferior to heparin + VKA IDRA superior to placebo EQUINOX (DVT) 757 5.2% Idrabiotaparinux Non significant CASSIOPEA (PE) 3202 5.9% Idrabiotaparinux ENO + IDRAB noninferior to ENO + VKA

Evidence regarding treatment of cancer-related VTE with the new oral anticoagulants is limited: Clinical trial Subjects (n) Cancer (%) Drug Conclusions EINSTEIN-DVT EINSTEIN-PE EINSTEIN- EXTENSION AMPLIFY-EXT 3449 6% 4845 4.6% 1196 4.5% 2486 1.7% Rivaroxaban RIV noninferior to ENO + WRF Rivaroxaban RIV noninferior to ENO + WRF Rivaroxaban Apixaban RIV superior to placebo API (both doses) superior to placebo RE-COVER 2564 4.8% Dabigatran DAB noninferior to WRF RE-MEDY 2856 4.2% Dabigatran DAB noninferior to WRF RE-SONATE 1343 < 1% Dabigatran DAB superior to placebo

Pooled analysis of recurrent venous thromboembolism and clinically relevant bleeding in patients with cancer included in the EINSTEIN-DVT and EINSTEIN-PE studies. Rivaroxaban seems to be effective and safe in cancer patients with VTE Vascular Health and Risk Management 2013:9

New anticoagulants seem to be very atractive but In my opinion we know too little about their Interactions with anticancer drugs activity (risk of cancer progression) Influence on cancer cells survival (risk of cancer progression) Vascular Health and Risk Management 2013:9

When may guidelines be useful and helpful in cancer patients? 1) Which anticoagulants are the best choice in cancer patients? 2) What does secondary antithrombotic prevention mean? what is the optimal dose of heparin? how long should be continued? 3) What does primary antithrombitic prevention mean? during pharmacological anticancer therapy during surgery due to cancer 4) What is recommended in special situation? bleeding thrombocytopenia severe renal failure

LMWH used in studies comparing early maintenance treatment (10 days to 3 months) and long-term (beyond 3 months) treatment It was only comparison between LMWH alone and short-term heparin followed by VKA LMWH dosage duration study Enoxaparin 1.5 mg / kg / day for 3 months CANTHANOX [MEYER 2002] Dalteparin 200 IU / kg / day 150 IU / kg / day for 1 month for 5 months CLOT [LEE 2003] Tinzaparin 175 IU / kg / day for 3 months LITE [HULL 2006] no head-to-head comparison between different doses of LMWH no study comparing 3 vs. 6 months of LMWH clinical trials have not been specifically designed to evaluate the duration of anticoagulation

What do guidelines say about long-term treatment of VTE in cancer patients? We can find the indication for a minimum of 3 months and information that the period of 6 months seem to be more effective Guidelines International consensus (2013) Recommendations LMWH should be used for a minimum of 3 months to treat established VTE in cancer patients; however, patients were treated for 6 months in the largest study in this setting [Grade 1A]. After 3 6 months, termination or continuation of anticoagulation (LMWH or VKA) should be based on individual evaluation of the benefit-risk ratio, tolerability, patients preference and cancer activity [Best clinical practice]. American College of Chest Physicians (2012) European Society of Medical Oncology (2011) In patients with DVT/PE and active cancer, if there is a low or moderate bleeding risk, we recommend extended anticoagulant therapy over 3 months of therapy (Grade 1B), and if there is a high bleeding risk, we suggest extended anticoagulant therapy (Grade 2B). Long-term treatment for 6 months with 75 80% (i.e. 150 U/kg once daily) of the initial dose of LMWH is safe and more effective than treatment with a VKA. This schedule is recommended [I, A].

But active cancer is a major risk factor for recurrence of VTE, the rate of recurrence being approximately 20% during the first 12 months after the first event Joung S, Robinson B. N Z Med J 2002;115(1155):257-260. Hutten BA et al. J Clin Oncol 2000;18(17):3078-3083. Can we understand cancer patients as candidates for indefinite anticoagulant treatment after a first episode of VTE?

What is the optimal duration of anticoagulant therapy in patients with cancerrelated deep vein thrombosis? Results of the Cancer-DACUS Study 409 patients with active cancer and a first episode of DVT received LMWH for 6 months and were then divided into three groups on the basis of the results of a duplex ultrasound examination Group Clinical decision Rates of VTE recurrence A1: with residual venous thrombosis A2: with residual venous thrombosis B: without residual venous thrombosis randomized to continuation of anticoagulation randomized to discontinuation of anticoagulation recommendation to discontinue anticoagulant therapy Rates of major bleeding 14.2% 4.2% p = 0.73 21.9% 1.6% p < 0.05 2.8% 1.9% After 6 months of treatment with LMWH, patients with active cancer and residual venous thrombosis may have better prognosis if they continue anticoagulation Siragusa S et al. Blood 2010; 116: 190.

In my opinion: For patients with PE and cancer, LMWH should be considered for the first 3 to 6 months. After this period, anticoagulant therapy with VKA or LMWH, or with a new oral anticoagulant, should be continued indefinitely, or until the cancer is considered active.

The decisions regarding chronic anticoagulation should be made on a case-by case basis after considering the success of anticancer therapy, the estimated risk of VTE recurrence, the bleeding risk, the preference of the patient. Periodic reassessment of the risk benefit ratio of chronic anticoagulant treatment should be recommended.

What do guidelines say about treatment of VTE recurrence in cancer patients under anticoagulation? Guidelines International consensus (2013) American College of Chest Physicians (2012) European Society of Medical Oncology (2011) Recommendations Three options can be considered: (i) switch from VKA to LMWH in patients treated with VKA; (ii) increase in LMWH dose in patients treated with LMWH, (iii) vena cava filter insertion [Best clinical practice] Not specified on long-term anticoagulation with VKA: A. INR is in the subtherapeutic range achieve a stable INR between 2.0 and 3.0. B. INR is in the therapeutic range there are two options: (i) shift to another method of anticoagulation, (ii) increase the INR to a target of 3.5 while receiving a reduced dose of LMWH escalating the dose [II, B]

In my opinion: Patients adequately anticoagulated who develop VTE recurrence should be checked for progression of their malignancy. We do not find such indication in guidelines

What should we understand as primary trombophylaxis of VTE in hospitalized cancer patients? Guidelines International consensus (2013) American College of Chest Physicians (2012) European Society of Medical Oncology (2011) Recommendations We recommend prophylaxis with LMWH, UFH or fondaparinux in hospitalized medical patients with cancer and reduced mobility [Grade 1B]. For acutely ill hospitalized medical patients at increased risk of thrombosis, we recommend anticoagulant thromboprophylaxis with low molecularweight heparin [LMWH], low-dose unfractionated heparin (LDUH) bid, LDUH tid, or fondaparinux (Grade 1B). Prophylaxis with UFH, LMWH or fondaparinux in hospitalized cancer patients confined to bed with an acute medical complication is recommended [I, A].

In choosing the specific anticoagulant drug to be used for pharmacoprophylaxis, choices should be based on 1) patient preference, 2) compliance, 3) ease of administration (eg, daily vs bid vs tid dosing), 4) costs

How to understand the recommendations in ambulatory medical cancer patients treated with chemotherapy? There are several conflicting indications Guidelines International consensus (2013) American College of Chest Physicians (2012) European Society of Medical Oncology (2011) Recommendations In patients receiving chemotherapy, prophylaxis is not recommended routinely [Grade 1B]. Primary pharmacological prophylaxis of VTE may be indicated in patients with locally advanced or metastatic pancreatic cancer treated with chemotherapy and having a low bleeding risk [Grade 1B]. Primary pharmacological prophylaxis of VTE may be indicated in patients with locally advanced or metastatic lung cancer treated with chemotherapy and having a low bleeding risk [Grade 2B]. In outpatients with cancer who have no additional risk factors for VTE, we suggest against routine prophylaxis with LMWH or LDUH (Grade 2B) and recommend against the prophylactic use of vitamin K antagonists (Grade 1B)

In outpatients with solid tumors who have additional risk factors for VTE and who are at low risk of bleeding, we suggest prophylactic dose LMWH or LDUH over no prophylaxis (Grade 2B) Remarks: Additional risk factors for venous thrombosis in cancer outpatients include: previous venous thrombosis, immobilization, hormonal therapy, angiogenesis inhibitors, thalidomide and lenalidomide. CHEST 2012; 141(2)(Suppl):e195S e226s

In outpatients with solid tumors who have additional risk factors for VTE and who are at low risk of bleeding, we suggest prophylactic dose LMWH or LDUH over no prophylaxis (Grade 2B) Remarks: And it may be understood as: patients with bone matastases and low activity ( immobilization ), patients treated with tamoxifen or aromatase inhibitors patients treated with bevacizumab or sunitinib / pazopanib or other TKI..should receive trombophylaxis.??????? CHEST 2012; 141(2)(Suppl):e195S e226s

Predictive model for chemotherapy-associated VTE in ambulatory cancer patients. This model might be used to identify ambulatory cancer patients who are clinically at high risk for VTE (II, B). The rates of VTE: low-risk category - 0,5% (score = 0) intermediate-risk category 2% (score = 1 2); high-risk category - 7% (score 3)

There is no evidence to recommend the use of anticoagulation to influence prognosis of cancer [I, B].

Although there are published data that some patients may achieve better overall survival within primary trombophylaxis and palliative chemotherapy Autor n heparin duration effect Lebeau 277 UFH 5 weeks 317 days vs. 261 days; p = 0.01 Kakkar FAMOUS 385 dalteparin 52 weeks or until death 44 months vs. 24 months; p = 0.03 Altinbas 84 dalteparin 18 weeks 13 months vs. 8 months; p = 0.01 Klerk MALT 302 nadroparin 6 weeks 8 months vs. 6.6 months; p = 0.02 Sideras 138 dalteparin 104 weeks or until death No significant effect on median survival Blood Reviews 23 (2009) 129 135

What is recommended in ptients treated with thalidomide or lenalidomide? Guidelines International consensus (2013) American College of Chest Physicians (2012) Recommendations In patients treated with IMiDs combined with steroids and/ or chemotherapy (doxorubicin), VTE prophylaxis is recommended: VKA at low or therapeutic doses, LMWH at prophylactic doses low-dose aspirin The efficacy of these regimens remains unclear [Grade 2C]. who have additional risk factors for VTE and who are at low risk of bleeding, we suggest prophylacticdose LMWH or LDUH over no prophylaxis (Grade 2B) thalidomide and lenalidomide on the list of additional risk factors European Society of Medical Oncology (2011) Consider LMWH, aspirin or adjusted-dose warfarin (INR=1.5) in myeloma patients receiving thalidomide plus dexamethasone or thalidomide plus chemotherapy [II, B].

Guidelines recommend primary pharmacoprophylaxis in all surgical cancer patients? The efficacy of prophylaxis is unquestionable Guidelines International consensus (2013) American College of Chest Physicians (2012) European Society of Medical Oncology (2011) Recommendations Use of LMWH once a day or a low dose of UFH three times a day is recommended to prevent postoperative VTE in cancer patients; pharmacological prophylaxis should be started 12 2 h preoperatively and continued for at least 7 10 days; there are no data allowing conclusions regarding the superiority of one type of LMWH over another [Grade 1A]. Use of the highest prophylactic dose of LMWH to prevent postoperative VTE in cancer patients is recommended [Grade 1A]. There is no evidence to support fondaparinux as an alternative to LMWH for the prophylaxis of postoperative VTE in cancer patients [Grade 2C]. Pharmacoprophylaxis of VTE in surgical cancer patients is recommended In surgical cancer patients, high dose s.c. LMWH (e.g. enoxaparin 4000 U of anti-xa activity, dalteparin 5000 U of anti-xa activity) once daily, or s.c.ufh 5000 U (three times daily) are recommended [I, A]. The role of prophylaxis is unquestionable (I, A).

But what do guidelines say about extended duration of prophylaxis in high risk surgical cancer patients? The proposed extended prophylaxis means only 4 weeks!!! Guidelines International consensus (2013) American College of Chest Physicians (2012) European Society of Medical Oncology (2011) Recommendations Extended prophylaxis (4 weeks) to prevent postoperative VTE after major laparotomy in cancer patients may be indicated in patients with a high VTE risk and low bleeding risk [Grade 2B]. For high-vte-risk patients undergoing abdominal or pelvic surgery for cancer who are not otherwise at high risk for major bleeding complications, we recommend extended-duration pharmacologic prophylaxis (4 weeks) with LMWH over limited-duration prophylaxis (Grade 1B). Cancer patients undergoing elective major abdominal or pelvic surgery should receive in hospital and post-discharge prophylaxis with s.c. LMWH for up to 1 month after surgery [I, A].

Relative risk of venous thromboembolism by time since inpatient surgery and by surgery type Six weeks after surgery 7-12 weeks after surgery 4-12 months after surgery 1 year after surgery Cancer 91.6 (73.9 to 113.4) 53.4 (40.0 to 71.4) 34.4 (29.3 to 40.2) 6.1 (4.9 to 7.6) Hip or knee replacement 220.6 (187.8 to 259.2) 39.7 (27.3 to 57.8) 4.6 (2.9 to 7.2) 2.7 (1.9 to 4.0) Fracture 89.0 (65.5 to 121.0) 39.8 (25.0 to 63.4) 2.9 (1.5 to 5.9) 0.6 (0.3 to 1.5) All other surgery 36.0 (29.6 to 43.8) 8.4 (5.6 to 12.6) 3.7 (2.9 to 4.8) 1.7 (1.4 to 2.0) The recommended extended duration of tromboprophylaxis in surgical cancer patients seems to be too short!!! Sweetland S, BMJ 2009;339:b4583.

Which anticoagulants are the best choice in cancer patients? Prophylaxis of VTE & severe renal faulire Guidelines International consensus (2013) American College of Chest Physicians (2012) Recommendations In the presence of severe renal failure (creatinine clearance < 30 ml /min.) we suggest using UFH followed by early VKA (possible from day 1) or LMWH adjusted to anti-xa level for the treatment of established VTE [Best clinical Practice] For patients receiving therapeutic LMWH who have severe renal insufficiency (calculated creatinine clearance, 30 ml/min), we suggest a reduction of the dose rather than using standard doses (Grade 2C). LMWH and fondaparinux are retained in patients with renal impairment, whereas this is not a concern with UFH European Society of Medical Oncology (2011) In patients with severe renal failure (creatinine clearance <25 30 ml), UFH i.v. or LMWH with anti-xa activity monitoring is recommended [I, A].

Which anticoagulants are the best choice in cancer patients? Prophylaxis of VTE & bleeding Guidelines International consensus (2013) American College of Chest Physicians (2012) European Society of Medical Oncology (2011) Recommendations LMWH may increase the bleeding risk, particularly in the context of thrombocytopenia For acutely ill hospitalized medical patients at increased risk of thrombosis who are bleeding or at high risk for major bleeding, we suggest the optimal use of mechanical thromboprophylaxis with graduated compression stockings (GCS) (Grade 2C) or intermittent pneumatic compression (IPC) (Grade 2C) For high-vte-risk general and abdominalpelvic surgery patients who are at high risk for major bleeding complications or those in whom the consequences of bleeding are thought to be particularly severe, we suggest use of mechanical prophylaxis, preferably with IPC, over no prophylaxis until the risk of bleeding diminishes and pharmacologic prophylaxis may be initiated (Grade 2C). The use of an inferior vena cava filter should be considered in patients with recurrent PE despite adequate anticoagulant treatment or with a contraindication to anticoagulant therapy (i.e. active bleeding and profound, prolonged thrombocytopenia) Once the risk of bleeding is reduced, patients with a vena cava filter should receive or resume anticoagulant therapy in order to reduce the risk of recurrent deep vein thrombosis of the lower extremities [II, A].

In cancer patients with thrombocytopenia, full doses of anticoagulant can be used for the treatment of established VTE if the platelet count is > 50 G/L and there is no evidence of bleeding; for patients with a platelet count below 50 G/L, decisions on treatment and dosage should be made on a case-by-case basis with the utmost caution [Best clinical practice] In cancer patients with mild thrombocytopenia if platelet count > 80 G/L pharmacological prophylaxis may be used; if the platelet count is below 80 G/L, pharmacological prophylaxis may only be considered on a case-by-case basis and careful monitoring is recommended [Best clinical practice]

Are guidelines for anticoagulation useful in cancer patients? Advantages of guidelines Conclusions Disadvantages of guidelines Strong recommendation for LMWH over VKA therapy No recommendations on the use of new anticoagulants Strong recommendation for > 3 months treatment of established VTE with LMWH Strong recommendation for primary trombophylaxis in surgical cancer patients Strong recommendation for primary trombophylaxis in HOSPITALIZED cancer patients Recommendation on extended secondary trombophylaxis after first 6 months IS NOT clear Primary trombophylaxis in high risk surgical patients should probably be more extended than currently recommended There is no good definition of patients receiving palliative anticancer treatment and requaring primary thrombophylaxis for better outcome