the Cancer Patient Marliese Alexander Pharmacy Department, Peter - - PowerPoint PPT Presentation
Cancer Pharmacists Group Advanced Practice Seminar on November 9th Melbourne Medicine, Nursing and Health Sciences Management of Thrombosis in the Cancer Patient Marliese Alexander Pharmacy Department, Peter MacCallum Cancer Centre School of
Medicine, Nursing and Health Sciences
Marliese Alexander Pharmacy Department, Peter MacCallum Cancer Centre School of Public Health and Preventative Medicine, Monash University
Cancer Pharmacists Group Advanced Practice Seminar on November 9th Melbourne
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Management of Thrombosis in the Cancer Patient
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Access Economics 2008
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13.9% 10.6% 8.2% 11.0% 19.2% 15.8% 1.4%
0.0% 5.0% 10.0% 15.0% 20.0% 25.0% Lung Colorectal Bladder Ovarian Pancreatic Stomach Control
Ambulant Cancer Patients Receiving Chemotherapy
Khorana AA, Cancer 2013;119:648-655
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Khorana A et al. Proc ASH 2011;Abstract 674.
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Palumbo Leukaemia 2008;22: 414-423
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Management of Thrombosis in the Cancer Patient
Alexander et al, Lung Cancer 84(3): 275-280
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Khorana predictive model for chemotherapy-associated TE(1) Risk Score Validation Studies Prediction Rate (4) Site of cancer PROTECHT 2009 (n=381) CATS 2010 (n=819) SAVE-ONCO 2012 (n=1583) 5/15 (33%) 16/61 (26%) 15/54 (28%) Very high risk (stomach, pancreas) 2 High risk (lung, lymphoma, gynaecologic, bladder, testicular) 1 Platelet count 350 x 109/L or more 1 Haemoglobin level less than 100 g/L or use of red cell growth factors 1 Leukocyte count more than 11 x 109/L 1 BMI 35 kg/m2 or more 1 Vienna predictive model for chemotherapy-associated TE(2) As Khorana plus: Risk Score Validation Studies Prediction Rate(4) Addition of high-grade glioma to very high risk cancers Addition of myeloma & kidney carcinoma to high risk cancers sP-selectin 53.1ng/mL D-Dimer 1.44μg/mL 2 1 1 1 CATS 2010 (n=819) 33/61 (54%) ASCO modified Khorana score (3) As Khorana plus: Risk Score Validation Studies Prediction Rate Addition of primary brain carcinoma to very high risk cancers Addition of renal carcinoma to high risk cancers 2 1 NA NA
TE (n=24) No (%) No TE (n=198) No (%) p value* Newly diagnosed 21 (88) 150 (76) 0.06 Advanced disease 21 (88) 149 (75) 0.25 Metastatic disease 17 (71) 91 (46) 0.01 Brain metastasis 10 (42) 42 (21) 0.06 Secondary malignancy 9 (38) 31 (16) 0.01 Prior history of TE 3 (13) 8 (4) 0.17 Age>65 13 (54) 122 (62) 0.57 ECOG PS >2 2 (8) 12 (6) 0.65 Charlson Index 5 18 (75) 103 (52) 0.03
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ECOG PS: Eastern Cooperative Oncology Group Performance Status. Charlson Index (Charlson et al 1987). *Log-rank test.
Crude HR Adjusted HR for age and sex Adjusted HR for potential confounding variables* CHT 5.69 (2.18-14.81) 5.57 (2.12-14.61) 4.97 (1.95-12.71) RT 5.19 (2.04-13.21) 5.26 (2.09-13.22) 4.97 (1.87-13.23) Surgery 1.66 (0.53-5.21) 1.51 (0.45-5.15) 0.96 (0.25-3.70) Biologic 1.66 (0.53-5.21) 1.51 (0.45-5.15) 1.01 (0.27-3.78)
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Time-varying cox proportional hazards model for hazard ratios, HR, and 95% confidence intervals, CI, . *Adjusted for metastatic disease, brain metastasis, secondary malignancy, new diagnosis, Charlson index 5, age and sex.
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Management of Thrombosis in the Cancer Patient
based chemo, n=932
last dose – 18.1%
Moore et al. JCO 2011
88% within 100d starting
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Management of Thrombosis in the Cancer Patient
based chemo in NSCLC, n=784
12.9 months)
Mellema et al. Lung Cancer 2014; 86:73-77
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Hurwitz et al. JCO 2012
data: n=6055 (10 RCT)
bevacizumab: 10.9% vs. 9.8%, ns
<1% severe bleeding event
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Huber et al. Arch Surg. 1992;127:310-3.
Days post surgery
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RISTOS - Agnelli G et al. Ann Surg 2006;243:89-95.
Days post surgery
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Alok A. Khorana, Michael B. Streiff, Dominique Farge, Mario Mandala, Philippe Debourdeau, Francis Cajfinger, Michel Marty, Anna Falanga, and Gary H. Lyman JCO 2009
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Cohen AT et al. Lancet 2008;371:387-94 Kakkar et al. Ann Surg 2010; 251(2):330-338
First patient enrolled August 2, 2006
42% 64% 70% 0% 20% 40% 60% 80% Australia Columbia Germany % 'high risk' medical patients receiving appropriate TP
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– Among 1046 patients undergoing high risk cancer surgery, <50% utilisation of extended TP
– Among 252,950 cancer surgeries 46% received TP
– Among 128 colorectal surgeons, 54% prescribe TP after hospital discharge. Lack of data, absence of recommendations and logistical issues prevent use in the neoadjuvant and post-discharge settings.
– Among 157 lung cancer clinicians 91% reported access to institutional guidelines yet
care settings.
– Among 190 cancer patients, 53% were unaware of the risk of TE yet 86% were willing to receive oral and 46% parenteral prophylaxis
Alexander et al. JSCC 2014 Lee et al. Ann Surg 2011 Kalka et al. Thromb Haemost 2009 Smart et al. ANZ Surg 2013 Sousou et al. Cancer Invest 2010
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Study n Population Design RCT – placebo TE rate Bleeding rate FRAGMATIC 2220 Lung cancer Dalteparin 6 mnth 7.8 vs 4.1% 0 vs 1% PROTECHT 769 381 279 Adv cancer GI cancer Lung cancer Nadroparin 4 mth 3.9 vs 2.0% 2.7 vs 1.5% 6.2 vs 4.0% 0 vs 0.7% 0 vs 0.5% 0 vs 1% TOPIC-2 532 Lung cancer Nadroparin 4 mth 8.3 vs 4.5% 2.2 vs 3.7% FRAGEM 123 APC Dalteparin 12w 31 vs 12% 3 vs 2.8% FAMOUS 385 Adv cancer Dalteparin 12mth 3.3 vs 2.4% 4.7 vs 2.7% CONKO 312 APC Enoxaparin: 1mg/kg BD 12 w → 40mg D 14.5 vs 5% 9.9 vs 1.3% 9.9 vs 6.3% 3.9 vs 2.4% PRODIGE 186 Malignant glioma Dalteparin 6mth (started 4w post-op) 15 vs 9% 1.2 vs 5.9% SAVE-ONCO 3212 Local and adv cancer Semuloparin 3.4 vs 1.2% 1.2 vs 1.1%
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Prevention Symptomatic VTE
Ben-Aharon et al Acta Oncologica; 2014; 53: 1230-1237
SCLC Breast Ca lung, GI, pancreatic, colorectal, bladder, ovarian
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Prevention Symptomatic DVT
Ben-Aharon et al Acta Oncologica; 2014; 53: 1230-1237
Breast Ca breast, lung, GI, pancreatic, liver, genitourinary, ovarian, uterus lung, GI, pancreatic, colorectal, bladder, ovarian Lung Ca
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Prevention Pulmonary Embolism
Ben-Aharon et al Acta Oncologica; 2014; 53: 1230-1237
breast, lung, GI, pancreatic, liver, genitourinary, ovarian, uterus Breast Lung lung, GI, pancreatic, colorectal, bladder, ovarian prostate, lung, pancreatic GI, pancreatic, breast, ovarian, head and neck
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Macbeth Journal Thoracic Oncology 2013;8, Supplement 2.
**Not in previous meta-analysis as full results yet to be published
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newly diagnosed or at disease progression
cumulative probability 7.9% after 1 year
3.3) with elevated (>611 nM)
after 6months 11% vs 4% with elevated vs. normal thrombin
Ay et al. JCO 2011
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Bottaro et al. Thromb Haemost. 2008 Jun;99(6):1104-11
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Palumbo Leukaemia 2008;22: 414-423
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Management of Thrombosis in the Cancer Patient
Heparins
LMWH – Xa UFH – Xa and IIa
Vitamin K Dependent Clotting Factor Inhibitors
Warfarin
Direct Xa Inhibitors
Rivaroxaban Apixaban Endoxaban Betrixaban
Direct Thrombin
Inhibitors
Dabigatran Ximelagatran
Thrombin
Inhibitors (via AT)
Fondaparinux Idraparinux Idrabiotaparinux
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Dabigatran Edoxaban Semuloparin Betrixaban Rivaroxaban Apixaban Enoxaparin Idrabiotaparinux Fondaparinux
LMWH (at the moment...)
Warfarin
Reversibility
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Erkens and Prins. Cochrane Sys Rev; 2010
Mortality Favors LMWH in pts with malignancy
Effect Size 6 446 0.53 [0.33, 0.85]
Mortality Favors LMWH in pts without malignancy
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Erkens and Prins. Cochrane Sys Rev; 2010
Incidence recurrent VTE favors LMWH
Effect Size 15 6060 0.68 [0.48, 0.97]
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Mismetti P et al. Br J Surg. 2001;88:913–930.
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Akl et al. Cochrane Sys Rev. 2011
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Death
Meyer et al. Arch Int Med. 2002
*no difference ca-related deaths
VTE Events
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Lee et al. New Eng J Med 2003
VTE Events Death
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Weitz et al. Chest 2012
Thrombin Inhibitor FVa or FVIIIa Inhibitor AT-Dependent FXa Inhibitor Direct FXa inhibitor FIXa Inhibitor FVIIa-TF Inhibitor PAR-1 Antagonist P2Y12 Inhibitor
Opidpareil, oral, halted development
(primes synthesis dermatan)
Drotecogin, IV, withdrawn
(inactivates Va & VIIIa)
Idraparinux, SC, halted (FXa
DX-9065a, IV, halted SB249417 , IV, halted, partial
(inhibitor Ixa)
Tifacogin, IV, phase 3,
(inhibits VIIa; Xa- dependent)
Vorapaxar, IV, phase 3 Cangrelor, IV, Phase 3,
(competitive inhibition at ADP binding site)
Dabigatran, oral, phase 3, approved TGA, funded PBS for AF, THR, TKR,
(reversible inhibitor free and fibrin-bound thrombin)
Recomodulin, SC, Phase 2
(binds thrombin & promotes activation protein C)
Idrabiotaparinu x, SC, Phase 3 (biotinylated form idrapariunux) Otamixaban, IV, phase 3 Pegnivac
Phase 2
(FIXa- directed inhibitory RNA aptamer)
NAPc2, SC, phase 2, (inhibits
VIIa;Xa- dependent)
Atopaxar, IV, phase 2 Ticagrelor,
Licenced USA, EU, Canada for ACS, MI, Angina, (non-
competitive inhibition at non- ADP binding site)
Dabigatran Etexilate, oral, phase 3, licenced some indications
(prodrug, reversible inhibitor active site thrombin)
Solulin, SC, Phase 2 (binds
thrombin & promotes activation protein C)
SR123781A, SC, halted
(hexadecasaccharid e inhibits Xa and thrombin equally)
Apixaban, Oral Phase 3, approved TGA, funded PBSfor TKR, AF TTP889, Oral, Halted,
(inhibitor FIXa)
FVIIai, IV, halted,
(competes with VIIa for tissue factor)
Elinogrel, IV, Phase 2,
(competitive inhibition at ADP binding site)
AZD083, oral, phase 2 (reversible
inhibitor active site thrombin)
TB-402, IV, Phase 2 (partially
inhibit VIIIa)
M118, IV/SC, Phase 2 (novel
LMWH inhibits Xa >> thrombin)
Rivaroxaban, Phase 3, approved TGA, funded PBS for THR, AF, DVT, PE, prev recurrent TE Semuloparin, SC, Phase 3
(ULMWH mainly inhibits Xa)
Edoxaban, Oral, Phase 3, Licenced Japan for TE prevention Fondaparinux , Oral, approved TGA, funded PBS for TKR, THR (FXa Darexaban, Oral, halted
Adapted from Weitz et al. Chest 2012
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Dabigatran Apixaban Fondaparinux Rivaroxaban Edoxaban Ticagrelor Thrombin Inhibitor FXa inhibitor FXa inhibitor FXa inhibitor FXa inhibitor P2Y12 Inhibitor Oral Oral Oral Oral Oral Oral Approved TGA, funded PBS for AF, THR, TKR, Approved TGA, funded PBS for TKR, AF Approved TGA, funded PBS for TKR, THR Approved TGA, funded PBS for THR, AF, DVT, PE, prevention recurrent TE Licenced Japan for TE prevention Licenced USA, EU, Canada for ACS, MI, Angina
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Vascular health and risk management 2013:9
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Bhutia et al. Cochrane Sys Rev. 2013
Recurrent VTE
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Bhutia et al. Cochrane Sys Rev. 2013
Bleeding Events
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Bhutia et al. Cochrane Sys Rev. 2013
Death
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Robust data underweight: <50kg
Increased weight: >150kg
– <100kg: 40mg sc D = 0.4-0.8mg/kg
– >100kg: ~ 40mg sc BD – >150kg: ~ 60mg sc BD
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LMWH @ 6months, those with RVT continued LMWH additional 6months
(95% CI, 0.7 to 2.5)
recurrent VTE
Napolitano et al. JCO 2013
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Boutitie et al. BMJ 2011
versus 3months: 1.52 (95%CI 1.14 – 2.02, p=0.004)
6months: 1.19 (95%CI 0.86 – 1.65, p=0.29)
(95%CI 0.34 – 0.71, p<0.001)
(95%CI 0.34 – 0.71, p<0.001)
0.87 – 1.63, p=0.27)
Additional / ongoing risk factors: duration of risk…and a bit more
– Presence of the cancer (bulk) – Ongoing anti-cancer therapy – Surgery – Hospitalisation – Indwelling CVAD/PICC – Lymphatic/venous incompetence – Infections – Comorbidities
Absence of ongoing risk factors: minimum duration
– 3 vs 6 months
– 12 months
– While in situ + – 3 months
– 3 months
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patients (= all cancer patients)
novel agents at this time
(inconsistency/ambiguity in agent)
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ASCO/ESMO = “may consider” “case-by-case’, NCCN = no recommendations, SISET = yes for Lung and GI
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Guideline Recommendation International Consensus 2013
metastatic pancreatic cancer treated with chemotherapy and having a low bleeding risk [Grade 1B].
metastatic lung cancer treated with chemotherapy and having a low bleeding risk [Grade 2B]. ASCO Update 2013
highly selected outpatients with solid tumors receiving chemotherapy. ACCP 9th Ed 2012
prophylaxis with LMWH or LDUH (Grade 2B) and recommend against the prophylactic use of vitamin K antagonists (Grade 1B ESMO 2011
recommended [I, A].
recommended, but may be considered in high-risk ambulatory cancer patients [II, C]. SISET 2012
radiotherapy or hormonal therapy (grade C) except for:
no more than 4 months (grade A)
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Palumbo Leukaemia 2008;22: 414-423
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Guideline Recommendation International Consensus 2013 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]. ASCO Update 2013 Patients undergoing major cancer surgery should receive prophylaxis, starting before surgery and continuing for at least 7 to 10 days ACCP 9th Ed 2012 No duration specified Suggest LMWH over no prophylaxis[2B] Suggest LDUH over no prophylaxis[2B] ESMO 2011 For patients having a laparotomy, laparoscopy, thoracotomy or thoracoscopy lasting >than 30 min, consider s.c. LMWH for at least 10 days postoperatively.
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Guideline Recommendation International Consensus 2013 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]. ASCO Update 2013 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) . ACCP 9th Ed 2012 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) . ESMO 2011 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].
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Guideline Recommendation International Consensus 2013 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]. ASCO Update 2013 LMWH is preferred over UFH for the initial 5 to 10 days of anticoagulation for the patient with cancer with newly diagnosed VTE who does not have severe renal impairment (defined as creatinine clearance <30 mL/min) ACCP 9th Ed 2012 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.
ESMO 2011 The standard initial treatment of an acute episode of VTE in cancer and non- cancer patients consists:
enoxaparin)
infusion adjusted to achieve and maintain an activated partial thromboplastin time (aPTT) prolongation of 1.5–2.5 times the basal value.
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Guideline Recommendation International Consensus 2013 Premature to issue recommendations due to absence of data and clinical experience ASCO Update 2013 Use of novel oral anticoagulants for either prevention or treatment of VTE in patients with cancer is not recommended at this time. ACCP 9th Ed 2012 In patients with DVT and cancer who are not treated with LMWH, we suggest VKA over Dabigatran or Rivaroxaban ESMO 2011 Not specified
28th February 2011 Presentation title 71
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Consider
pharmacological)
(if any)
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70 F with newly diagnosed multiple myeloma commencing DT-PACE (see below for regimen details). Her BMI is 22.3, creatinine clearance is 80mL/min, no history of prior TE, no history cardiovascular disease
relevant concomitant medications, and no blood clotting disorders.
DT PACE Dexamethasone 40mg PO D1-4; Cisplatin 10mg/m2/day IVCI D1-4; Etoposide 40mg/m2/day IVCI D1-4; Cyclophosphamide 400mg/m2/day IVCI D1-4; Doxorubicin 10mg/m2/day IVCI D1-4; Thalidomide 100mg PO daily continuous
1) What is the risk profile of this patient for VTE? 2) What thromboprophylaxis recommendations would you give?
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MM working group – Palumbo 2008 Regardless of other risk factors, combination of thalidomide plus multi-agent chemotherapy indicates for LMWH 40mg daily or full dose warfarin ACCP 9th Edition 2012 4.2.2. In outpatients with solid tumours who have additional risk factors for VTE (includes Thal/Len) and who are at low risk of bleeding, we suggest prophylactic dose LMWH or LDUH over no prophylaxis (Grade 2B) . ASCO Update 2013 2.3 Patients with multiple myeloma receiving thalidomide- or lenalidomide-based regimens with chemotherapy and/or dexamethasone should receive pharmacologic thromboprophylaxis with either aspirin or LMWH for lower risk patients and LMWH for higher-risk patients.
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75 M with multiple myeloma being commenced on single agent lenalidomide having progressed through a trial of 6 weeks of thalidomide therapy. His BMI is 20, creatinine clearance is 60mL/min, no history of prior TE, no history cardiovascular disease or diabetes, no recent infection, fully mobile, no recent surgery, no relevant concomitant medications, and no blood clotting disorders. 1) What is the risk profile of this patient for VTE? 2) What thromboprophylaxis recommendations would you give? 3) Would this change if he had prior history of VTE? 4) Would this change if he had prior history VTE and chronic renal disease (CrCl 30mL/min)
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MM group – Palumbo 2008 Single agent lenalidomide with no other risk factors: aspirin 81-325mg daily Single agent lenalidomide with one risk factor: aspirin 81-325mg daily Single agent lenalidomide with two or more risk factors: LMWH or full dose warfarin ACCP 9th Edition 2012 4.2.2. In outpatients with solid tumors who have additional risk factors for VTE (includes Thal/Len) and who are at low risk of bleeding, we suggest prophylactic dose LMWH or LDUH over no prophylaxis (Grade 2B) . ASCO Update 2013 2.3 Patients with multiple myeloma receiving thalidomide- or lenalidomide-based regimens with chemotherapy and/or dexamethasone should receive pharmacologic thromboprophylaxis with either aspirin or LMWH for lower risk patients and LMWH for higher-risk patients.
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65 M with newly diagnosed Non-Small Cell Lung Cancer commencing definitive treatment for stage IIIA disease.
Regimen – Cisplatin/Etoposide Phos (Combined RTx) Cisplatin 50mg/m2 IV D1,8,29,36; Etoposide Phosphate 50mg/m2 IV D1-5, 29-33
1) What is the risk profile of this patient for VTE? 2) What thromboprophylaxis recommendations would you give? 3) Would this change if he had prior history of VTE?
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SISET 2012 (Italian Society Haemostasis and Thrombosis) Pharmacological prophylaxis is not routinely recommended in patients undergoing chemotherapy or radiotherapy or hormonal therapy (grade C) except in the following cases:
more than 4 months (grade A)
dexamethasone should receive LMWH or aspirin or warfarin (Grade C) ACCP 9th Edition 2012 4.2.1. 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 VKAs (Grade 1B) .
*Remarks: Additional risk factors for venous thrombosis in cancer outpatients include previous venous thrombosis, immobilization, hormonal therapy, angiogenesis inhibitors, thalidomide, and lenalidomide.
ASCO Update 2013 2.1 Routine pharmacologic thromboprophylaxis is not recommended in cancer outpatients. 2.2 Based on limited RCT data, clinicians may consider LMWH prophylaxis on a case-by-case basis in highly selected outpatients with solid tumors receiving chemotherapy. Consideration of such therapy should be accompanied by a discussion with the patient about the uncertainty concerning benefits and harms as well as dose and duration of prophylaxis in this setting.
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65 M with stage IV renal cancer, brain metastasis (stable) and current active treatment with pazopanib. Patient develops new proximal leg DVT. Patient is an outpatient but reports extreme lethargy and spend much of the day on the couch resting and has ECOG 2-3.
Anticancer Regimen – Pazopanib (Tyrosine Kinase Inhibitor) Pazopanib 800mg daily
1) What is the risk profile of this patient for VTE? 2) What thrombosis treatment recommendations would you give?
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ASCO 2013 – Limited data support use of antithrombotic therapy in patients with primary or metastatic brain tumours who develop concurrent venous
improved overall survival or reduced intracranial haemorrhage in small retrospective series Clinical Outcome – Patient was started on Rivaroxaban (privately treated patient). We converted to LMWH for benefits of:
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Consider
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43 F presenting for High Dose Radiotherapy for Cervical Ca. The case is booked as 60 minutes. She has had 2 DVTs in the past and is know to have Factor V Leiden mutation. Her BMI is 28 & she weighs 61 Kg. Her renal function & bloods are normal. She is on
1) What is the risk profile of this patient for VTE? 2) What thromboprophylaxis recommendations would you give?
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59 Male for surveillance colonoscopy. He has a previous PE 6 years
arthritis, a history of Asthma. He is on Methotrexate & salbutamol puffers prn. His bloods are normal. 1) What is the risk profile of this patient for VTE? 2) What thromboprophylaxis recommendations would you give?
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72 M presenting for superficial parotidectomy for a parotid SCC. The procedure is booked for 120 minutes. He weighs 98 kg & has a BMI of 36. He has a history of AF and is on Warfarin. His warfarin was reversed preoperatively with Fast Track Warfarin Reversal with Vitamin K. He is hypertensive, has dyslipidaemia, has congestive heart failure, and had a previous TIA. He has normal renal function. 1) What is the risk profile of this patient for VTE? 2) What thromboprophylaxis recommendations would you give?