Revisión sistemática y metanálisis del tratamiento anticoagulante en la trombosis asociada al cáncer. Implicaciones en estudios de no inferioridad. / Systematic review and meta analysis of anticoagulant treatment in cancer-associated thrombosis. Implications about non-inferiority studies.

Gilberto Vizcaíno, Jesús Weir Medina, Jesús Quintero, Jennifer Vizcaíno Carruyo

Resumen


Resumen.

La trombosis asociada al cáncer (TAC) constituye una complicación frecuente en pacientes con esta enfermedad. Existen tres opciones para la tromboprofilaxis: los anticoagulantes orales directos (ACOD), las heparinas de bajo peso molecular (HBPM) y las anti-vitamina K (warfarina). Se realizó una revisión sistemática para comparar las tres alternativas de tratamiento sobre efectividad bajo criterios de no inferioridad. Adicionalmente se analizaron el empleo de los ACOD y las HBPM contra placebo para evidenciar superioridad. El evento primario fue la trombosis venosa profunda recurrente (TVPr) y para seguridad, la hemorragia mayor. Un total de 9353 pacientes fueron clasificados en cuatro categorías: ACOD vs warfarina (4 estudios), ACOD vs HBPM (3 estudios), HBPM vs warfarina (3 estudios) y ACOD o HBPM vs placebo (4 estudios). Los resultados mostraron una superioridad de los ACOD sobre la warfarina en TVPr, RR(IC95%) igual a 0,70 (0,58-0,87), p<0,001] y una no inferioridad entre los ACOD vs las HBPM y entre las HBPM vs la warfarina, [RR;(IC95%) igual a 0,78; (0,59-1,03), p=0,081 y 0,71 (0,44-1,14), P=0,159 respectivamente]. El análisis de seguridad para hemorragia mayor mostró superioridad de las HBPM sobre los ACOD y la warfarina [RR; (IC95%) igual a 1,69; (1,22-2,33), p<0,002 y 0,72; (0,56-0,93), p<0,001 respectivamente]. Se demostró superioridad de los ACOD y las HBPM versus el placebo, pero el riesgo de hemorragia fue mayor. Se concluye que la ligera ventaja que presentan los ACOD en la reducción de TVPr se ve cuestionada por el mayor riesgo de hemorragia. Se sugiere que la elección del anticoagulante debe ser personalizada, teniendo en consideración el riesgo de hemorragia, el sitio del cáncer, además de los valores y preferencias del paciente.

Abstract.

Cancer-associated thrombosis (CAT) is a frequent complication in cancer patients. There are three options for thromboprophilaxis: new direct oral anticoagulants (NOAC), low molecular weight heparins (LMWH) and antivitamin K (warfarin). The present systematic review was carried out to compare these alternatives on their effectiveness and safety under criteria of non-inferiority. Additionally, the use of NOAC and LMWH against a placebo was analyzed to show superiority. The primary event was deep venous thrombosis recurrence (DVTr) and for security, major bleeding. A total of 9353 patients were classified in four categories: NOAC vs warfarin (4 studies), NOAC vs LMWH (3 studies), LMWH vs. warfarin (3 studies) and NOAC or LMWH vs placebo (4 studies). The results show a superiority of NOAC over warfarin [RR; (95% CI) = 0.70; (0.58-0.87), p <0.001] and a non-inferiority of NOAC vs LMWH and LMWH vs. warfarin (RR; (95%CI) = 0.78;(0.59-1.03), p= 0.081 and 0.71; (0.44-1.14), p= 0.159 respectively]. Safety analysis for major bleeding showed superiority of LMWH over NOAC and warfarin [RR; (95%CI) = 1.69; (1.22-2.33), p <0.002 and 0.72;(0.56-0.93), p <0.001 respectively]. Studies showed superiority of NOAC / LMWH vs placebo, but the risk of bleeding was higher. It is concluded that the slight advantage of NOAC in the prevention and reduction of DVTr is questioned by the increased risk of bleeding. It is suggested that the choice of anticoagulant should be personalized, considering the risk of bleeding from the patient, the cancer site and the patient’s values and preferences.


Palabras clave


trombosis; cáncer; anticoagulantes orales directos; warfarina; heparinas de bajo peso molecular; metanálisis; no inferioridad; thrombosis; cancer; new oral anticoagulants; warfarin; low molecular weight heparins; meta-analysis; non-inferiority.

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Referencias


Lee AYY, Levine MN. Venous thromboem- bolism and cancer: risks and outcomes. Cir- culation 2003;107(Suppl 23):117-121.

Timp JF, Braekkan SK, Versteeg HH, Can- negieter SC. Epidemiology of venous throm- bosis. Blood 2013; 122(10):1712–1723.

Khorana AA, Francis CW, Culakova E, Ku- derer NM, Lyman GH. Thromboembolism is a leading cause of death in cancer pa- tients receiving outpatient chemotherapy. J Thromb Haemost 2007;5(3):632–634.

Soff G. Thrombosis and Hemostasis in Cancer. Scope of the Problem and Overview. In Can- cer Treatment and Research; Volume 179:1-9. Springer Nature Switzerland AG 2019. ISBN 978-3-030-20315-3 (eBook). https://doi.org/10.1007/978-3-030-20315-3.

Falanga A, Marchetti M. Venous throm- boembolism in the hematologic malignan- cies. J Clin Oncol 2009;27(29):4848–4857.

Piccioli A, Falanga A, Baccaglini U, Mar- chetti M, Prandoni P. Cancer and venous thromboembolism. Semin Thromb Hemost 2006;32(7):694–699.

Thalin C, Hisada Y, Lundström S, Mackman N, Wallén H. Neutrophil extracellular traps. Villains and targets in arterial, venous, and cancer-associated thrombosis. Arterioscler Thromb Vasc Biol. 2019;39(9):1724-1738. doi: 10.1161/ATV BAHA.119.312463.

Mauracher LM, Posch F, Martinod K, Grilz E, Däullary T, Hell L, Brostjan C, Zielinski C, Ay C, Wagner DD, Pabinger I, Thaler J. Citrullinated histone H3, a biomarker of neutrophil extracellular trap formation, predicts the risk of venous thromboembo- lism in cancer patients. J Thromb Haemost 2018;16:508–518. doi: 10.1111/jth.13951.

Leal AC, Mizurini DM, Gomes T, Rochael NC, Saraiva EM, Dias MS, Werneck CC, Sielski MS, Vicente CP, Monteiro RQ. Tumor-derived exosomes induce the forma- tion of neutrophil extracellular traps: impli- cations for the establishment of cancer-as- sociated thrombosis. Sci Rep. 2017;7:6438. doi: 10.1038/s41598-017-06893-7.

Falanga A, Schieppati F, Russo L. Pathophy- siology, Mechanisms of Thrombosis in Cancer Patients. In Thrombosis and Hemostasis in cancer. Cancer Treatment and Research; Volume 179:12-36. Springer Nature Switzerland AG 2019. ISBN 978-3-030-20315-3 (eBook). https://doi.org/10.1007/978-3-03 0-20315-3.

Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a predictive model for che- motherapy-associated thrombosis. Blood 2008;111(10):4902–4907.

Ay C, Dunkler D, Marosi C, Chiriac AL, Vormittag R, Simanek R, Quehenberger P, Zielinski C, Pabinger I. Prediction of ve- nous thromboembolism in cancer patients. Blood 2010;116(24):5377–5382.

Pabinger I, van Es N, Heinze G, Posch F, Riedl J, Reitter EM, Di Nisio M, Ce- sarman-Maus G, Kraaijpoel N, Zielinski CC, Büller HR, Ay C. A clinical predic- tion model for cancer-associated venous thromboembolism: a development and validation study in two independent prospective cohorts. Lancet Haematol 2018;5(7):e289-e298. doi: 10.1016/S2352-3026(18)30063-2.

Louzada ML, Carrier M, Lazo-Langner A, Dao V, Kovacs MJ, Ramsay TO, Rodger MA, Zhang J, Lee AY, Meyer G, Wells PS. Development of a clinical prediction rule for risk stratification of recurrent venous thromboembolism in patients with cancer- associated venous thromboembolism. Cir- culation 2012;126:448–454.

Murray GD, Best CH. The use of heparin in thrombosis. Ann Surg 1938;108(2):163–177.

Barritt DW, Jordan SC. Anticoagulant drugs in the treatment of pulmonary em- bolism. A controlled trial. Lancet 1960; 1(7138):1309–1312.

Quintero González JA. Cincuenta años de uso clínico de la warfarina. Invest Clin 2010;51:269-287.

Galanaud JP, Laroche JP, Righini M. The history and historical treatments of deep vein thrombosis. J Thromb Haemost 2013;11(3):402–411.

Hyers TM. Management of venous throm- boembolism: past, present, and future. Arch Intern Med 2003;163(7):759–768.

Xiong Q, Lau YC, Lip GY. Pharmacodynamic profile and drug interactions with non-vitamin K antagonist oral anticoagulants: implications for patients with atrial fibrillation. Expert Opin Drug Metab Toxicol 2015;11:937-948.

Hellwig T, Gulseth M. Pharmacokinetic and pharmacodynamic drug interactions with new oral anticoagulants: what do they mean for patients with atrial fibrillation? Ann Pharmacother 2013;47:1478-1487.

Lyman GH, Bohlke K, Khorana AA, Ku- derer NM, Lee AY, Arcelus JI, Balaban EP, Clarke JM, Flowers CR, Francis CW, Gates LE, Kakkar AK, Key NS, Levine MN, Lieb- man HA, Tempero MA, Wong SL, Somer- field MR, Falanga A. Venous thromboembo- lism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update 2014. J Clin Oncol 2015;33(6):654–656.

Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, Huisman M, King CS, Morris TA, Sood N, Stevens SM, Vintch JRE, Wells P, Woller SC, Moores L. Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report. Chest 2016;149(2):315–352.

Carrier M, Soff G, Le Gal G. Treatment of Venous Thromboembolism in Cancer. His- torical Perspective and Evolving Role of the Direct Oral Anticoagulants. In Thrombosis and Hemostasis in Cancer. Cancer Treat Res 2019; 179:104-115. Springer Nature Switzerland AG 2019. ISBN 978-3-030-20315-3 (eBook). https://doi.org/10.1007/978-3-03 0-20315-3.

Ferreira-González I. Bases para la inter- pretación de los estudios de no inferiori- dad: a propósito de los estudios ROCKET– AF, RE-LY y ARISTOTLE. Rev Esp Cardiol 2014;67(6):432–435.

Vizcaíno G. La Estadística al alcance del Médico. Análisis crítico de ensayos clínicos. Capítulo III. Los estudios de no inferioridad en clínica médica. Maracaibo (Ven). Edicio- nes Astro Data; 2017, ISBN 978-980-402-254-8, pp 53-69.

Hung HM, Wang SJ, Tsong Y, Lawrence J, O’neil RT. Some fundamental issues with non-inferiority testing in active controlled trials. Stat Med 2003;22:213-225.

Pluchino S. Estudios clínicos de no infe- rioridad y de equivalencia: metodología, análisis e interpretación de los resultados. Avances Cardiol 2009; 29:76-81.

Schulman S, Kearon C. Subcommittee on Control of Anticoagulation of the Scientific and Standardization Com- mittee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investiga- tions of antihemostatic medicinal pro- ducts in non-surgical patients. J Thromb Haemost 2005;3:692–694.

Streiff MB, Milentijevic D, McCrae K, Yan- nicelli D, Fortier J, Nelson WW, Laliberté F, Crivera C, Lefebvre P, Schein J, Khora- na AA. Effectiveness and safety of anticoa- gulants for the treatment of venous throm- boembolismin patients with cancer. Am J Hematol 2018;93:664–671.

Agnelli G, Buller HR, Cohen A,Gallus AS, Lee TC, Pak R, Raskob GE, Weitz JI, Ya- mabe DT. Oral apixaban for the treatment of venous thromboembolism in cancer pa- tients: results from the AMPLIFY trial. J Thromb Haemost 2015;13: 2187–2191.

Schulman S, Goldhaber SZ, Kearon C, Kakkar AK, Schellong S, Eriksson H, Han- tel S, Feuring M, Kreuzer J. Treatment with dabigatran or warfarin in patients with venous thromboembolism and cancer. Thromb Haemost 2015;114(1):150-157.

Prins MH, Lensing AW, Brighton TA, Lyons RM, Rehm J, Trajanovic M, Davidson BL, Beyer-Westendorf J, Pap ÁF, Berkowitz SD, Cohen AT, Kovacs MJ, Wells PS, Pran- doni P. Oral rivaroxaban versus enoxaparin with vitamin K antagonist for the treatment of symptomatic venous thromboembolism in patients with cancer (EINSTEIN-DVT and EINSTEIN-PE): a pooled subgroup analysis of two randomised controlled trials. Lancet Haematol 2014;1(1):e37-46.

Raskob GE, van Es N, Verhamme P, Ca- rrier M, Di Nisio M, Garcia D, Grosso MA, Kakkar AK, Kovacs MJ, Mercuri MF, Me- yer G, Segers A, Shi M, Wang TF, Yeo E, Zhang G, Zwicker JI, Weitz JI, Büller HR; Hokusai VTE Cancer Investigators. Edoxa- ban for the treatment of cancer-associated venous thromboembolism. N Engl J Med 2018;378(7):615-624.

Young AM, Marshall A, Thirlwall J, Cha- pman O, Lokare A, Hill C, Hale D, Dunn JA, Lyman GH, Hutchinson C, MacCallum P, Kakkar A, Hobbs FDR, Petrou S, Dale J, Poole CJ, Maraveyas A, Levine M. Compa- rison of an oral Factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: re- sults of a randomized trial (SELECT-D). J Clin Oncol 2018;36:2017-2023.

Woodruff S, Lee AYY, Carrier M, Feugère G, Abreu P, Heissler J. Low-molecular-weight- heparin versus a coumarin for the prevention of recurrent venous thromboembolism in high- and low-risk patients with active can- cer: a post hoc analysis of the CLOT Study. J Thromb Thrombolys 2019;47:495–504.

Agnes Y. Y. Lee AYY, Kamphuisen PW, Me- yer G, Bauersachs R, Janas MS, Jarner MF, Khorana AA, for the CATCH Investigators. Tinzaparin vs warfarin for treatment of acu- te venous thromboembolism in patients with active cancer. A randomized clinical trial. JAMA 2015;314(7):677-686.

Khorana AA, Soff GA, Kakkar AK, Vad- han Raj S, Riess H, Wun T, and the CASSINI Investigators. Rivaroxaban for thromboprophylaxis in high-risk ambula- tory patients with cancer. N Engl J Med 2019;380:720-728.

Kuruvilla P, Hill D, Spadafora S, Marquis K, Trinkaus M, Tomiak A, Lee AYY, Gross PL, Lazo-Langner A, El-Maraghi R, Goss G, Le Gal G, Stewart D, Ramsay T, Rod- ger M, Witham D, Wells PS, AVERT In- vestigators. Apixaban to prevent venous thromboembolism in patients with cancer. N Engl J Med 2019;380(8):711-719.

Ek L, Gezelius E, Bergman B, Bendahl PO, Anderson H, Sundberg J, Wallberg M, Falkmer U, Verma S, Belting M. Randomi- zed phase III trial of low-molecular-weight heparin enoxaparin in addition to standard treatment in small-cell lung cancer: the RASTEN trial. Ann Oncol 2018;29:398–404.

Barni S, Labianca R, Agnelli G, Bonizzoni E, Verso M, Mandalà M, Brighenti M, Pe- trelli F, Bianchini C, Perrone T, Gasparini G. Chemotherapy-associated thromboem- bolic risk in cancer outpatients and effect of nadroparin thromboprophylaxis: results of a retrospective analysis of the PROTE- CHT study. J Translat Med 2011;9:179-186.

Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred Reporting Items for Systematic Reviews and Meta- Analysis. PLoS Med. 2009;6(7):e1000097. doi: 10.1371/journal.pmed.1000097.

Higgins JPT, Thompson SG, Deeks JJ, Alt- man DG. Measuring inconsistency in meta- analyses. BMJ 2003;327:557-60.

Wang Y, Lv H, Li D, Chen C, Gu G, Sun Y, Yang X, Liu Y, Fang F, Liu J, Tse G, Xia Y. Efficacy and safety of direct oral anticoa- gulants for secondary prevention of cancer- associated thrombosis: a systematic review and meta-analysis of randomized controlled trials and prospective cohort studies. Front Pharmacol 2019. 10:773. doi: 10.3389/ fphar.2019.00773.

Carrier M, Cameron C, Delluc A, Caste- llucci L, Khorana AA, Lee AYY. Efficacy and safety of anticoagulant therapy for the treatment of acute cancer-associated thrombosis: a systematic review and meta- analysis. Thromb Res 2014;134(6):1214-9.

Carrier M, Prandoni P. Controversies in the management of cancer-associated thrombo- sis. Expert Rev Hematol 2017;10(1):15-22.

Farge D, Debourdeau P, Beckers M, Baglin C, Bauersachs RM, Brenner B, Brilhante D, Falanga A, Gerotzafias GT, Haim N, Kakkar AK, Khorana AA, Lecumberri R, Mandala M, Marty M, Monreal M, Mousa SA, Noble S, Pabinger I, Prandoni P, Prins MH, Qari MH, Streiff MB, Syrigos K, Bou- nameaux H, Büller HR. International cli- nical practice guidelines for the treatment and prophylaxis of venous thromboembo- lism in patients with cancer. J Thromb Hae- most 2013;11:56–70.

Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, Huisman M, King CS, Morris TA, Sood N, Stevens SM, Vintch JRE, Wells P, Woller SC, Moores L. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest 2016;149:315–352.

Khorana AA. The NCCN Clinical Practi- ce Guidelines on Venous Thromboembolic Disease: strategies for improving VTE pro- phylaxis in hospitalized cancer patients. Oncologist 2007;12:1361–1370.

Noble S, Matzdorff A, Maraveyas A, Holm MV, Pisa G. Assessing patients’ anticoa- gulation preferences for the treatment of cancer-associated thrombosis using conjoint methodology. Haematologica 2015;100:1486–1492.

Carrier M, Khorana AA, Zwicker J, Noble S, Lee AYY; Subcommittee on Haemos- tasis and Malignancy for the SSC of the ISTH. Management of challenging cases of patients with cancer-associated thrombosis including recurrent thrombosis and blee- ding: guidance from the SSC of the ISTH. J Thromb Haemost 2013;11:1760–1765.

Khorana AA, Carrier M, Garcia DA, Lee AYY. Guidance for the prevention and treatment of cancer-associated venous thromboembolism. J Thromb Thrombolysis 2016;41:81–91.

Chee CE, Ashrani AA, Marks RS, Petter- son TM, Bailey KR, Melton LJ, Heit JA. Predictors of venous thromboembolism re- currence and bleeding among active cancer patients: a population-based cohort study. Blood 2014;123(25):3972-3978.

Schulman S, Zondag M, Linkins L, Pas- ca S, Cheung YW, de Sancho M, Gallus A6, Lecumberri R, Molnar S, Ageno W, Le Gal G, Falanga A, Hulegårdh E, Ran- ta S, Kamphuisen P, Debourdeau P, Riga- monti V, Ortel TL, Lee A. Recurrent ve- nous thromboembolism in anticoagulated patients with cancer: management and short-term prognosis. J Thromb Haemost 2015;13:1010–1018.

Rossel A1, Robert-Ebadi H, Combescure C, Grosgurin O, Stirnemann J, Addeo A, Garin N, Agoritsas T, Reny JL, Marti C. Anticoagulant therapy for acute venous thrombo-embolism in cancer patients: A systematic review and network meta-analy- sis. PLoS One 2019;14(3):e0213940. doi:10.1371/journal.pone.0213940. eCollec- tion 2019.

Suryanarayan D, Lee AYY, Wu C. Direct oral anticoagulants in cancer patients. Se- min Thromb Hemost. 2019;45(6):638-647.

Soff GA, Mones J, Wilkins C, Devlin S, Haegler‐Laube E, Wills J, Sarasohn DM, Juluru K, Singer M, Miao Y, Batista J, Mantha S. Rivaroxaban treatment of can cer‐associated venous thromboembolism: Memorial Sloan Kettering Cancer Center institutional experience. Res Pract Thromb Haemost. 2019;3:349–356.

Francis CW, Kessler CM, Goldhaber SZ, Kovacs MJ, Monreal M, Huisman MV, Ber- gqvist D, Turpie AG, Ortel TL, Spyropou- los AC, Pabinger I, Kakkar AK. Treatment of venous thromboembolism in cancer pa- tients with dalteparin for up to 12 months: the DALTECAN Study. J Thromb Haemost. 2015 Jun;13(6):1028-1035.

Witt DM, Nieuwlaat R, Clark NP, Ansell J, Holbrook A, Skov J, Shehab N, Mock J, Myers T, Dentali F, Crowther MA, Agarwal A, Bhatt M, Khatib R, Riva JJ, Zhang Y, Guyatt G. American Society of Hematolo- gy 2018 guidelines for management of ve- nous thromboembolism: optimal manage- ment of anticoagulation therapy. Blood Adv 2018;2(22):3257–3291.

Wang TF, Li A, Garcia D. Managing thrombosis in cancer patients. Res Pract Thromb Haemost. 2018;2(3),429–438. doi: 10.1002/rth2.12102.

Noble S, Sui J. The treatment of cancer as- sociated thrombosis: does one size fit all? Who should get LMWH/warfarin/DOACs? Thromb Res. 2016 Apr;140 Suppl 1:S154-9. doi: 10.1016/S0049-3848(16)30115-3.

Connors JM. Prophylaxis against venous thromboembolism in ambulatory patients with cancer. N Engl J Med 2014;370:2515- 2519.

Key NS, Khorana AA, Kuderer NM, Bo- hlke K, Lee AYY, Arcelus JI, Wong SL, Ba- laban EP, Flowers CR, Francis CW, Gates LE, Kakkar AK, Levine MN, Liebman HA, Tempero MA, Lyman GH, Falanga A. Ve- nous thromboembolism prophylaxis and treatment in patients with cancer: ASCO Clinical Practice Guideline Update. J Clin Oncol 2019;JCO1901461. doi: 10.1200/ JCO.19.01461.




DOI: http://dx.doi.org/10.22209/IC.v61n2a07

Universidad del Zulia / Venezuela / Investigación Clínica /riclinicas@gmail.com / p-ISSN: 0535-5133 / e-ISSN: 2477-9393

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