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
ID: 73 yo female, 54 kg CC: Worsening SOB, especially on exertion HPI:
nodule (metastatic melanoma)
prednisone for AE COPD
Allergies: Caffeine, metals Family Hx: Unknown Social Hx:
Vaccination Status: Pt declined to answer
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)
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:
CV ?Metoprolol 37.5 mg PO BID GI Pantoprazole 40mg PO daily HEME Hydromorphone 1-3 mg PO q4h PRN
Vitals T 36.3OC , HR 100, RR 16, BP 132/84 mmHg, O2 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) GI Abdomen flat and soft, bowel sounds present x 4, diarrhea 2O to 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
– COPD
– Constipation
– GERD + esophagitis
– Osteoarthrosis
– Hiatus Hernia
– Diverticulosis
– Macular Degeneration
– Psoriasis
– Hx of Substance Abuse
– Fluticasone/Salmeterol 250/25 mcg
– Tiotropium 18 mcg one puff daily – Ipratropium/salbutamol 2.5 mL neb inhaled q4h PRN
– Bowel Protocol – Pantoprazole 40 mg PO daily – Zopiclone 7.5 mg PO HS PRN
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
– 15%, ranging 3.8% - 30.7%
– Higher risk in clinically aggressive (pancreatic, brain, stomach) and hematologic (leukemia, lymphoma) cancers
– Higher risk with disease progression (metastatic disease)
– Higher risk in first 3-6 months
– 2-4 fold higher risk of VTE post surgery compared to non-cancer patients
Wun et al. Best Pract Res Clin Haematol 2009;22(1):9-23.
Chemotherapy Hormonal Therapy Malignant Cells
Immobility Extrinsic tumor vascular compression Complex cell interactions Surgery 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.
rivaroxaban are acceptable
– Referenced by BCCA Nov 2016
CANTHANOX (2002) CLOT (2003) ONCENOX (2006) LITE (2006) CATCH (2015) Population Symptomatic VTE, n=138 Symptomatic VTE, n=672 Symptomatic VTE, n=101 Symptomatic DVT, n=200 Symptomatic VTE, n=900 Interventions Enoxaparin vs warfarin Dalteparin vs warfarin Enoxaparin (1 or 1.5 mg) vs warfarin Tinzaparin vs warfarin Tinzaparin vs warfarin Outcomes Composite VTE and MB VTE, MB VTE, MB VTE, MB VTE*, MB, CRNMB Results: VTE RR= 2.02 (0.88-4.65) Favors enox. HR = 0.48, P=0.002 Favors dalt. 3.4% vs 3.1% vs 6.7%(NSS) RR=0.44, P=0.044 Favors tinz. HR=0.65 (0.41=1.03) 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
Trials Einstein-DVT, PE (2010, 2013) RE-COVER II (2011) Amplify (2013) Hokusai-VTE (2013) Population Symptomatic VTE, n=655 Symptomatic VTE, n=221 Symptomatic VTE, n=169 Symptomatic VTE, n=771 Interventions Rivaroxaban vs enoxaparin/ warfarin Dabigatran* vs UFH or LMWH/ warfarin Apixaban vs enoxaparin/ warfarin Edoxaban* vs enoxaparin or UFH/warfarin Cancer Subgroup: VTE HR=0.67 (0.34- 1.30) RR=0.75# RR=0.56 (0.13- 2.37) HR=0.53 (0.28- 1.00) Cancer Subgroup: Major Bleeding HR= 0.42 (0.18- 0.99 Not reported RR=0.45 (0.08- 2.46) HR=0.80 (0.35- 1.83)
*Initial treatment with LMWH or UFH (≥ 5 days)
#Manual calculation
Becattini et al. J Am Coll Cardiol 2016;67(16):1941-55
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 (N=2)
cancer.mp or exp*neoplasms/ AND exp*venous thromboembolism/ or exp*pulmonary embolism AND dabigatran.mp or apixaban.mp or rivaroxaban.mp
Results specific to PICO 2 RCT protocols 4 Retrospective analyses (2 included) 1 Prospective cohort
Comparative effectiveness and safety of direct oral anticoagulants (DOACs) versus conventional anticoagulation for the treatment of cancer-related venous thromboembolism: a retrospective analysis P Cancer patients with an ICD-9 diagnosis of VTE, treated with a therapeutic dose of anticoagulant at the University of Texas MD Anderson Cancer Centre during 2014-2105 I Low molecular weight heparins C DOACs (Apixaban or Rivaroxaban) O Primary: VTE recurrence at 6 and 12 months after initiation of anticoagulation Secondary: Clinically relevant bleeding; event free survival for VTE recurrence Design Retrospective cohort analysis with electronic medical record data
Ross et al. Thromb Res 2017;150:86-89.
Intervention LMWH DOAC P value VTE Recurrence at 6 months 5.7% 3.3% P=1.000 VTE Recurrence at 12 months 8.1% 6.7% P=1.000 Major Bleed 11% 13% P=0.746 Clinically Relevant Non-Major Bleed 7.3% 6.7% P=1.000
N= 30 N= 123 P=0.697
Ross et al. Thromb Res 2017;150:86-89.
Ross et al. Thromb Res 2017;150:86-89.
Retrospective comparison of low molecular weight heparin vs. warfarin vs. oral Xa inhibitors for the prevention of recurrent venous thromboembolism in
P Cancer patients 18 years or older, treated with anticoagulants for a VTE, from June 2013-September 2015. I Enoxaparin C Rivaroxaban, Apixaban, Warfarin O Primary Objective: VTE recurrence within 3 months Secondary Objectives: VTE recurrence after 3 months, mortality and major bleeding within 3 months and beyond Design Retrospective chart review
Alzghari et al. J Oncol Pharm Pract 2017;0(0):1-7.
0.0 0.2 0.4
Recurrence-free probability
0.6 0.8 1.0 10 20
Rivaroxaban/Apixaban
P = 0.10; log rank test
Enoxaparin Warfarin
30 40 50
Time to VTE recurrence (months)
60 70 80
Intervention Riv./ Apix. Enoxaparin Warfarin P Value VTE at 3 months %(n) 0% (0) 4.3% (1) 2.6% (2) P=0.8319 VTE >6 months %(n) 8.3% (4) 21.7% (5) 12.5% (7) P=0.100 MB >6 months %(n) 6.2% (3) 4.2% (4) 7.1% (4) P=1.000
N=48 (44 rivaroxaban, 4 apixaban) N=23 N=56
MB= major bleed
Alzghari et al. J Oncol Pharm Pract 2017;0(0):1-7.
Alzghari et al. J Oncol Pharm Pract 2017;0(0):1-7.
– OC-11 – CASTA DIVA – PRIORITY
– ADAM-VTE – CARAVAGGIO – Apixaban or dalteparin in reducing blood clots in patients with cancer related venous thromboembolism
– Cancer Venous Thromboembolism
– CONKO-011à LMWHs vs Rivaroxaban – CANVASàLMWHs vs DOACs
Efficacy Safety Frequency CNS S/Sx of PE Anxiety Head trauma (falls) Daily RESP S/Sx of PE Dyspnea (RR), chest pain, cough Daily CV S/Sx of PE Tachycardia (HR) Daily GI/GU Hematuria, hematemesis, melena, frank blood in stool Daily MSK/SKIN Prolonged bleeding from cuts
injection site hematoma/pain Daily Labs Thrombocytopenia (PLTs) Baseline, periodically
Safe and effective use of rivaroxaban for treatment of cancer associated venous thromboembolic disease: a prospective cohort study P Cancer patients at the Memorial Sloan Kettering Cancer Center with PE
January to May 2015 I Rivaroxaban 15 mg PO BID x 3 weeks, then 20mg daily for 6 months total (10mg PO BID x 3 weeks, then 15 mg PO daily if >75 year old) C No comparator O Efficacy: Recurrent VTE Safety: Major bleeding, clinically relevant non-major bleeding, death from any cause Design Prospective Cohort Study
Mantha et al. J Thromb Thrombolysis 2017;43(2):166-171.
6 Month Cumulative Incidence Estimates (95% CI) Outcome Recurrent VTE Major Bleed CRNMB <75 years old N=200 4.4% (1.4-7.4) 2.2% (0.0-4.2) 3.8% (1.0-6.5) ≥75 years old N=39 5.3% (0.0-12.1) 2.6% (0.0-7.4) 3.0% (0.0-8.7)
for 24 h. Rivaroxaban was not held in four cases: one was a diagnostic endoscopy, and three were emergency proce-
unclear in one additional case. No major bleeding episode occurred during the interrup- tion of rivaroxaban, within 7 days of the procedure. Only
tion for a procedure. That patient was a 52-year-old woman with stage IV ovarian cancer who had multiple discontinu- ations of rivaroxaban for debulking surgery and subsequent abscess drainages. Three days after an abscess drainage, prior to restarting rivaroxaban, she developed a symptom- atic popliteal vein DVT. Of note, this patient was heterozy- gous for both factor V Leiden and prothrombin G20210A, with a history of multiple thromboses prior to her cancer, and therefore was at particularly high risk for VTE. Thrombocytopenia There were 11 episodes of thrombocytopenia (platelets 50,000/mcL) in ten patients (Table 2). Rivaroxaban was held in seven episodes, and dose-reduced in one episode. In three episodes rivaroxaban dose was not adjusted, two
mcL and one patient had already been on reduced dose of
discontinuation, death or recurrent VTE associated with an episode of thrombocytopenia. Renal insuffjciency Transient renal insuffjciency, as defjned by a creatinine clearance of 30 mL/min (using Cockroft–Gault equation [14]) was observed in seven episodes in fjve patients during rivaroxaban treatment (Table 2). Rivaroxaban dose was held in two episodes, and not altered in fjve episodes. None of the patients experienced a major bleed, CRNMB, or recurrent VTE event within 7 days of such an episode.
ing surgical procedure in eight cases (and not restarted), for a medical reason in 18 cases, and following the patient’s wishes in one case. Slightly more than half of patients (105 individuals) were observed for the full 6 months, with an
Additional events
Invasive procedures There were 70 invasive procedures during the rivaroxaban treatment period (Table 2). In 59 procedures rivaroxaban was held for at least 48 h, and in six procedures it was held
Table 2 Management of rivaroxaban anticoagulation in the setting of thrombocytopenia, renal insuffjciency, liver dysfunction and invasive pro- cedures Episodes of rivaroxaban interruption/ dose adjustments Rivaroxaban dose-reduced Rivaroxa- ban held No change in dosage Major bleeding CRNMBa Recurrent VTE Death
hospice Platelet count 50,000/mcL (N 11) 1 7 3 Creatinine clearance 30 mL/min (N 7) 2 5 1 Elevated liver enzymes (AST, ALT or bilirubin 3 upper limit of normal) (N 18) 6 12 1 1 Interventionsb (N 70) 65 4 1 3
aCRNMB leading to discontinuation of Rivaroxaban bThe exact management approach is unknown in the case of one intervention
Limitations:
Mantha et al. J Thromb Thrombolysis 2017;43(2):166-171.
Ross et al. 2017 Alzghari et al. 2017 Mantha et al. 2017 Bottom Line
VTE and bleeds
evidence
VTE and bleeds
evidence
4.4%
evidence Relevance for ED