Giannini-trombosi venosa profonda diagnosi e
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Giannini-trombosi venosa profonda diagnosi e
Giornate di Aggiornamento in Oncologia 1°Edizione “PROBLEMATICHE ACUTE DEL PAZIENTE ONCOLOGICO” Trombosi venosa profonda: diagnosi e trattamento Giannini SDO Cardio-Angiologia Introduction Within the last six years 31 practice guidelines and major reviews on cancer and venous thromboembolism (VTE) have been published in international oncology journals. Why has this subject become so noteworthy? Introduction In parallel with this epidemiologic development, the number of cancer patients with VTE has increased. VTE jeopardizes the net benefit of any new drug and its future market approval,not to mention the economic impact from the VTE itself. VTE is frequent and serius ► ► The overall risk in cancer patients is 4–7 fold higher than in non-cancer patients Some10–20% of cancer patients develop VTE during the course of their disease ► VTE is a signum malum:a significantly worse prognosis compared to patients without cancer Mechanisms of CancerCancer-Induced Thrombosis: The Interface 1. Pathogenesis Pathogenesis? ? 2. Biological significance? 3. Potential importance for cancer therapy? Pathogenesis of Thrombosis in Cancer A Modification of Virchow’s Triad 1. Stasis ● ● Prolonged bed rest Extrinsic compression of blood vessels by tumor 2. Vascular Injury ● ● ● ● Direct invasion by tumor Prolonged use of central venous catheters Endothelial damage by chemotherapy drugs Effect of tumor cytokines on vascular endothelium 3. Hypercoagulability ● ● ● Tumor-associated procoagulants and cytokines (tissue factor, CP, TumorTNFα TNF α, ILIL-1β, VEGF, etc.) Impaired endothelial cell defense mechanisms (APC resistance; deficiencies of AT, Protein C and S) Enhanced selectin/integrinselectin/integrin-mediated, adhesive interactions between tumor cells,vascular endothelial cells, platelets and host macrophages Interface of Clotting Activation and Tumor Biology FVII/FVIIa Tumor Cell TF Blood Coagulation Activation VEGF THROMBIN FIBRIN Angiogenesis ILIL-8 PAR--2 PAR Angiogenesis TF Endothelial cells Falanga and Rickles, New Oncology:Thrombosis, 2005 Mechanisms of CancerCancer-Induced Thrombosis: Clot and Cancer Interface 1. Pathogenesis? 2. Biological significance? 3. Potential importance for cancer therapy? therapy? Activation of Blood Coagulation in Cancer Biological Significance? ► Epiphenomenon? Epiphenomenon ? Is this a research generic secondary 4 Recent supports event the where concept that thrombosis is an incidentalisfinding oncogenic transformation closely linked to procoagulant conversion of the tumor microenvironment. or, is clotting activation . . . 4 Hypercoagulability seems to confer a growth advantage to the tumor, supports cell motility, and invasion of healthy tissues. ► A Primary Event? Linked to malignant transformation Mechanisms of CancerCancer-Induced Thrombosis: Implications 1. Pathogenesis? 2. Biological significance? 3. Potential importance for cancer therapy? Cancer and Thrombosis State--ofState of-the the--Science Update Key Questions 1. Does activation of blood coagulation affect the biology of cancer positively or negatively? 2. Can we treat tumors more effectively using coagulation protein targets? 3. Can anticoagulation alter the biology of cancer? Cancer and Thrombosis State--ofState of-the the--Science Update Tentative Answers 1. Epidemiologic evidence is suggestive that VTE is a bad prognostic sign in cancer 2. Experimental evidence is supportive of the use of antithrombotic strategies for both prevention of thrombosis and inhibition of tumor growth 3. Results of recent, randomized clinical trials of LMWH in cancer patients indicate superiority in preventing recurrent VTE and suggest increased survival (not due to just preventing VTE)— VTE)— “Titillating” Coagulation Cascade and Tumor Biology TF ClottingClottingdependent VIIa ClottingClottingindependent Thrombin Xa ClottingClottingindependent ? ClottingClottingdependent Fibrin Clottingdependent PARs Angiogenesis, Tumor Growth and Metastasis LMWH (e.g. dalteparin) Fernandez, Patierno and Rickles. Sem Hem Thromb 2004;30:31; Ruf. J Thromb Haemost 2007; 5:1584 Cancer and Thrombosis Diagnosis of VTE Diagnosis of VTE Diagnostica ultrasonografica • L’ultrasonografia (eco color Doppler) va considerata la metodica diagnostica • di prima scelta per la diagnosi della TVP prossimale nel paziente a rischio intermedio o alto. • Il criterio diagnostico validato è la incomprimibilità (CUS). Dosaggio dei D-Dimeri • Per il dosaggio dei DD è necessario utilizzare metodi sensibili e per i quali siano disponibili valori di cut-off ben determinati mediante studi clinici su pazienti con TVP comprovata. • Il test non va considerato isolatamente ma va integrato con informazioni di ordine clinico e strumentale. • Un risultato negativo del test in soggetti nei quali l’intervallo di tempo tra l’ insorgenza dei sintomi e il controllo di laboratorio sia superiore a 7-10 giorni non va considerato come conclusivo. Linee guida SISET-SIAPAV-SIDV 2000 – CIF 2000-2003 Diagnosis of VTE Cancer and Thrombosis VTE Treatment Standard Treatment of VTE Can We Do Better Than This? Initial treatment 5 to 7 days LMWH or UFH Long-term therapy Vitamin K antagonist (INR 2.0 - 3.0) > 3 months Recurrent VTE in Cancer Subset Analysis of the Home Treatment Studies (UH/VKA vs. LMWH/VKA) Recurrent VTE Events per 100 patient years Malignant Non Non-- Malignant 27.1 9.0 Hutten et.al. J Clin Oncol 2000;18:3078 P value 0.003 Recurrent VTE in Cancer Subset Analysis of the Home Treatment Studies Major Bleeding Events per 100 patient years Malignant NonNonmalignant 13.3 2.1 Hutten et.al. J Clin Oncol 2000;18:3078 P-value 0.002 Oral Anticoagulant Therapy in Cancer Patients: Problematic ► Warfarin ● ● ● ● ► therapy is complicated by: Increased risk of both recurrence and bleeding Difficulty maintaining tight therapeutic control, due to anorexia, vomiting, drug interactions, etc. Frequent interruptions for thrombocytopenia and procedures Difficulty in venous access for monitoring Is it reasonable to substitute longlong-term LMWH for warfarin ? When? How? Why? Treatment of CancerCancer-Associated VTE Study Design Length of Therapy (Months) N Recurrent VTE (%) Major Bleeding (%) Death (%) CLOT Trial (Lee 2003) Dalteparin OAC 6 336 336 9 0.002 17 6 4 NS 39 NS 41 CANTHENOX (Meyer 2002) Enoxaparin OAC 3 67 71 11 0.09 21 7 16 0.09 11 0.03 23 LITE (Hull ISTH 2003) Tinzaparin OAC 3 80 87 6 11 6 8 NS 23 NS 22 ONCENOX (Deitcher ISTH 2003) Enox (Low) Enox (High) OAC 6 32 36 34 3.4 NS 3.1 6.7 0.03 NS NR Initial management of a first episode of cancer-associated VTE Choice of anticoagulant ► no difference in efficacy between LMWH and UFH in patients with cancer ► a statistically significant reduction in mortality risk with LMWH at 3 months of follow-up has been noted. ► LMWH vs UFH : lower cost (because hospitalization and laboratory monitoring are not required) and simple dosing (because the total daily dose is based on body weight), lower risk for heparin-induced thrombocytopenia (HIT). ► Data on the use of fondaparinux: In the Matisse trials, the 3-month rate for symptomatic, recurrent VTE was higher for fondaparinux vs enoxaparin in DVT treatment (12.7% vs 5.4%) but was lower for fondaparinux vs UFH in PE treatment (8.9% vs 17.2%). ► Like LMWH, fondaparinux is administered as a once-daily, weight-based subcutaneous injection. Rarely associated with the development of drug-induced thrombocytopenia ► Barriers to its use in oncology patients include a relatively long half-life of 17 to 21 hours, the lack of a reversal agent, and 100% dependence on renal clearance. Initial management of a first episode of cancer-associated VTE Choice of anticoagulant ► LMWH is the recommended anticoagulant for the initial therapy of VTE in most patients with cancer ► UFH can be used in those with severe renal impairment (creatinine clearance [CrCl],30 mL/min) given its shorter half-life, reversibility with protamine sulfate, and dependence on hepatic clearance. ► Fondaparinux is a reasonable choice in patients with a history of HIT. Initial management of a first episode of cancer-associated VTE Use of thrombolysis in cancer-associated VTE ► the safety, cost-effectiveness, and longterm benefit of thrombolysis remain uncertain ► it is prudent to review each patient carefully and exclude patients with central nervous system lesions or other risk factors for bleeding Long-term management of a first episode of cancer-associated VTE Choice of anticoagulant ► LMWH is recommended for both initial and long-term anticoagulation in cancerassociated thrombosis by major consensus guidelines ► If LMWH is unavailable, the American Society of Clinical Oncology (ASCO) 2013 VTE Prevention and Treatment Guideline recommends the use of VKA with a target INR of 2 to 3 as an acceptable alternative Long-term management of a first episode of cancer-associated VTE Duration of anticoagulation and anticoagulant options for extended therapy ► The decision regarding the continuation of anticoagulation beyond the first 3 to 6 months is largely based on weighing the risk for recurrent thrombosis against the risk of major bleeding. ► it has been generally accepted that continuing anticoagulation is warranted in patients with ongoing risk factors such as metastatic or progressive disease and ongoing chemotherapy ► The choice of anticoagulant for extended anticoagulant therapy (beyond 6 months) also has not been investigated ► As with duration of therapy, the anticoagulant of choice needs to be discussed with each patient and individualized Long-term management of a first episode of cancer-associated VTE Anticoagulation in patients with renal impairment ► Renal insufficiency is associated with some cancers (e.g.multiple myeloma), nephrotoxic agents (e.g.cisplatin chemotherapy),and renovascular disease in the elderly. ► LMWHs accumulate when the creatinine clearance deteriorates, and dosage adjustments for renal failure are available for each approved LMWH. ► With severe renal insufficiency (creatinine clearance o 30 ml/min),unfractionated heparin should be substituted for LMWH, and doses adjusted based on the activated partial thromboplastin time. Long-term management of a first episode of cancer-associated VTE Inferior vena cava (IVC) filters IVC filters should be restricted to patients with acute VTE and contraindications to anticoagulation. ► Rates of recurrent VTE up to 32% have been reported in patients with cancer treated with IVC filters, and fatal PE after filter insertion has been well documented. ► Insertion problems occur in 4% to 11% of patients ► Long-term adverse effects such as thrombosis of the IVC or lower extremity veins occur in 4% to 32%. ► absence of data to support their efficacy ► Their use in patients with recurrent thrombotic events despite standard anticoagulant therapy goes against biological rationale ► The use of IVC filters may provide a sense of false security regarding the risk for recurrent PE, causing delays or discontinuation of anticoagulant therapy. If retrievable filters are placed, efforts should be made to remove the device and reinitiate anticoagulation as soon as the high-risk period for bleeding has passed Treatment of recurrent VTE during anticoagulant therapy Treatment of incidental VTE ► incidental VTE rates of up to 6% ► represents a significant proportion of thrombotic complications in patients with cancer, comprising up to 60% in large series ► the occurrence of incidental VTE can have a negative impact on both patient quality of life and clinical outcome ► Whether anticoagulation is indicated or beneficial in patients with incidental VTE remains controversial ► Nonetheless, based on published literature to date, it is recommended that patients with incidental DVT and PE receive therapeutic anticoagulation if there are no contraindications Treatment of cancer-associated thrombosis in patients with a high risk of bleeding ► Bleeding is frequently associated with anticoagulant use in patients with cancer : 12.4%, with one third of the bleeding events occurring during the initial phase of anticoagulation ► Features specific to oncology patients that contribute to bleeding include: The extent, location, and histologic features of the cancer need for invasive diagnostic or treatment procedures the development of thrombocytopenia from chemotherapy or from the underlying malignancy. Other comorbidities : renal impairment and coagulopathy from liver dysfunction, disseminated intravascular coagulopathy, or sepsis - ► all patients require an individualized assessment of their bleeding risk before the initiation of anticoagulation ► Current and potential bleeding sources should be identified and managed, and the risk of serious bleeding should be weighed against the severity of the thrombotic event and risk for recurrent VTE NCCN Practice Guidelines in VTE Disease Relative Contraindications to Prophylactic or Therapeutic Anticoagulation ► ► ► ► ► ► ► ► ► Recent CNS bleed, intracranial or spinal lesion at high risk for bleeding Active bleeding (major): more than 2 units transfused in 24 hours Chronic, clinically significant measurable bleeding > 48 hours Thrombocytopenia (platelets < 50,000/mcL) Severe platelet dysfunction (uremia, medications, dysplastic hematopoiesis) Recent major operation at high risk for bleeding Underlying coagulopathy Clotting factor abnormalities - Elevated PT or aPTT (excluding lupus inhibitors) - Spinal anesthesia/lumbar puncture High risk for falls http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf Treatment of cancer-associated thrombosis in patients with a high risk of bleeding ► In patients with minor bleeding anticoagulation may be continued as long as close follow-up is available. ► In patients with absolute contraindications to anticoagulation: - anticoagulants should be withheld. - follow-up imaging should be performed to assess for thrombus progression - IVC filter insertion can be considered. Treatment of cancer-associated thrombosis in patients with a high risk of bleeding ► If severe cancer- or chemotherapy-induced thrombocytopenia is present: (<1 month) (>1 month) Treatment of cancer-associated thrombosis in patients with a high risk of bleeding ► Management of VTE in patients with intracranial malignancies ► No randomized controlled data exist for management of patients with primary or metastatic intracranial tumors and VTE ► small retrospective studies indicate that anticoagulation can be safely used. ► The ASCO 2013 VTE Guideline recommends treating patients with intracranial malignancies with standard anticoagulation Treatment of catheter-related thrombosis ► To date, published data and clinical experience suggest that catheter-related thrombosis is associated with a low risk for thrombosis recurrence and post-thrombotic syndrome ► conservative treatment is recommended ► A sensible approach is to remove the catheter only if : - (1) central venous access is no longer required; - (2) the device is nonfunctional or defective; - or (3) line-related sepsis is suspected or documented therapeutic anticoagulation should be given using either LMWH alone or LMWH followed by warfarin therapy. A short period of anticoagulation (3-5 days of LMWH) may even salvage some thrombosed catheters and obviate the need to remove and replace the line. Anticoagulation is recommended for a minimum of 3 months and while the catheter remains in place. Use of NOACs in cancer-associated thrombosis ► No studies have specifically addressed the treatment of cancerassociated VTE using these direct inhibitors ► interactions do exist with some chemotherapeutic agents ► gastrointestinal tract problems in patients with cancer can potentially alter drug delivery and absorption ► the current ASCO Guideline does not recommend the use of these new agents CONCLUSIONI Lyman et al, JCO 2013 DVT, PE Diagnosis and Treatment http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf Thrombosis in Malignancy 7TH ACCP Consensus Conference Recommendations Initial Phase Chronic Phase 5-7 days Dalteparin 200/kg q24h (GRADE 1A) Continue anticoagulation (warfarin or LMWH) long-term or until malignancy resolves (GRADE 1C) 5 - 7 days 3 - 6 mos 6 mos - indefinite Subacute Phase 3 - 6 months PRESS RELEASE: May 2, 2007 Dalteparin 150 units/kg q24h FDA Approves Dalteparin as First LowLow-Molecular Weight Heparin for Extended (GRADE 1A) Treatment to Reduce the Recurrence of Blood Clots in Patients with Cancer Buller HR, et al. Chest 2004; 126 (suppl 3): 401s401s-428s NCCN Practice Guidelines— Guidelines—Venous Thromboembolic Disease Therapeutic Anticoagulation Treatment for DVT, PE, and CatheterCatheter-Associated Thrombosis Immediate ► LMWH - Dalteparin (200 units/kg subcutaneous daily) - Enoxaparin (1 mg/kg subcutaneous every 12 hrs) -Tinzaparin (175 units/kg subcutaneous daily) ► Pentasaccharide - Fondaparinux (5.0 mg [<50 kg]; 7.5 mg [50[50-100 lg]; 10 mg [>100 kg] subcutaneous daily ► Unfractionated heparin (IV) (80 units/kg load, then 18 units kg/hour, target aPTT to 2.02.0-2.9 x control) http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf NCCN Practice Guidelines— Guidelines—Venous Thromboembolic Disease Therapeutic Anticoagulation Treatment for DVT, PE, and CatheterCatheter-Associated Thrombosis Long Term ► ► LMWH is preferred as monotherapy without warfarin in patients with proximal DVT or PE and prevention of recurrent VTE in patients with advanced or metastatic cancer Warfarin (2.5(2.5-5 mg every day initially, subsequent dosing based on INR value; target INR 2.02.0-3.0) Duration of Long Term Therapy ► ► ► Minimum time of 33-6 mo for DVT and 6 6--12 mo for PE Consider indefinite anticoaugulation if active cancer or persistent risk factors For catheter associated thrombosis, anticoagulate as long as catheter is in place and for 11-3 mo after catheter removal http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf ► What is the best treatment for patients with cancer with established VTE to prevent recurrent VTE ? ● LMWH is the preferred approach for the initial 55-10 days. LMWH, given for at least 6 months, is the preferred for longlong-term anticoagulant therapy. After 6 months, anticoagulation therapy should be considered for select patients. For CNS malignancies, elderly patients anticoagulation is recommended with careful monitoring and dose adjustment. ● ● ● Lyman GH et al. J Clin Oncol (25) 2007; 34: 54905490-5505. ► Should patients with cancer receive anticoagulants in the absence of established VTE to improve survival? ● “Anticoagulants are not recommended to improve survival in patients with cancer without VTE.” Lyman GH et al. J Clin Oncol (25) 2007; 34: 54905490-5505. CLOT: Landmark Cancer/VTE Trial Dalteparin Dalteparin CANCER PATIENTS WITH Randomization ACUTE DVT or PE [N = 677] Dalteparin Oral Anticoagulant ► Primary Endpoints: Recurrent VTE and Bleeding ► Secondary Endpoint: Endpoint: Survival Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146 Landmark CLOT Cancer Trial Probability of Recurrent VTE, % Reduction in Recurrent VTE 25 Recurrent VTE Risk reduction = 52% p-value = 0.0017 20 OAC 15 10 Dalteparin 5 0 0 Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146 30 60 90 120 150 Days Post Randomization 180 210 Bleeding Events in CLOT Dalteparin OAC N=338 N=335 Major bleed 19 ( 5.6%) 12 ( 3.6%) 0.27 Any bleed 46 (13.6%) 62 (18.5%) 0.093 * Fisher’s exact test Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146 P-value* Treatment and 2° 2° Prevention of VTE in Cancer – Bottom Line New Development ► New standard of care is LMWH at therapeutic doses for a minimum of 33-6 months (Grade 1A recommendation— recommendation —ACCP) ► NOTE: Dalteparin is only LMWH approved (May, NOTE: 2007) for both the treatment and secondary prevention of VTE in cancer ► Oral anticoagulant therapy to follow for as long as cancer is active (Grade 1C recommendation— recommendation—ACCP) Buller et.al. Chest Suppl 2004;126:401S2004;126:401S-428S CLOT 1212-month Mortality All Patients Probability of Survival, % 100 90 80 70 Dalteparin 60 OAC 50 40 30 20 10 0 HR 0.94 PP-value = 0.40 0 30 60 90 120 180 240 300 Days Post Randomization Lee A, et al. ASCO. 2003 360 Anti-Tumor Effects of LMWH AntiCLOT 1212-month Mortality Patients Without Metastases (N=150) Probability of Survival, % 100 Dalteparin 90 80 70 OAC 60 50 40 30 20 10 HR = 0.50 PP-value = 0.03 0 0 30 60 90 120 150 180 240 300 Days Post Randomization Lee A, et al. ASCO. 2003 360 LMWH for Small Cell Lung Cancer Turkish Study ► 84 patients randomized: CEV +/+/- LMWH (18 weeks) ► Patients balanced for age, gender, stage, smoking history, ECOG performance status Chemotherapy plus Dalteparin Chemo alone P-value 1-y overall survival, % 51.3 29.5 0.01 2-y overall survival, % 17.2 0.0 0.01 Median survival, m 13.0 8.0 0.01 CEV = cyclophosphamide, epirubicin, vincristine; LMWH = Dalteparin, 5000 units daily Altinbas et al. J Thromb Haemost 2004;2:1266. Rate of Appropriate Prophylaxis, % VTE Prophylaxis Is Underused in Patients With Cancer 100 90 Cancer: FRONTLINE Survey1— 3891 Clinician Respondents Major Surgery2 89 80 70 60 Cancer: Surgical Major Abdominothoracic Surgery (Elderly)3 52 50 38 40 30 Medical Inpatients4 Confirmed DVT (Inpatients)5 42 33 Cancer: Medical 20 10 5 0 FRONTLINE FRONTLINE: Surgical Medical 1. Kakkar AK et al. Oncologist. 2003;8:381-388 2. Stratton MA et al. Arch Intern Med. 2000;160:334-340 3. Bratzler DW et al. Arch Intern Med. 1998;158:1909-1912 Stratton Bratzler Rahim DVT FREE 4. Rahim SA et al. Thromb Res. 2003;111:215-219 5. Goldhaber SZ et al. Am J Cardiol. 2004;93:259-262 Clotting, Cancer, and Clinical Strategies Venous Thromboembolism (VTE) Prophylaxis in the Cancer Patient and Beyond Guidelines and Implications for Clinical Practice John Fanikos, RPh, MBA Assistant Director of Pharmacy Brigham and Women’s Hospital Assistant Clinical Professor of Pharmacy Northeastern University Massachusetts College of Pharmacy Boston, MA Outline of Presentation ► Guidelines for VTE prevention ► Performance to date ► Opportunities for improvement ► Guidelines for VTE Treatment ► Performance to date • www.nccn.org • NCCN Clinical Practice Guidelines in Oncology™ • “…The panel of experts includes medical and surgical oncologists, hematologists, cardiologists, internists, radiologists. And a pharmacist.” • www.asco.org •Recommendations for VTE Prophylaxis & Treatment in Patients with Cancer 2004 ACCP Recommendations Cancer patients undergoing surgical procedures receive prophylaxis that is appropriate for their current risk state (Grade 1A) ● General, Gynecologic, Urologic Surgery • Low Dose Unfractionated Heparin 5,000 units TID • LMWH > 3,400 units Daily – Dalteparin 5,000 units – Enoxaparin 40 mg – Tinzaparin 4,500 units • GCS and/or IPC Cancer patients with an acute medical illness receive prophylaxis that is appropriate for their current risk state (Grade 1A) • Low Dose Unfractionated Heparin • LMWH Contraindication to anticoagulant prophylaxis (Grade 1C+) • GCS or IPC 1A is the highest possible grade Indicates that benefits outweigh risks, burdens, and costs, with consistent RCT level of evidence Geerts WH et al. Chest. 2004;126(suppl):338S-400S NCCN Practice Guidelines in VTE Disease At Risk Population ► ► ► ► ► ► ► ► ► ► ► ► ► ► Adult patient Diagnosis or clinical suspicion of cancer Inpatient Relative contracontraindication to anticoagulation treatment RISK FACTOR ASSESSMENT Age Prior VTE Familial thrombophilia Active cancer Trauma Major surgical procedures Acute or chronic medical illness requiring hospitalization or prolonged bed rest Central venous catheter/IV catheter Congestive heart failure Pregnancy Regional bulky lymphadenopathy with extrinsic vascular compression http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf Initial Prophylaxis Continue Prophylaxis After Modifiable risk factors: Lifestyle, Discharge ? smoking, tobacco, obesity, Prophylactic anticoagulation therapy (category 1) + sequential compression device (SCD) Mechanical prophylaxis (options) - SCD - Graduated compression stockings activity level/exercise ► ► ► AGENTS ASSOCIATED WITH INCREASED RISK Chemotherapy Exogenous estrogen compounds - HRT - Oral contraceptives - Tamoxifen/Raloxifene - Diethystilbestrol Thalidomide/lenalidomide NCCN Practice Guidelines in VTE Disease Inpatient Prophylactic Anticoagulation Therapy ► LMWH - Dalteparin 5,000 units subcutaneous daily - Enoxaparin 40 mg subcutaneous daily - Tinzaparin 4,500 units (fixed dose) subcutaneous daily or 75 units/kg subcutaneous daily ► Pentasaccharide - Fondaparinux 2.5 mg subcutaneous daily ► Unfractionated heparin 5,000 units subcutaneous 3 times daily http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf ► Should hospitalized patients with cancer receive anticoagulation for VTE prophylaxis ? ● “Hospitalized patients with cancer should be considered candidates for VTE prophylaxis in the absence of bleeding or other contraindications to anticoagulation” Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505. ► Should ambulatory patients with cancer receive anticoagulation for VTE prophylaxis during systemic chemotherapy? ● “Routine prophylaxis is not recommended.” ● “Patients receiving thalidomide or lenalidomide with chemotherapy or dexamethasone are at high risk for thrombosis and warrant prophylaxis.” Lyman GH et al. J Clin Oncol (25) 2007; 34: 54905490-5505. ► Should hospitalized patients with cancer undergoing surgery receive perioperative VTE prophylaxis ? ● All patients should be considered for thromboprophylaxis. Procedures greater than 30 minutes should receive pharmacologic prophylaxis. Mechanical methods should not be used as monotherapy. Prophylaxis should continue for at least 77-10 days post--op. Prolonged prophylaxis may be considered post for cancer with high risk features. ● ● ● Lyman GH et al. J Clin Oncol (25) 2007; 34: 54905490-5505. Compliance With ACCP VTE Prophylaxis Guidelines Is Poor Compliance With VTE Prophylaxis Guidelines in Hospitals by Patient Group 62,012 70,000 At risk for DVT/PE 35,124 Received compliant care Number of patients 10,000 9175 5,000 2324 1388 0 52.4% Orthopedic Surgery 15.3% 12.7% At-risk Medical Conditions General Surgery 9.9% Urologic Surgery 6.7% Gynecologic Surgery Data collected January 2001 to March 2005; 123,340 hospital admissions. Compliance assessment was based on the 6th American College of Chest Physicians (ACCP) guidelines. HT Yu et al. Am J Health-Syst Pharm 2007; 64:69-76 Reasons for Inadequate Duration of VTE Prophylaxis At At--Risk Medical (n=5,994) Abdominal Surgery (n=3,240) Urologic surgery (n=158) Gynecologic surgery (n=163) Neurosurgery (n=250) Started Late Started late & Ended Early Ended Early 1,347 (22.5) 2,961 (49.4) 1,686 (28.1) 824 (25.4) 1,764 (54.4) 652 (20.1) 18 (11.4) 73 (46.2) 67 (42.4) 13 (8.0) 43 (26.4) 107 (65.6) 66 (26.4) 125 (50.0) 59 (23.6) HT Yu et al. Am J HealthHealth-Syst Pharm 2007; 64:69 64:69--76 Predictors of the Use of Thromboprophylaxis Effect Odds Ratio (95% CI) Malignancy 0.40 Others 0.58 Infection 0.83 Bleeding Risk 0.91 Gender Hospital Size 0.92 0.93 Age 1.00 LOS 1.05 Cardiovascular Disease 1.06 Internal Medicine 1.33 Respiratory 1.35 AMC Duration of Immobility VTE Risk Factors 1.46 1.60 1.78 0.0 0.5 1.0 Kahn SR et Al. Thromb Res 2007; 119:145119:145-155 1.5 2.0 2.5 Odds Ratio 3.0 3.5 4.0 Computer Reminder System ► Computer program linked to patient database to identify consecutive hospitalized patients at risk for VTE ► Patients randomized to intervention group or control group ► In the intervention group the physicians were alerted to the VTE risk and offered the option to order VTE prophylaxis ► Point scale for VTE risk ● Major risk: risk: Cancer Cancer,, prior VTE, hypercoagulability (3 points) ● Intermediate risk: risk: Major surgery (2 points) ● Minor risk: risk: Advanced age, obesity, bedrest, HRT, use of oral contraceptives (1 point) ► VTE prophylaxis (graduated (graduated elastic stockings stockings,, IPC, UFH, LMWH, warfarin) Kucher N, et al. N Engl J Med. 2005;352:9692005;352:969-77 MD Computer Alert Electronic Alerts to Prevent VTE Freedom from DVT or PE (%) 100 98 96 Intervention group 94 92 Control group P<0.001 90 88 0 Number at risk Intervention group Control group 30 1,255 1,251 Kucher N, et al. N Engl J Med. 2005;352:9692005;352:969-77 60 Time (days) 977 876 90 900 893 853 839 Mechanical Thromboprophylaxis In Critically Ill Patients: Review And MetaMeta-analysis RESULTS: 21 relevant studies (5 randomized controlled trials, 13 RESULTS: observational studies, and 3 surveys) were found. A total of 811 patients were randomized in the 5 randomized controlled trials; 3421 patients participated in the observational studies. Trauma patients only were enrolled in 4 randomized controlled trials and 4 observational studies. MetaMeta-analysis of 2 randomized controlled trials with similar populations and outcomes revealed that use of compression and pneumatic devices did not reduce the incidence of venous thromboembolism. The pooled risk ratio was 2.37 (CI,95% 0.57 - 9.90). A range of methodological issues, including bias and confounding variables, make meaningful interpretation of the observational studies difficult. CONCLUSIONS: The role of mechanical approaches to CONCLUSIONS: thromboprophylaxis for intensive care patients remains uncertain Limbus A et al. Am J Crit Care, 2006;15:4022006;15:402-10 Fatal Pulmonary Embolism During Anticoagulant Prophylaxis Study, Prophylaxis Year (Reference) Placebo n/n n/n RR Fixed RR Fixed (95% CI) (95% CI) Dahan et al, 1986 (41) 1/132 3/131 0.33 (0.03 to 3.14) Garlund at al, 1996 (35) 3/5776 12/5917 0.26 (0.07 to 0.91) Leizorovic et al, 2004 (23) 0/1829 2/1807 0.20 (0.01 to 4.11) 10/1230 17/1244 0.59 (0.27 to 1.29) 0/321 5/323 0.09 (0.01 to 1.65) Mahe et al, 2005 (22) Cohen at, 2006 (42) Total (95% CI) Total events 0.38 (0.21 to 0.69) 14 39 0.001 0.01 0.1 1.0 10 100 1000 Favors Treatment Dentali, F. et. al. Ann Intern Med 2007;146:2782007;146:278-288 Favors Placebo Unfractionated Heparin Prophylaxis: BID vs TID— TID—What Works, What Doesn’t? Meta-analysis: 12 MetaRCTs ► DVT, PE, all VTE events, Bleeding ► Proximal ● ● DVT plus PE BID VTE event rate: 2.34 events per 1,000 patient days TID event rate: 0.86 events per 1,000 patient days P=0.05 ► NNT ● ● 676 hospital prophylaxis days with UFH TID to prevent 1 major bleed with 1,649 hospital prophylaxis days of TID dosing King CS et al. CHEST 2007;131:5072007;131:507-516 Heparin, Low Molecular Weight Heparin Prophylaxis ►Meta Meta--analysis ►36 randomized controlled trials ►23,000 hospitalized medical patients ►UFH 5,000 units TID is more effective in preventing DVT than UFH BID ►Low molecular weight heparin is 33% more effective than unfractionated heparin in preventing DVT ● RR for DVT 0.68 (p=0.004) LMWH vs UFH DVT Risk Study Reduction (95% CI) Weight % Harenberg et al, 1990 0.70 (0.16-3.03) 3.4 Turpie et al, 1992 0.29 (0.10-0.81) 11.4 Dumas et al, 1994 0.74 (0.38-1.43) 14.4 Bergmann & Neuhart 0.94 (0.39-2.26) 8.1 Harenberg et al, 1996 2.89 (0.30-27.71) 0.8 Lechler et al, 1996 0.25 (0.03-2.23) 3.3 Hillbom et al, 2002 0.55 (0.31-0.98) 20.5 Kleber, et al 2003 0.77 (0.43-1.38) 19.4 Diener et al, 2006 0.76 (0.42-1.38) 18.9 Overall (95% CI) 0.68 (0.52-0.88) et al, 1996 Wein L et al. Arch Intern Med. 2007;167:1476 2007;167:1476--86. 0.1 1.0 10 Risk Ratio LMWH Better LMWH Worse BWH/DFCI Partners Cancer Care Experience Reasons for Non-Compliance 100 90 80 70 60 50 40 30 20 10 0 95 80 82 68 70 60 29 Percent Percent Compliance with UFH TID 50 40 28 30 20 <3 doses Day 1 <3 Doses Day 2+ • Consecutive 4 doses 10 4 0 Off Floor Refused patients, < 60 days • 2 Nursing units • LOS ranged from 3 days to 31 days • Number of days where doses were omitted ranged from 1 to 6 days Unknown VTE Incidence: More Common in the Outpatient Setting ► Medical records of residents (n=477,800) ► 587 VTE events (104 per 100,000 population) ► 30 Day recurrence 4.8 % VTE Event Location 25% 75% Inpatient Outpatient Spencer FA, et al. Jour Gen Int Med 2006; 21 (7):722-777 52% 51% 51% 50% 50% 49% 49% 48% Patients receiving prophylaxis during high risk periods Prophylaxis None Antithrombotic Therapy Practices in U.S. Hospitals ►Survey ►n=939 DVT or PE 60% Percent (%) of 38 U.S. Hospitals 70% 40% patients reached INR >2 for 2 consecutive days 26.6% 30% 20% 10% ►50% 50.7% 50% 14.8% 7.9% 0% Acute (n=72) Bridge (n=241) Long Term (n=460) Other (n=134) Therapy 14 12.7 Therapy n (%) LMWH 527 (56.1%) UFH 562 (59.8%) UFH SC 78 (8.3%) DTI 6 (0.6%) LO S, Days 12 10 8 8.1 6.1 6 4 4 2 0 Acute (n=72) Tapson V et al. Arch Intern Med 2005 Bridge (n=241) Long term (n=460) Other (n=134) Self--Managed Long Term LMWH Therapy Self 2212 patients with proximal vein thrombosis assessed for eligibility 1475 excluded for anticoagulant violations or inability to give written consent 737 Randomized 369 assigned to LMWH 369 assigned to usual care with heparin & warfarin 3 lost to follow=up 3 lost to follow-up 1 withdrew consent 5 withdrew consent 369 included in Analysis Hull R. Am Jour Med 2007; 120:72120:72-82 369 included in Analysis Self--Managed Long Term LMWH Therapy Self Tinzaparin Usual Care Absolute Difference (n=369) (n=368) (95% CI) New VTE at 3 Mos 18 (4.9) 21 (5.7) -0.8 ((--4.24.2-2.4) NS New VTE at 12 Mos 33 (8.9) 36 (9.8) -0.8 ((--5.55.5-3.5) NS All Bleeding 48 (13.0) 73 (19.8) -6.8 ((--12.4 12.4---1.5) p=.011 Major Bleeding 12 (3.3) 17 (4.6) -1.4 ((-4.34.3-1.4) NS Minor Bleeding 36 (9.8) 56 (15.2) -5.5 ((--10.4 10.4---0.6) p=.022 Stratified BleedingBleedingHigh Risk 31/144 (21.5) 39/146 (26.7) -5.2 ((--15% 15%--4.6%) NS Stratified BleedingBleeding-Low Risk 17/225 (7.6) 34/222 (15.3) -7.8 ((--13.6 13.6---1.9%) p=.01 Thrombocytopenia (<150) 21 (5.7) 9 (2.4) 1.6 ((-3.63.6-0.3) NS Bone Fracture 4 (1.1) 7 (1.9) -0.8 ((--0.90.9-2.6) NS Outcomes Hull R. Am Jour Med 2007; 120:72120:72-82 p-value LMWHs and Bleeding in Patients with Renal Dysfunction Dosage adjustments for renal dysfunction Lim W et al. Ann Intern Med 2006; 144:673144:673-84 Conclusions Examine your current practices of VTE prophylaxis and treatment ► Review available guidelines as a benchmark ► Consider the use of a pharmacologic or mechanical intervention ► Evaluate use of Reminder or Risk Scoring Systems ► Utilize the regimen providing the best efficacy in reducing events and offering best compliance ► Follow Follow--up with patients to monitor and avoid adverse events and to ensure optimal outcomes Dosaggio dei D-Dimeri • Prodotti di degradazione della fibrina stabilizzata • Elevati livelli plasmatici di DD, oltre che per la presenza di trombi (sia venosi che arteriosi), possono essere frequentemente causati da molte altre condizioni come ematomi sottocutanei, ferite chirurgiche, necrosi cutanea, ustioni estese, ascite, versamenti pleurici. • Un aumento dei DD si osserva con estrema frequenza in una grande varietà di situazioni cliniche (CID, neoplasie, angina instabile, infarto miocardico, eclampsia, infezioni, malattie epatiche e renali, chirurgia). Linee guida SISET-SIAPAV-SIDV 2000 – CIF 2000-2003 Trousseau’s Observations (continued) “There appears in the cachexiae…a particular condition of the blood that predisposes it to spontaneous coagulation.” Lectures in Clinical Medicine, 1865 Interface of Biology and Cancer Tumor cells Angiogenesis, Basement matrix degradation. Fibrinolytic activities: t-PA, u-PA, u-PAR, PAI-1, PAI-2 Procoagulant Activities IL-1, TNF-α, α, VEGF PMN leukocyte Activation of coagulation FIBRIN Platelets Monocyte Endothelial cells Falanga and Rickles, New Oncology:Thrombosis, Oncology:Thrombosis, 2005; Hematology, 2007 VTE is frequent and serius Patient Related • • • • Increased Age Obesity Co-morbidities Performance Status Treatment Related • Chemotherapy, antiangiogenesis agents, hormonal therapy • Radiation therapy • Surgery • Indwelling venous access Risk Factors Cancer Related • • • • Primary Site Stage Histology Time since diagnosis Biomarkers • Platelets > 350 x 109/L • Leukocyte count > 11x 109/L • Hgb < 10 g/dL Cancer and Thrombosis