Risk of Cncer-Associted Thrombosis nd Bleeding in Veterns With Mlignncy Who Are Receiving Direct Orl Anticogulnts Mtthew Stnkowicz, PhrmD; Megn Bnszynski, PhrmD, BCOP; nd Russell Crwford, BPhrm, BCOP The low incidence of venous thromboembolism formtion in this study nd similr rtes of bleeding in other clinicl trils indicte tht direct orl nticogulnt gents re sfe lterntives in ptients with cncer. Dr. Stnkowicz is PGY2 Oncology Phrmcy Resident, Mr. Crwford is Clinicl Phrmcist, nd Dr. Bnszynski is Clinicl Phrmcist, ll t Southern Arizon VA Helth Cre System in Tucson. Mr. Crwford is President of the Assocition of VA Hemtology/Oncology (AVAHO). Correspondence: Dr. Stnkowicz (mtt. stnkowicz@gmil.com) Ptients with cncer re t n incresed risk of both venous thromboembolism (VTE) nd bleeding complictions. Risk fctors for development of cncer-ssocited thrombosis (CAT) include indwelling lines, ntineoplstic therpies, lck of mobility, nd physicl/chemicl dmge from the tumor. 1 Venous thromboembolism my mnifest s either deep vein thrombosis (DVT) or pulmonry embolism (PE). Cncer-ssocited thrombosis cn led to significnt mortlity in ptients with cncer nd my increse helth cre costs for dditionl medictions nd hospitliztions. Zullig nd collegues estimted tht 46,666 veterns received cncer cre from the US Deprtment of Vetern Affirs (VA) helth cre system in 2010. This number equtes to bout 3% of ll ptients with cncer in the US who receive t lest some of their helth cre from the VA helth cre system. 2 In ddition to cncer cre, these veterns receive tretment for vrious comorbid conditions. One such condition tht is of concern in prothrombotic stte is tril fibrilltion (). For this condition, ptients often require nticogultion therpy with spirin, wrfrin, or one of the recently pproved direct orl nticogulnt gents (DOACs), depending on risk fctors. BACKGROUND Due to their ese of dministrtion, limited monitoring requirements, nd proven sfety nd efficcy in ptients with requiring nticogultion, the Americn Hert Assocition (AHA) nd Americn College of Crdiology recently switched their recommendtions for rivroxbn nd dbigtrn for orl stroke prevention to clss 1/level B recommendtion. 3 The Americn College of Chest Physicins (ACCP) recommends tretment with DOACs over wrfrin therpy for cute VTE in ptients without cncer; however, the ACCP prefers low moleculr-weight heprin (LMWH) over the DOACs for tretment of CAT. 4 Recently, the Ntionl Comprehensive Cncer Network (NCCN) updted its guidelines for the tretment of cncer-ssocited thromboembolic disese to recommend 2 of the DOACs (pixbn, rivroxbn) for tretment of cute VTE over wrfrin. These guidelines lso recommend LMWH over DOACs for tretment of cute VTE in ptients with cncer. 5 These NCCN recommendtions re lrgely bsed on prespecified subgroup met-nlyses of the DOACs compred with those of LMWH or wrfrin in the cncer popultion. In ddition to stroke prevention in ptients with, DOACs hve dditionl FDA-pproved indictions, including tretment of cute VTE, prevention of recurrent VTE, nd postopertive VTE tretment nd prophylxis. Due to lck of hed-to-hed, rndomized controlled trils compring LMWH with DOACs in ptients with cncer, these gents hve not found their forml plce in the tretment or prevention of CAT. Severl met-nlyses hve suggested similr efficcy nd sfety outcomes in ptients with cncer compred with those of LMWH. 6-8 These met-nlysis studies lrgely looked t subpopultions nd compred the outcomes with those of the lndmrk CLOT (Rndomized Comprison of Low-Moleculr-Weight Heprin S28 FEDERAL PRACTITIONER SPECIAL ISSUE MAY 2018
versus Orl Anticogulnt Therpy for the Prevention of Recurrent Venous Thromboembolism in Ptients with Cncer Investigtors) nd CATCH (Comprison of Acute Tretments in Cncer Hemostsis) trils. 9,10 As it is still uncler whether the DOACs re effective nd sfe for tretment/prevention of CAT, some confusion remins regrding the best mngement of these t-risk ptients. In ptients with cncer on DOAC therpy for n pproved indiction, it is ssumed tht the therpeutic benefit seen in pproved indictions would trnslte to tretment nd prevention of CAT. This study ims to determine the incidence of VTE nd rtes of mjor nd cliniclly relevnt nonmjor bleeding (CRNMB) in veterns with cncer who received DOAC. METHODS This retrospective, single-center chrt review ws pproved by the locl institutionl review bord nd reserch sfety committee. A serch within the VA Corporte Dt Wrehouse identified ptients who hd n ctive prescription for one of the DOACs (pixbn, dbigtrn, edoxbn, nd rivroxbn) long with n ICD 9 or ICD 10 code corresponding to mlignncy. Ptients were included in the finl nlysis if they were ged 18 to 89 yers t time of DOAC receipt, undergoing ctive tretment for mlignncy, hd evidence of history of mlignncy (either dignostic or chrted evidence of previous tretment), or received cncer-relted surgery within 30 dys of DOAC prescription with curtive intent. Ptients were excluded from the finl nlysis if they did not receive DOAC prescription or hve ny cler evidence of mlignncy documented in the medicl chrt. Ptients chrts were evluted for the following clinicl endpoints: ptient ge, height (cm), weight (kg), type of mlignncy, type of tretment for mlignncy, serum cretinine (SCr), cretinine clernce (CrCl) clculted with the Cockcroft-Gult eqution using ctul body weight, serum hemoglobin, sprtte minotrnsferse, lnine minotrnsferse, totl bilirubin, indiction for DOAC, type of VTE, presence of prior VTE, nd dignostic test performed for VTE. Mjor bleeding nd CRNMB criteri were bsed on the definitions provided by the Interntionl Society on Thrombosis nd Hemostsis (ISTH). 11 All lbortory vlues nd demogrphic informtion were gthered t the time of initil DOAC prescription. FIGURE Study Prticiption Flowchrt 343 ptients identified Excluded: 115 ptients without evidence of mlignncy 23 ptients whose chrts were unvilble 22 ptients without record of DOAC receipt 15 ptients whose DOAC receipt ws not within the dte rnge Abbrevition: DOAC, direct orl nticogulnt. 177 ptient chrts evluted The primry endpoint for this study ws incidence of VTE. The secondry endpoints included mjor bleeding nd CRNMB. All dt collection nd sttisticl nlysis were done using Microsoft Excel 2016 (Redmond, WA). Comprisons of dt between trils were done using the chi-squred clcultion. RESULTS From initil FDA pprovl of dbigtrn (first DOAC on the mrket) on October 15, 2012, to Jnury 1, 2017, there were 343 ptients who met initil inclusion criteri. Of those, 115 did not hve ny cler evidence of mlignncy, 22 did not hve ny records of DOAC receipt, 15 did not receive DOAC within the dte rnge, nd 23 ptients chrts were unvilble. In ddition, 9 of the ptients identified hd multiple mlignncies. This resulted in 177 evluble medicl chrts for this study (Figure). The mjority of the ptients were mles (96.6%), with n verge ge of 74.5 yers. The verge weight of ll ptients ws 92.5 kg, with n verge SCr of 1.1 mg/dl. This equted to n verge CrCl of 85.5 ml/min bsed on the Cockcroft-Gult eqution using ctul bodyweight. Of the 177 ptients evluted, 30 (16.9%) were receiving ctive cncer tretment t time of DOAC initition. Ninety ptients (50.8%) received pixbn, 53 ptients (29.9%) received dbigtrn, nd 34 ptients (19.2%) received rivroxbn; no ptients received edoxbn therpy. Most of the ptients (79.1%) received DOAC for stroke prevention with / tril flutter, nd the reminder received DOAC +9 ptients with multiple mlignncies (chrts) MAY 2018 FEDERAL PRACTITIONER SPECIAL ISSUE S29
TABLE 1 Bseline Demogrphics t DOAC Initition Chrcteristics Results Mle,. (%) 171.0 (96.6) Age, men (SD), y 74.5 (0.7) Height, men (SD), cm 175.7 (0.9) Weight, men (SD), kg 92.5 (1.8) Body mss index, men (SD), kg/m 2 30.0 (8) Serum cretine, men (SD), mg/dl 1.1 (0.3) Cretinine clernce, men (SD), (ml/min) 85.5 (2.7) Receiving cncer tretment,. (%) 30.0 (16.9) DOAC received,. (%) Edoxbn Indiction for DOAC,. (%) Acute venous thromboembolism Atril fibrilltion/tril flutter History of venous thromboembolism 90.0 (50.8) 53.0 (29.9) 0.0 (0) 34.0 (19.2) 22 (12.4) 140 (79.1) 15 (8.5) History of DVT,. (%) 24 (13.6) Abbrevitions: DOAC, direct orl nticogulnt gents; DVT, deep vein thrombosis. Cretinine clernce clculted using Cockcroft-Gult eqution with ctul body weight. for VTE tretment (12.4%) or VTE prophylxis due to history of prior VTE (8.5%). Bseline demogrphics re presented in Tble 1 nd re compred with the bseline demogrphics from the CLOT nd CATCH trils in Tble 2. Two (1.1%) ptients developed VTE while receiving DOAC. One ptient ws on rivroxbn 20 mg dily for prior VTE; the other ws on dbigtrn 150 mg twice dily for stroke prevention due to. Both ptients developed DVT, which ws dignosed by ultrsound (Tble 3). The rte of VTE incidence in the CLOT tril ws 8% nd in the CATCH tril ws 7.2%, both of which were much higher thn the rte reported in this study (P <.01). 9,10 Among the 177 evluble ptients in this study, there were 7 ptients (4%) who developed mjor bleed nd 13 ptients (7.3%) who developed cliniclly relevnt nonmjor bleed ccording to the definitions provided by ISTH. 11 The verge time from first DOAC prescription to the bleeding event ws bout 9.6 months for mjor bleed nd 7.4 months for CRNMB. Of the ptients who hd mjor bleed, 3 were receiving pixbn, 2 were receiving dbigtrn, nd 2 were receiving rivroxbn (P =.79 for ll DOACs). Of the ptients who developed CRNMB, 8 were receiving pixbn, 2 were receiving dbigtrn, nd 3 were receiving rivroxbn (P =.88 for ll DOACs). The brekdown of bleeding rtes is presented in Tble 4. The comprison of mjor nd CRNMB rtes in this study nd the lndmrk trils re presented in Tble 5. As previously mentioned, only 30 of the ptients were ctively receiving tretment during DOAC dministrtion. Most of the documented cses of mlignncy were either history of nonmelnom skin cncer (NMSC) or prostte cncer. The most common method of tretment ws surgicl resection for both mlignncies. Of the 30 ptients who received ctive mlignncy tretment while on DOAC, there were 4 ptients with multiple myelom, 6 ptients with NMSC, 4 ptients with colon cncer, 1 ptient with chronic lymphocytic leukemi (CLL), 1 ptient with chronic myelogenous leukemi (CML), 1 ptient with smll lymphocytic leukemi (SLL), 4 ptients with non-smll cell lung cncer (NSCLC), 1 ptient with unspecified brin cncer, nd 1 ptient with brest cncer. The vrious chrcteristics of these ptients re presented in Tble 6. Among these 30 ptients, only 1 ptient developed DVT. Another ptient developed mjor bleed 12 months fter inititing rivroxbn 20 mg dily due to history of prior VTE. DISCUSSION The CLOT nd CATCH trils were chosen s historic comprtors. Although the ctive tretment interventions nd comprtor rms were not similr between the ptients included in this study nd the CLOT nd CATCH trils, the uthors felt the comprison ws pproprite s these trils were designed specificlly for ptients with mlignncy. Additionlly, these trils sought to ssess rtes of VTE formtion nd bleeding in the ptient with mlignncies outcomes tht ligned with this study. Alterntive trils for comprison re the subgroup nlyses of ptients with mlignncies in the AMPLIFY, RE-COVER, nd EINSTEIN trils. 12-14 Although these trils were designed to strtify ptients bsed on presence of mlignncy, they were S30 FEDERAL PRACTITIONER SPECIAL ISSUE MAY 2018
TABLE 2 Comprison of Bseline Demogrphics Among Trils Study (n = 177) CLOT b Dlteprin (n = 338) CLOT b Wrfrin (n = 338) CATCH b Tinzprin (n = 449) CATCH b Wrfrin (n = 451) Mle,. (%) 171 (96.6) 159 (47.0) 170 (50.3) 187 (48.6) 178 (39.5) Age (SD), y 74.5 (0.7) 62 ± 12 63 ± 13 59.7 ± 12.7 58.8 ± 12.5 Weight (SD), kg 92.5 (1.8) t reported t reported 67.3 ± 17.3 67.1 ± 16.3 Receiving cncer tretment,. (%) 30 (16.9) 266 (78.7) 259 (76.6) 228 (50.8) 248 (55) History of DVT,. (%) 24 (13.6) 39 (11.5) 36 (10.7) 27 (6) 30 (6.7) Abbrevitions: CATCH, Comprison of Acute Tretments in Cncer Hemostsis tril; CLOT, Rndomized Comprison of Low-Moleculr-Weight Heprin versus Orl Anticogulnt Therpy for the Prevention of Recurrent Venous Thromboembolism in Ptients with Cncer Investigtors tril; DVT, deep vein thrombosis. Descriptive sttistics presented s men + SEM unless otherwise noted. b All dt presented s men + SD unless otherwise noted. not powered to ccount for incresed risk of VTE in ptients with mlignncies. There re multiple risk fctors tht increse the risk of CAT. Khornn nd collegues identified primry stomch, pncres, brin, lung, lymphom, gynecologic, bldder, testiculr, nd renl crcinoms s high risk of VTE formtion. 15 Additionlly, Khornn nd collegues noted tht elderly ptients nd ptients ctively receiving tretment re t n incresed risk of VTE formtion. 15 The low rte of VTE formtion (1.1%) in the ptients in this study my be due to the low risk for VTE formtion. As previously mentioned, only 30 of the ptients (16.9%) in this study were receiving ctive tretment. Additionlly, there were only 42 ptients (23.7%) who hd high-risk mlignncy. The incresed ge of the ptient popultion (74.5 yers old) in this study is one risk fctor tht could lrgely skew the risks of VTE formtion in the ptient popultion. In ddition to ge, the verge body mss index (BMI) of this study s ptient popultion (30 kg/m 2 ) my further increse risk of VTE. Although Khornn nd collegues identified BMI of 35 kg/m 2 s the cutoff for incresed risk of CAT, the incresed risk bsed on BMI of 30 kg/m 2 cnnot be ignored in the ptients in this study. 15 Another risk inherent in the tretment of ptients with cncer is pncytopeni, which my led to incresed risks of bleeding nd infection. When ptients re exposed to n nticogulnt gent in the setting of decresed pltelets nd hemoglobin (from tretment or disese process), the risk for mjor bleeds nd TABLE 3 Chrcteristics of Ptients Who Developed VTE While on DOAC Chrcteristics Mle, 67 y Height: 196.9 cm Weight: 138.4 kg Mle, 71 y Height: 175.3 cm Weight: 86.2 kg DOAC 150 mg po bid for tril fibrilltion 20 mg po dily for cute VTE Mlignncy (With Tretment) CRNMB re incresed drsticlly. In this ptient popultion, the combined rte of bleeding (11.3%) ws reltively decresed compred with tht of the CLOT (16.5% for ll bleeding events) nd CATCH (15.7% for ll bleeding events) trils. 9,10 Compred with the oncology subgroup nlysis of the AMPLIFY, RE-COVER, nd EINSTEIN trils, the differences re more noticeble. The AMPLIFY tril reported 1.1% incidence of bleeding in ptients with cncer on pixbn, wheres the RE-COVER tril did not report bleeding rtes, nd the EINSTEIN tril reported 14% incidence of bleeding in ll ptients with cncer on rivroxbn for VTE tretment. 12-14 This study found bleeding incidence of 12.2% with pixbn, 5.7% with dbigtrn, nd 14.7% with rivroxbn. In this tril nmelnom skin cncer (excision, rdition nd djuvnt cpecitbine, topicl fluorourcil) Rectl (Previously treted with rdition nd djuvnt cpecitbine) Time to VTE 25 mo 11 mo Abbrevitions: DOAC, direct orl nticogulnt gent, VTE, venous thromboembolism. MAY 2018 FEDERAL PRACTITIONER SPECIAL ISSUE S31
TABLE 4 Bleeding Events Events,. Averge Time to Event, mo,. (%) (n = 90),. (%) (n = 53),. (%) (n = 34) Totl 20 8.2 11 (12.2) 4 (7.5) 5 (14.7) Mjor 7 9.6 3 (3.3) 2 (3.8) 2 (5.9) CRNMB 13 7.4 8 (8.9) 2 (3.8) 3 (8.8) Abbrevition: CRNMB, cliniclly relevnt nonmjor bleeding. TABLE 5 Comprison of Bleeding Rtes Among Trils Study (n = 177) CLOT LMWH (n = 338) CLOT Wrfrin (n = 335) CATCH LMWH (n = 449) CATCH Wrfrin (n = 451) P Vlue Totl 20 47 64 61 80 Mjor 7 19 12 12 11.03 CRNMB 13 28 52 49 69.43 P vlue.02.005 Abbrevitions: CATCH, Comprison of Acute Tretments in Cncer Hemostsis Tril; CLOT, Rndomized Comprison of Low-Moleculr-Weight Heprin versus Orl Anticogulnt Therpy for the Prevention of Recurrent Venous Thromboembolism in Ptients with Cncer Investigtors Tril; CRNMB, cliniclly relevnt nonmjor bleeding; LMWH, low-moleculr-weight heprin. P vlue is bsed on chi-squred comprison of ech tril to study tril. Significnce level set t P <.05. the incidence of bleeding with rivroxbn were similr; however, the incidence of bleeding with pixbn ws mrkedly higher. There is no obvious explntion for this, s the dosing of pixbn ws pproprite in ll ptients in this tril except for one. There ws no documented bleed in this ptient s medicl chrt. A met-nlysis conducted by Vedovti nd collegues identified 6 studies in which ptients with cncer received either DOAC (with or without heprin product) or vitmin K ntgonist. 16 Tht nlysis found nonsignificnt reduction in VTE recurrence (odds rtio [OR], 0.63; 95% confidence intervl [CI], 0.31-1.1), mjor bleeding (OR, 0.77; 95% CI, 0.41-1.44), nd CRNMB (OR, 0.85; 95% CI, 0.62-1.18). 16 The met-nlysis dds to the growing body of evidence in support of both sfety nd efficcy of DOACs in ptients with cncer. Although the Vedovti nd collegues study does not directly compre rtes between 2 tretment groups, the findings of similr rtes of VTE recurrence, mjor bleed, nd CRNMB re consistent with the current study. Despite differing ptient chrcteristics, the met-nlysis by Vedovti nd collegues supports the ongoing use of DOACs in ptients with mlignncy, s does the current study. 16 Limittions Although it seems tht pixbn, dbigtrn, nd rivroxbn re effective in reducing the risk of VTE in veterns with mlignncy, there re some inherent weknesses in the current study. Most notbly is the choice of comprtor trils. The uthors believe tht the CLOT nd CATCH trils were the most pproprite bsed on similrities in popultion nd outcomes. Considering the CLOT nd CATCH trils compred LMWH to coumrin products for tretment of VTE, future studies should compre use of these gents with DOACs in the cncer popultion. In ddition, the study did not include outcomes tht would dequtely ssess risks of VTE nd bleeding formtion. This informtion would hve been beneficil to more effectively ctegorize this study s ptient popultion bsed on risks of ech of its predetermined outcomes. Understnding sfety nd efficcy of DOACs in ptients t vrious risks would help prctitioners to choose more pproprite gents in prctice. Lst, this study S32 FEDERAL PRACTITIONER SPECIAL ISSUE MAY 2018
TABLE 6 Chrcteristics of Ptients Receiving Active Tretment Mlignncy Tretment Regimen Metsttic DOAC DOAC Indiction Brin Unknown Brest Anstrozole, rdition therpy CLL Ibrutinib CML Bosutinib Colon Cpecitbine, oxlipltin Regorfenib Surgery Cpecitbine, oxlipltin History of VTE Multiple myelom Bortezomib, dexmethsone Bortezomib, cyclophosphmide, dexmethsone Lenlidomide Lenlidomide, crfilzomib, dexmethsone NMSC Imiquimod topicl Resection Excised Excised Excised, fluorourcil Rdition, djuvnt cpecitbine, excision, fluorourcil b Rdition Erlotinib Crbopltin-txol, docetxel, nivolumb Rdition History of VTE Prostte Leuprolide Leuprolide Rdition Biclutmide, leuprolide Docetxel, biclutmide Rdition, biclutmide, leuprolide Rdition SLL Prednisone Abbrevitions:, tril fibrilltion; CLL, chronic lymphocytic leukemi, CML, chronic myelogenous leukemi; DOAC, direct orl nticogulnt; NMSC, nonmelnom skin cncer; NSCLC, non-smll cell lung cncer; SLL, smll lymphocytic lymphom; VTE, venous thromboembolism. This ptient developed mjor bleed 12 months fter DOAC initition. b This ptient developed deep vein thrombosis. did not ssess the incidence of stroke in study ptients. This is importnt becuse the DOACs were used mostly for stroke prevention in nd tril flutter. The incresed risk of VTE in ptients with cncer cnnot directly correlte to risk of stroke with comorbid crdic condition, but the hypercogulble stte cnnot be ignored in these ptients. CONCLUSION This study provided some preliminry evidence for the sfety nd efficcy of DOACs in ptients with cncer. The low incidence of VTE formtion nd similr rtes of bleeding mong other clinicl trils indicte tht DOACs re sfe lterntives to currently recommended nticogultion mediction in ptients with cncer. AUTHOR DISCLOSURES The uthors report no ctul or potentil conflicts of interest with regrd to this rticle. DISCLAIMER The opinions expressed herein re those of the uthors nd do not necessrily reflect those of Federl Prctitioner, Frontline Medicl Communictions Inc., the US Government, or ny of its gencies. This rticle my discuss unlbeled or investigtionl use of certin drugs. Plese review the complete prescribing informtion for specific drugs or drug MAY 2018 FEDERAL PRACTITIONER SPECIAL ISSUE S33
combintions including indictions, contrindictions, wrnings, nd dverse effects before dministering phrmcologic therpy to ptients. REFERENCES 1. Motykie GD, Zebl LP, Cprini JA, et l. A guide to venous thromboembolism risk fctor ssessment. J Thromb Thrombolysis. 2000;9(3):253-262. 2. Zullig LL, Sims KJ, McNeil R, et l. Cncer incidence mong ptients of the U.S. Veterns Affirs Helth Cre System: 2010 updte. Mil Med. 2017;182(7):e1883-e1891. 3. Jnury CT, Wnn S, Alpert JS, et l; ACC/AHA Tsk Force Members. 2014 AHA/ACC/HRS guideline for the mngement of ptients with tril fibrilltion: executive summry. Circultion. 2014;130(23):2071-2104. 4. Keron C, Akl EA, Ornels J, et l. Antithrombotic therpy for VTE disese: CHEST guideline nd expert pnel report. Chest. 2016;149(2):315-352. 5. Ntionl Comprehensive Cncer Network. NCCN Clinicl Prctice Guidelines in Oncology (NCCN Guidelines). Cncer-ssocited venous thromboembolic disese. Version 1.2018. https://www.nccn.org/store/login/login. spx?returnurl=https://www.nccn.org/professionls /physicin_gls/pdf/vte.pdf. Updted Mrch 22, 2018. Accessed April 9, 2018. 6. Brunetti ND, Gesuete E, De Gennro L, et l. Direct-cting orl nticogulnts compred to vitmin K inhibitors nd low moleculr weight heprin for the prevention of venous thromboembolism in ptients with cncer: met-nlysis study. Int J Crdiol. 2017;230: 214-221. 7. Posch F, Konigsbrügge O, Zielinski C, Pbinger I, Ay C. Tretment of venous thromboembolism in ptients with cncer: network met-nlysis compring efficcy nd sfety of nticogulnts. Thromb Res. 2015;136(3): 582-589. 8. vn Es N, Coppens M, Schulmn S, Middledorp S, Büller HR. Direct orl nticogulnts compred with vitmin K ntgonists for cute venous thromboembolism: evidence from phse 3 trils. Blood. 2014;124(12):1968-1975. 9. Lee AY, Levine MN, Bker RI, et l; Rndomized Comprison of Low-Moleculr-Weight Heprin versus Orl Anticogulnt Therpy for the Prevention of Recurrent Venous Thromboembolism in Ptients with Cncer (CLOT) Investigtors. Low moleculr weight heprin versus coumrin for the prevention of recurrent venous thromboembolism in ptients with cncer. N Engl J Med. 2003;349(2):146-153. 10. Lee AY, Kmphuisen PW, Meyer G, et l; CATCH Investigtors. Tinzprin vs wrfrin for tretment of cute venous thromboembolism in ptients with ctive cncer: rndomized clinicl tril. JAMA. 2015;314(7):677-686. 11. Ktz S, Ahmd D, Spyropoulos AC, Schulmn S; Subcommittee on Control of Anticogultion. Definition of cliniclly relevnt non-mjor bleeding in studies of nticogulnts in tril fibrilltion nd venous thromboembolic disese in non-surgicl ptients: communiction from the SSC of the ISTH. J Thromb Hemost. 2015;13(11):2119-2126. 12. Agnelli G, Büller HR, Cohen A, et l. Orl pixbn for the tretment of venous thromboembolism in cncer ptients: results from the AMPLIFY tril. J Thromb Hemost. 2015;13(12):2187-2191. 13. Schulmn S, Goldhber SZ, Keron C, et l. Tretment with dbigtrn or wrfrin in ptients with venous thromboembolism nd cncer. Thromb Hemost. 2015;114(1):150-157. 14. Prins MH, Lensing AW, Brighton TA, et l. Orl rivroxbn versus enoxprin with vitmin K ntgonist for the tretment of symptomtic venous thromboembolism in ptients with cncer (EINSTEIN-DVT nd EINSTEIN-PF): pooled subgroup nlysis of two rndomised controlled trils. Lncet Hemtol. 2014;1(1):e37-e46. 15. Khornn AA, Connolly GC. Assessing risk of venous thromboembolism in the ptient with cncer. J Clin Oncol. 2009;27(9):4839-4847. 16. Vedovti MC, Germini F, Agnelli G, Becttini C. Direct orl nticogulnts in ptients with VTE nd cncer: systemtic review nd met-nlysis. Chest. 2015;147(2):475-483. S34 FEDERAL PRACTITIONER SPECIAL ISSUE MAY 2018