A Cancer Clot Conundrum General Medicine Case Presentation Jennifer - PowerPoint PPT Presentation

A Cancer Clot Conundrum General Medicine Case Presentation Jennifer Pitman, Pharmacy Resident September 26 th 2017

Objectives • Understand the pathophysiology and risk factors for VTE in cancer • Recall current guidelines and trials for treatment of VTE in cancer • Evaluate the role of NOACs in treatment of VTE in cancer patients • Recommend appropriate therapy for a cancer patient with VTE, considering pt specific factors

Patient: ED ID: 73 yo female, 54 kg CC: Worsening SOB, especially on exertion HPI: Surgical admission Aug 21-27 for excision of upper left lobe lung • nodule (metastatic melanoma) ER visit on Aug 29 for SOB à prescribed moxifloxacin and oral • prednisone for AE COPD No improvement à re-admitted Sept 5 th with PE diagnosis • Allergies: Caffeine, metals Family Hx: Unknown Social Hx: Lives alone in mobile home; single with no children • EtOH- recovering alcoholic (sober since 1990) • Smoking- Ex smoker (20-30 pack-years) • • Marijuana- regular (daily) user until lung tumor diagnosis Feb/17 Vaccination Pt declined to answer Status:

Patient: PMHx CNS Hx of substance abuse (EtOH, marijuana) Neuralgia Paresthesia (2001) HEENT Macular Degeneration RESP COPD CV Aortic Sclerosis GI GERD + Esophagitis (2017) Hiatus Hernia Diverticulosis MSK/SKIN Osteoarthrosis Osteopenia Psoriasis Right Carpal Tunnel Syndrome HEME Metastatic melanoma Surgical Left lung upper lobe resection (2017) Left shin squamous cell carcinoma excision (2016) Colonoscopy and polypectomy (2016) Melanoma in situ excision (2012)

Patient: MPTA CNS Gabapentin 100mg PO TID RESP Ciclesonide 100 mcg inhale 1-2 puffs daily Tiotropium/olodateraol 2.5/2.5 mcg inhale 2 puffs once daily Salbutamol 100 mcg inhale 2 puffs QID Suspected Exacerbation Aug 29: -Moxifloxacin 400 mg PO daily x 7 days -Prednisone 50 mg PO daily x 5 days CV ?Metoprolol 37.5 mg PO BID GI Pantoprazole 40mg PO daily HEME Hydromorphone 1-3 mg PO q4h PRN

Review of Systems Vitals T 36.3 O C , HR 100, RR 16, BP 132/84 mmHg, O 2 97% on 1L/min CNS/Psych A&Ox3, CAM-, emotional and frustrated after terminal cancer diagnosis CV NSR, T wave abnormality (?anterior ischemia), Trop 46, QTc 500 RESP SOB, dry cough, CT showing multiple bilateral PEs and left pleural effusion, left chest pain (surgical site) Abdomen flat and soft, bowel sounds present x 4, diarrhea 2 O to GI home made laxative Renal/GU Scr 66 mmol/L, CrCl 56mL/min (calculated), stable MSK/Skin Independent to mobilize, low falls risk Hematology Metastatic melanoma , WBC 10.4, Hgb 142, MCV 92, PLT 354, B12 511 Fluids/Lytes Na 136, K 4.0, Ca 2.22, Mg 0.81, PO4 0.88

Current Conditions & Medications • Medical Problems • Medications in Hospital – Bilateral pulmonary – Dalteparin 10,000 units subcut emboli daily – Malignant melanoma – Acetaminophen 1g PO QID PRN – Hydromorphone 1 mg subcut or – Left chest pain ∘ 2 to left 2 mg PO q4h PRN lobe resection – Fluticasone/Salmeterol 250/25 mcg – COPD one puff q12h – Constipation – Tiotropium 18 mcg one puff daily – GERD + esophagitis – Ipratropium/salbutamol 2.5 mL neb – Osteoarthrosis inhaled q4h PRN – Hiatus Hernia – Bowel Protocol – Diverticulosis – Macular Degeneration – Pantoprazole 40 mg PO daily – Psoriasis – Zopiclone 7.5 mg PO HS PRN – Hx of Substance Abuse

Course in Hospital • Admitted to VGH general medicine floor on September 5 th – Three night stay • Treatment initiated with dalteparin 10,000 units SC daily for multiple bilateral PEs in setting of malignancy – Terminal diagnosis, 3-6 months • Pt resistant to self-injecting at home and has little home support – Physician inquiring about DOACs as PO alternative

DRPs 1. ED is experiencing SOB and multiple bilateral PEs and requires anticoagulation therapy 2. ED has left chest pain secondary to surgery and requires pain management 3. ED is experiencing diarrhea secondary to home made laxative and requires therapy evaluation 4. ED is a risk of constipation secondary to hydromorphone and requires therapy evaluation 5. ED is experiencing tachycardia and requires therapy evaluation 6. ED is at risk of Achilles tendonitis and tendon rupture secondary concomitant to use of prednisone + moxifloxacin

Goals of Therapy • Reduce risk of VTE recurrence • Improve or resolve shortness of breath • Minimize ADRs secondary to anticoagulation • Facilitate ease of administration of anticoagulation therapy • Maintain or improve quality of life

VTE Risk in Cancer • VTE Incidence in Cancer – 15%, ranging 3.8% - 30.7% • Cancer Type – Higher risk in clinically aggressive (pancreatic, brain, stomach) and hematologic (leukemia, lymphoma) cancers • Cancer Stage – Higher risk with disease progression (metastatic disease) • Time after diagnosis – Higher risk in first 3-6 months • Major Surgery – 2-4 fold higher risk of VTE post surgery compared to non-cancer patients Deitcher. Semin Thromb Hemost 2003;29(3):247-58. Wun et al. Best Pract Res Clin Haematol 2009;22(1):9-23.

Hypercoagulability in Cancer Immobility Extrinsic tumor vascular compression Chemotherapy Complex cell interactions Hormonal Therapy Surgery Malignant Cells Central venous catheters Factors for ED: Surgery, immobility, malignancy Piccioli et al. Semin Thromb Hemost 2006;32(7):694-9. Mandala et al. Ann Oncol 2011;22 Suppl 6:vi85-92.

Current Guidelines NCCN Guidelines 2017: • LMWH preferred • For pts who refuse or have compelling reason to avoid LMWH, apixaban or rivaroxaban are acceptable CHEST 2016 Guidelines: Cancer Patients • LMWH over VKA (Grade 2B) • LMWH over dabigatran, rivaroxaban, apixaban, or edoxaban (Grade 2C) • Extended (no scheduled stop date) over 3 months of therapy (Grade 1B) ASCO 2015 Guideline Update: • LMWH for at least 6 months • DOACs not currently recommended – Referenced by BCCA Nov 2016

What we know… CANTHANOX CLOT (2003) ONCENOX LITE (2006) CATCH (2002) (2006) (2015) Population Symptomatic Symptomatic Symptomatic Symptomatic Symptomatic VTE, n=138 VTE, n=672 VTE, n=101 DVT, n=200 VTE, n=900 Interventions Enoxaparin Dalteparin vs Enoxaparin Tinzaparin vs Tinzaparin vs vs warfarin warfarin (1 or 1.5 mg) warfarin warfarin vs warfarin Outcomes Composite VTE, MB VTE, MB VTE, MB VTE*, MB, VTE and MB CRNMB Results: VTE RR= 2.02 HR = 0.48 , 3.4% vs 3.1% RR=0.44 , HR=0.65 (0.88-4.65) P=0.002 vs 6.7% (NSS) P=0.044 (0.41=1.03) Favors enox. Favors dalt. Favors tinz. Favors tinz. Results: Bleed NSS bleeds NSS bleeds NSS bleeds HR 0.58 (0.4- 0.84)CRNMB MB= major bleed, CRNMB= clinically relevant non-major bleed *included incidental findings Bottom line: LMWH > warfarin

What we know… Trials Einstein-DVT, RE-COVER II Amplify (2013) Hokusai-VTE PE (2010, 2013) (2011) (2013) Population Symptomatic Symptomatic Symptomatic Symptomatic VTE, VTE, n=655 VTE, n=221 VTE, n=169 n=771 Interventions Rivaroxaban vs Dabigatran* vs Apixaban vs Edoxaban* vs enoxaparin/ UFH or LMWH/ enoxaparin/ enoxaparin or warfarin warfarin warfarin UFH/warfarin Cancer HR=0.67 (0.34- RR=0.75 # RR=0.56 (0.13- HR=0.53 (0.28- Subgroup: VTE 1.30) 2.37) 1.00) Cancer HR= 0.42 (0.18- Not reported RR=0.45 (0.08- HR=0.80 (0.35- Subgroup: 0.99 2.46) 1.83) Major Bleeding *Initial treatment with LMWH or UFH (≥ 5 days) # Manual calculation Bottom Line: DOAC = warfarin

How do they work? Becattini et al. J Am Coll Cardiol 2016;67(16):1941-55

Therapeutic Alternatives • LMWH – Dalteparin 200 units/kg subcut daily x 30 days, then 150 units/kg SC daily – Enoxaparin 1 mg/kg subcut BID – Tinzaparin 175 units/kg subcut daily • DOACs – Rivaroxaban 15 mg PO BID x 21 days, then 20mg PO daily – Apixaban 10 mg PO BID x 7 days, then 5 mg PO BID – Dabigatran 150 mg PO BID (LMWH/UFH for first 5-10 days) – Edoxaban 60 mg PO daily (LMWH/UFH for first 5-10 days)

Clinical Question P 73 year old female with bilateral pulmonary emboli and metastatic melanoma (palliative) I Low Molecular Weight Heparin C Direct Oral Anticoagulant O Recurrent of VTE, major and minor bleeding

Literature Search PubMed (N=263) ((((((((anticoagulants[MeSH Terms]) OR ((edoxaban[MeSH Terms]) OR edoxaban)) OR ((apixaban[MeSH Terms]) OR apixaban)) OR ((dabigatran[MeSH Terms]) OR dabigatran)) OR ((rivaroxaban[MeSH Terms]) OR rivaroxaban))) AND ((heparin, low molecular weight[MeSH Terms]) OR low molecular weight heparin)) AND ((cancer[MeSH Terms]) OR cancer)) AND ((((pulmonary embolism[MeSH Terms]) OR pulmonary embolism)) OR ((venous thrombosis[MeSH Terms]) OR venous thromboembolism)) Filters: published in the last 5 years EMBASE (N=26) cancer.mp or malignant neoplasm/ AND exp*venous thromboembolism/ or exp*lung embolism/ AND exp*rivaroxaban or exp*dabigatran etexilate/ or exp*dabigatran/ or exp*apixaban/ or exp*edoxaban/ AND exp*low molecular weight heparin/ Cochrane CRCT cancer.mp or exp*neoplasms/ AND exp*venous thromboembolism/ or exp*pulmonary embolism AND dabigatran.mp or apixaban.mp or rivaroxaban.mp (N=2) or edoxaban.mp AND exp*heparin, low-molecular-weight/ Results specific to 2 RCT protocols PICO 4 Retrospective analyses (2 included) 1 Prospective cohort