New Anticoagulant Agents: Incidence of Adverse Drug Reactions and New Signals Thereof

Carlos Treceño-Lobato; María-Isabel Jiménez-Serranía; Raquel Martínez-García; Francisco Corzo-Delibes; Luis H. Martín Arias

doi:10.1055/s-0038-1657783

Seminars in Thrombosis and Hemostasis, Table of Contents

Semin Thromb Hemost 2019; 45(02): 196-204
DOI: 10.1055/s-0038-1657783

Review Article

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

New Anticoagulant Agents: Incidence of Adverse Drug Reactions and New Signals Thereof

Authors

Carlos Treceño-Lobato

¹Consejo de Colegios Profesionales de Farmacéuticos de Castilla y León, Castilla y León, Spain

²Departamento de Ciencias de la Salud, Facultad de Ciencias de la Salud, Universidad Europea Miguel de Cervantes (UEMC), Valladolid, Spain
María-Isabel Jiménez-Serranía

¹Consejo de Colegios Profesionales de Farmacéuticos de Castilla y León, Castilla y León, Spain

²Departamento de Ciencias de la Salud, Facultad de Ciencias de la Salud, Universidad Europea Miguel de Cervantes (UEMC), Valladolid, Spain
Raquel Martínez-García

¹Consejo de Colegios Profesionales de Farmacéuticos de Castilla y León, Castilla y León, Spain
Francisco Corzo-Delibes

³Consejería de Sanidad de la Junta de Castilla y León, Dirección General de Salud Pública (DGSP), Valladolid, Spain
Luis H. Martín Arias

⁴Centro Regional de Farmacovigilancia de Castilla y León, Centro de Estudios sobre la Seguridad de los Medicamentos (CESME), Facultad de Medicina, Universidad de Valladolid, Valladolid, Spain

Abstract

The aim of this study was to evaluate the adverse drug reaction (ADR) incidence rate and new signals thereof for classic compared with new anticoagulants in real-life ambulatory settings. The authors performed an observational cross-sectional study in two cohorts of surveyed patients treated with vitamin K antagonists (VKAs; acenocoumarol or warfarin) or nonvitamin K antagonist oral anticoagulants (NOACs; apixaban, edoxaban, rivaroxaban, dabigatran etexilate). Descriptive, clinical, and ADRs data were reported and analyzed through a bivariate analysis (odds ratio [OR]) to compare the ADRs incidence rate and an adaptation of Bayesian methodology (false discovery rate [FDR] < 0.05) to detect new signals. A total of 334 patients were surveyed—average international normalized ratio (INR) of 2.6—and 45.4% taking new anticoagulants. Note that 835 ADRs were reported; 2.5 per patient (2.8 in the VKA cohort, 2.1 in the NOAC cohort). The authors obtained higher risk of epistaxis (OR, 2.18; 95% confidence interval [CI], 1.01–4.74) and hematoma (OR, 2.43; 95% CI, 1.39–4.25) with VKAs and lower risk of global bleeding symptoms with NOACs (OR, 0.45; 95% CI, 0.28–0.71). After standardizing the data, a significant risk of diarrhea with VKAs was observed (OR, 3.37; 95% CI, 1.09–10.41). They also detected an intense positive signal regarding the use of VKAs and osteoporosis (FDR < 0.001), specifically acenocoumarol (FDR < 0.002). NOACs presented lower risk of bleeding, especially dabigatran (FDR < 0.031), and of dermatological pathologies with apixaban being the safest (FDR = 0.050). The lower risk of global bleeding and a potential protective effect against osteoporosis in patients treated with NOACs postulate them as safer than VKAs.

Keywords

new oral anticoagulant - vitamin K antagonist - bleeding - osteoporosis

Full Text

References

References
1 Portal estadístico del Ministerio de Sanidad, Servicios Sociales e Igualdad. Gobierno de España. Tasas de mortalidad ajustadas por edad a partir de; 1999. Ministerio de Sanidad, Servicios Sociales e Igualdad. Available at: http://pestadistico.inteligenciadegestion.msssi.es/publicoSNS/ comun/Informe.aspx?IdNodo=5012 . Accessed February 15, 2017
2 de Abajo F, García J. Utilización De Antiagregantes Y Anticoagulantes En España (1992–2006). Agencia Española de Medicamentos y Productos Sanitarios (AEMPS). Available at: https://www.aemps.gob.es/medicamentos UsoHumano/observatorio/docs/antiagregantes.pdf . Accessed December 15, 2017
3 Franchini M, Liumbruno GM, Bonfanti C, Lippi G. The evolution of anticoagulant therapy. Blood Transfus 2016; 14 (02) 175-184
4 Giugliano RP, Ruff CT, Braunwald E. , et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369 (22) 2093-2104
5 Connolly SJ, Ezekowitz MD, Yusuf S. , et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361 (12) 1139-1151
6 Büller HR, Décousus H, Grosso MA. , et al; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013; 369 (15) 1406-1415
7 Granger CB, Alexander JH, McMurray JJV. , et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365 (11) 981-992
8 Hori M, Matsumoto M, Tanahashi N. , et al; J-ROCKET AF study investigators. Rivaroxaban vs. warfarin in Japanese patients with atrial fibrillation – The J-ROCKET AF study. Circ J 2012; 76 (09) 2104-2111
9 Schulman S, Kearon C, Kakkar AK. , et al; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361 (24) 2342-2352
10 Patel MR, Mahaffey KW, Garg J. , et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365 (10) 883-891
11 Carvajal A, Sáinz M, Velasco V. , et al. Emergency contraceptive pill safety profile. Comparison of the results of a follow-up study to those coming from spontaneous reporting. Pharmacoepidemiol Drug Saf 2015; 24 (01) 93-97
12 Bate A, Lindquist M, Edwards IR. , et al. A Bayesian neural network method for adverse drug reaction signal generation. Eur J Clin Pharmacol 1998; 54 (04) 315-321
13 Vega Alonso AT, Zurriaga Llorens O, Galmés Truyols A. , et al; Group of Research for the RECENT Project. Health sentinel networks in Spain. Consensus for a guide of principles and methods [in Spanish]. Gac Sanit 2006; 20 (06) 496-502
14 Ahmed I, Haramburu F, Fourrier-Réglat A. , et al. Bayesian pharmacovigilance signal detection methods revisited in a multiple comparison setting. Stat Med 2009; 28 (13) 1774-1792
15 Gould AL. Practical pharmacovigilance analysis strategies. Pharmacoepidemiol Drug Saf 2003; 12 (07) 559-574
16 Nóren N. . ed. A Monte Carlo Method for Bayesian Dependency Derivation . Gothenburg: Chalmers University of Technology; 2002
17 Adelborg K, Grove EL, Sundbøll J, Laursen M, Schmidt M. Sixteen-year nationwide trends in antithrombotic drug use in Denmark and its correlation with landmark studies. Heart 2016; 102 (23) 1883-1889
18 de Abajo F, García del Pozo J. Utilización De Antiagregantes Y Anticoagulantes En España (1992–2006). Agencia Española de Medicamentos y Productos Sanitarios (AEMPS) [Internet]; 2006. Available at: https://www.aemps.gob.es/medicamentosUsoHumano/observatorio/docs/antiagregantes.pdf . Accessed December 28, 2016
19 Catalá-López F, Tobías A. Meta-analysis of randomized trials, heterogeneity and prediction intervals [in Spanish]. Med Clin (Barc) 2014; 142 (06) 270-274
20 Bahit MC, Lopes RD, Wojdyla DM. , et al. Non-major bleeding with apixaban versus warfarin in patients with atrial fibrillation. Heart 2017; 103 (08) 623-628
21 Sauter TC, Hegazy K, Hautz WE. , et al. Epistaxis in anticoagulated patients: Fewer hospital admissions and shorter hospital stays on rivaroxaban compared to phenprocoumon. Clin Otolaryngol 2017; ; Epub ahead of print
22 Gökdoğan O, Akyildiz I, Sayin BY, Okutucu S, Tanalp AC, Arslan N. The Rate of epistaxis incidence in new-generation anticoagulants and perioperative approach in otorhinolaryngological practices. J Craniofac Surg 2017; 28 (02) e178-e182
23 Roux E, Thiessard F, Fourrier A, Bégaud B, Tubert-Bitter P. Evaluation of statistical association measures for the automatic signal generation in pharmacovigilance. IEEE Trans Inf Technol Biomed 2005; 9 (04) 518-527
24 Bate A, Lindquist M, Edwards IR. The application of knowledge discovery in databases to post-marketing drug safety: example of the WHO database. Fundam Clin Pharmacol 2008; 22 (02) 127-140
25 Bate A. Bayesian confidence propagation neural network. Drug Saf 2007; 30 (07) 623-625
26 Bate A, Lindquist M, Orre R, Edwards IR, Meyboom RH. Data-mining analyses of pharmacovigilance signals in relation to relevant comparison drugs. Eur J Clin Pharmacol 2002; 58 (07) 483-490
27 Zorych I, Madigan D, Ryan P, Bate A. Disproportionality methods for pharmacovigilance in longitudinal observational databases. Stat Methods Med Res 2013; 22 (01) 39-56
28 Bate A, Evans SJ. Quantitative signal detection using spontaneous ADR reporting. Pharmacoepidemiol Drug Saf 2009; 18 (06) 427-436
29 Lindquist M, Ståhl M, Bate A, Edwards IR, Meyboom RH. A retrospective evaluation of a data mining approach to aid finding new adverse drug reaction signals in the WHO international database. Drug Saf 2000; 23 (06) 533-542
30 Agencia Española de Medicamentos y Productos Sanitarios (AEMPS). Centro de Información online de Medicamentos de la AEMPS-CIMA. Ministerio de Sanidad, Servicios Sociales e Igualdad. Sintrom® SPC [Internet]; 2017. Available at: https://www.aemps.gob.es/cima/dochtml/ft/58994/ FichaTecnica_58994.html . Accessed August 15, 2017
31 Agencia Española de Medicamentos y Productos Sanitarios (AEMPS). Centro de Información online de Medicamentos de la AEMPS-CIMA. Ministerio de Sanidad, Servicios Sociales e Igualdad. Xarelto® SPC [Internet]; 2017. Available at: http://www.ema.europa.eu/docs/es_ES/document library/EPAR_Product_Information/human/000944/WC500057108.pdf . Accessed August 15, 2017
32 Agencia Española de Medicamentos y Productos Sanitarios (AEMPS). Centro de Información online de Medicamentos de la AEMPS-CIMA. Ministerio de Sanidad, Servicios Sociales e Igualdad. Lixiana® SPC [Internet]; 2017. Available at: http://www.ema.europa.eu/docs/es_ES/document_library /EPAR_-_Product_Information/human/002629/WC500189045.pdf . Accessed August 15, 2017
33 Agencia Española de Medicamentos y Productos Sanitarios (AEMPS). Centro de Información online de Medicamentos de la AEMPS-CIMA. Ministerio de Sanidad, Servicios Sociales e Igualdad. Eliquis® SPC [Internet]; 2017. Available at: http://www.ema.europa.eu/docs/es_ES/document_library/ EPAR_-_Product_Information/human/002148/WC500107728.pdf . Accessed August 15, 2017
34 Agencia Española de Medicamentos y Productos Sanitarios (AEMPS). Centro de Información online de Medicamentos de la AEMPS-CIMA. Ministerio de Sanidad, Servicios Sociales e Igualdad. Pradaxa SPC [Internet]; 2017. Available at: http://www.ema.europa.eu/docs/es_ES/document_library/ EPAR_-_Product_Information/human/000829/WC500041059.pdf . Accessed August 15, 2017
35 Namba S, Yamaoka-Tojo M, Hashikata T. , et al. Long-term warfarin therapy and biomarkers for osteoporosis and atherosclerosis. BBA Clin 2015; 4: 76-80
36 Gage BF, Birman-Deych E, Radford MJ, Nilasena DS, Binder EF. Risk of osteoporotic fracture in elderly patients taking warfarin: results from the National Registry of Atrial Fibrillation 2. Arch Intern Med 2006; 166 (02) 241-246
37 Iwamoto J. Vitamin K₂ therapy for postmenopausal osteoporosis. Nutrients 2014; 6 (05) 1971-1980
38 Namba S, Yamaoka-Tojo M, Kakizaki R. , et al. Effects on bone metabolism markers and arterial stiffness by switching to rivaroxaban from warfarin in patients with atrial fibrillation. Heart Vessels 2017; 32 (08) 977-982
39 Lau WC, Chan EW, Cheung CL. , et al. Association between dabigatran vs warfarin and risk of osteoporotic fractures among patients with nonvalvular atrial fibrillation. JAMA 2017; 317 (11) 1151-1158