Vitamin-K-antagonist phenprocoumon versus low-dose direct oral anticoagulants (DOACs) in patients with atrial fibrillation: a real-world analysis of German claims data.
Atrial fibrillation
Direct oral anticoagulants
Low-dose therapy
Phenprocoumon
Vitamin-K-antagonists
Journal
Thrombosis journal
ISSN: 1477-9560
Titre abrégé: Thromb J
Pays: England
ID NLM: 101170542
Informations de publication
Date de publication:
26 May 2022
26 May 2022
Historique:
received:
19
10
2021
accepted:
15
05
2022
entrez:
26
5
2022
pubmed:
27
5
2022
medline:
27
5
2022
Statut:
epublish
Résumé
For stroke prevention in patients with atrial fibrillation (AF), direct oral anticoagulants (DOACs) have been increasingly prescribed instead of vitamin-K-antagonists (VKA). For some patients a lower dosage of DOACs (ld-DOACs) is recommended. Ld-DOAC prescribing seems to be common, although previous studies did not show clear superiority of ld-DOACs over warfarin. In Germany, phenprocoumon is used almost exclusively as VKA. Randomized controlled trials comparing DOACs and phenprocoumon in the general population of patients with AF do not exist. Therefore, we aimed to compare ld-DOACs and phenprocoumon in a real-world setting in Germany. In a retrospective observational cohort study, claims data from a group of small to medium-sized health insurance companies were analysed. Risks for the outcomes thromboembolism, death and major bleeding were estimated by Cox regression. Out of 93,685 patients with atrial fibrillation and a first prescription of an oral anticoagulant, 20,179 receiving VKA and 21,724 ld-DOACs (29.6% of all DOAC patients) were included. For the sensitivity analysis phenprocoumon was compared to the five ld-DOAC groups (ld-apixaban, ld-dabigatran, ld-edoxaban, ld-rivaroxaban, and the composite of all ld-DOACs) after propensity-score matching. Phenprocoumon was associated with statistically significant fewer thromboembolic events (HR = 1.29, 95% CI [1.13, 1.48], p < .001) and deaths (HR = 1.52, 95% CI [1.41, 1.63], p < .001) and a non-significant higher bleeding risk (HR = 0.89, 95% CI [0.79, 1.00], p = .051) than composite ld-DOAC. Regarding the subgroups, only patients with ld-apixaban had a statistically significant higher risk for thromboembolic events (HR = 1.42, 95% CI [1.21, 1.65], p < .001) and a lower bleeding risk (HR = 0.75, 95% CI [0.65, 0.86], p < .001). Ld-apixaban, ld-edoxaban, and ld-rivaroxaban were associated with a higher risk of death. The sensitivity analysis confirmed these associations. Phenprocoumon seems to be superior to ld-DOACs for patients with AF. As a hypothesis phenprocoumon might turn out to be the wiser choice for high-risk patients with AF as compared to ld-DOACs, especially regarding thromboembolic events and death. Therefore, RCTs comparing ld-DOACs with phenprocoumon are needed.
Sections du résumé
BACKGROUND
BACKGROUND
For stroke prevention in patients with atrial fibrillation (AF), direct oral anticoagulants (DOACs) have been increasingly prescribed instead of vitamin-K-antagonists (VKA). For some patients a lower dosage of DOACs (ld-DOACs) is recommended. Ld-DOAC prescribing seems to be common, although previous studies did not show clear superiority of ld-DOACs over warfarin. In Germany, phenprocoumon is used almost exclusively as VKA. Randomized controlled trials comparing DOACs and phenprocoumon in the general population of patients with AF do not exist. Therefore, we aimed to compare ld-DOACs and phenprocoumon in a real-world setting in Germany.
METHODS
METHODS
In a retrospective observational cohort study, claims data from a group of small to medium-sized health insurance companies were analysed. Risks for the outcomes thromboembolism, death and major bleeding were estimated by Cox regression. Out of 93,685 patients with atrial fibrillation and a first prescription of an oral anticoagulant, 20,179 receiving VKA and 21,724 ld-DOACs (29.6% of all DOAC patients) were included. For the sensitivity analysis phenprocoumon was compared to the five ld-DOAC groups (ld-apixaban, ld-dabigatran, ld-edoxaban, ld-rivaroxaban, and the composite of all ld-DOACs) after propensity-score matching.
RESULTS
RESULTS
Phenprocoumon was associated with statistically significant fewer thromboembolic events (HR = 1.29, 95% CI [1.13, 1.48], p < .001) and deaths (HR = 1.52, 95% CI [1.41, 1.63], p < .001) and a non-significant higher bleeding risk (HR = 0.89, 95% CI [0.79, 1.00], p = .051) than composite ld-DOAC. Regarding the subgroups, only patients with ld-apixaban had a statistically significant higher risk for thromboembolic events (HR = 1.42, 95% CI [1.21, 1.65], p < .001) and a lower bleeding risk (HR = 0.75, 95% CI [0.65, 0.86], p < .001). Ld-apixaban, ld-edoxaban, and ld-rivaroxaban were associated with a higher risk of death. The sensitivity analysis confirmed these associations.
CONCLUSION
CONCLUSIONS
Phenprocoumon seems to be superior to ld-DOACs for patients with AF. As a hypothesis phenprocoumon might turn out to be the wiser choice for high-risk patients with AF as compared to ld-DOACs, especially regarding thromboembolic events and death. Therefore, RCTs comparing ld-DOACs with phenprocoumon are needed.
Identifiants
pubmed: 35619140
doi: 10.1186/s12959-022-00389-9
pii: 10.1186/s12959-022-00389-9
pmc: PMC9137171
doi:
Types de publication
Journal Article
Langues
eng
Pagination
31Informations de copyright
© 2022. The Author(s).
Références
Khurshid S, Choi SH, Weng LC, Wang EY, Trinquart L, Benjamin EJ, et al. Frequency of cardiac rhythm abnormalities in a half million adults. Circ Arrhythm Electrophysiol. 2018;11(7):e006273. https://doi.org/10.1161/CIRCEP.118.006273 .
doi: 10.1161/CIRCEP.118.006273
pubmed: 29954742
pmcid: 6051725
Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham study. Stroke. 1991;22(8):983–8. https://doi.org/10.1161/01.STR.22.8.983 .
doi: 10.1161/01.STR.22.8.983
pubmed: 1866765
Arzneimittelkommission der deutschen Ärzteschaft (AkdÄ). Orale Antikoagulation bei nicht valvulärem Vorhofflimmern Empfehlungen zum Einsatz der direkten oralen Antikoagulanzien Dabigatran, Apixaban, Edoxaban und Rivaroxaban 2019. Available from: https://www.akdae.de/Arzneimitteltherapie/LF/PDF/OAKVHF.pdf .
Hein L, Wille H. Antithrombotika und Antihämorrhagika. In: Schwabe U, Paffrath D, Ludwig W-D, Klauber J, editors. Arzneiverordnungs-Report 2019. Berlin, Heidelberg: Springer Berlin Heidelberg; 2019. p. 531–55.
doi: 10.1007/978-3-662-59046-1_19
Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981–92. https://doi.org/10.1056/NEJMoa1107039 .
doi: 10.1056/NEJMoa1107039
pubmed: 21870978
Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139–51. https://doi.org/10.1056/NEJMoa0905561 .
doi: 10.1056/NEJMoa0905561
pubmed: 19717844
Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093–104. https://doi.org/10.1056/NEJMoa1310907 .
doi: 10.1056/NEJMoa1310907
pubmed: 24251359
Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883–91. https://doi.org/10.1056/NEJMoa1009638 .
doi: 10.1056/NEJMoa1009638
pubmed: 21830957
European Medicines Agency. Eliquis: EPAR - Product Information 2011. Available from: https://www.ema.europa.eu/en/documents/product-information/eliquis-epar-product-information_en.pdf .
European Medicines Agency. Xarelto : EPAR - Product Information: 2009. Available from: https://www.ema.europa.eu/en/documents/product-information/xarelto-epar-product-information_en.pdf .
European Medicines Agency. Lixiana : EPAR - Product Information: 2015. Available from: https://www.ema.europa.eu/en/documents/product-information/lixiana-epar-product-information_en.pdf .
European Medicines Agency. Pradaxa : EPAR - Product Information: 2009. Available from: https://www.ema.europa.eu/en/documents/product-information/pradaxa-epar-product-information_en.pdf .
Steinberg BA, Shrader P, Pieper K, Thomas L, Allen LA, Ansell J, et al. Frequency and outcomes of reduced dose non-vitamin K antagonist anticoagulants: results from ORBIT-AF II (the outcomes registry for better informed treatment of atrial fibrillation II). J Am Heart Assoc. 2018;7(4):e007633. https://doi.org/10.1161/JAHA.117.007633 .
doi: 10.1161/JAHA.117.007633
pubmed: 29453305
pmcid: 5850192
Hohnloser SH, Basic E, Hohmann C, Nabauer M. Effectiveness and safety of non-vitamin K Oral anticoagulants in comparison to Phenprocoumon: data from 61,000 patients with atrial fibrillation. Thromb Haemost. 2018;118(3):526–38. https://doi.org/10.1160/TH17-10-0733 .
doi: 10.1160/TH17-10-0733
pubmed: 29359278
Mueller S, Groth A, Spitzer SG, Schramm A, Pfaff A, Maywald U. Real-world effectiveness and safety of oral anticoagulation strategies in atrial fibrillation: a cohort study based on a German claims dataset. Pragmat Obs Res. 2018;9:1–10. https://doi.org/10.2147/POR.S156521 .
doi: 10.2147/POR.S156521
pubmed: 29750067
pmcid: 5935078
Zeymer U, Lober C, Wolf A, Richard F, Schäfer H, Taggeselle J, et al. Use, persistence, efficacy, and safety of Apixaban in patients with non-Valvular atrial fibrillation in unselected patients in Germany. Results of the prospective Apixaban in atrial fibrillation (APAF) registry. Cardiol Ther. 2020;9(2):467–78. https://doi.org/10.1007/s40119-020-00188-1 .
doi: 10.1007/s40119-020-00188-1
pubmed: 32638266
pmcid: 7584711
Staerk L, Gerds TA, Lip GYH, Ozenne B, Bonde AN, Lamberts M, et al. Standard and reduced doses of dabigatran, rivaroxaban and apixaban for stroke prevention in atrial fibrillation: a nationwide cohort study. J Intern Med. 2018;283(1):45–55. https://doi.org/10.1111/joim.12683 .
doi: 10.1111/joim.12683
pubmed: 28861925
Miyazaki M, Matsuo K, Uchiyama M, Nakamura Y, Sakamoto Y, Misaki M, et al. Inappropriate direct oral anticoagulant dosing in atrial fibrillation patients is associated with prescriptions for outpatients rather than inpatients: a single-center retrospective cohort study. J Pharm Health Care Sci. 2020;6:2. https://doi.org/10.1186/s40780-020-0157-z .
doi: 10.1186/s40780-020-0157-z
pubmed: 32071730
pmcid: 7014592
Nielsen PB, Skjoth F, Sogaard M, Kjaeldgaard JN, Lip GY, Larsen TB. Effectiveness and safety of reduced dose non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study. BMJ. 2017;356:j510. https://doi.org/10.1136/bmj.j510 .
doi: 10.1136/bmj.j510
pubmed: 28188243
pmcid: 5421446
Beinema M, Brouwers JR, Schalekamp T, Wilffert B. Pharmacogenetic differences between warfarin, acenocoumarol and phenprocoumon. Thromb Haemost. 2008;100(6):1052–7. https://doi.org/10.1160/TH08-04-0116 .
doi: 10.1160/TH08-04-0116
pubmed: 19132230
Prochaska JH, Göbel S, Keller K, Coldewey M, Ullmann A, Lamparter H, et al. Quality of oral anticoagulation with phenprocoumon in regular medical care and its potential for improvement in a telemedicine-based coagulation service–results from the prospective, multi-center, observational cohort study thrombEVAL. BMC Med. 2015;13:14. https://doi.org/10.1186/s12916-015-0268-9 .
doi: 10.1186/s12916-015-0268-9
pubmed: 25616558
pmcid: 4333875
Le Heuzey JY, Ammentorp B, Darius H, De Caterina R, Schilling RJ, Schmitt J, et al. Differences among western European countries in anticoagulation management of atrial fibrillation. Data from the PREFER IN AF registry. Thromb Haemost. 2014;111(5):833–41. https://doi.org/10.1160/TH13-12-1007 .
doi: 10.1160/TH13-12-1007
pubmed: 24651882
Swart E, Gothe H, Geyer S, Jaunzeme J, Maier B, Grobe T, et al. Gute Praxis Sekundärdatenanalyse (GPS): Leitlinien und Empfehlungen. Das Gesundheitswesen. 2015;77(2):120–6. https://doi.org/10.1055/s-0034-1396815 .
doi: 10.1055/s-0034-1396815
pubmed: 25622207
Benchimol EI, Smeeth L, Guttmann A, Harron K, Moher D, Petersen I, et al. The REporting of studies conducted using observational routinely-collected health data (RECORD) statement. PLoS Med. 2015;12(10):e1001885. https://doi.org/10.1371/journal.pmed.1001885 .
doi: 10.1371/journal.pmed.1001885
pubmed: 26440803
pmcid: 4595218
Schulman S, Kearon C, Subcommittee on control of anticoagulation of the S, standardization Committee of the International Society on T, Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3(4):692–4. https://doi.org/10.1111/j.1538-7836.2005.01204.x .
doi: 10.1111/j.1538-7836.2005.01204.x
pubmed: 15842354
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373–83. https://doi.org/10.1016/0021-9681(87)90171-8 .
doi: 10.1016/0021-9681(87)90171-8
pubmed: 3558716
Yao X, Gersh BJ, Sangaralingham LR, Kent DM, Shah ND, Abraham NS, et al. Comparison of the CHA2DS2-VASc, CHADS2, HAS-BLED, ORBIT, and ATRIA Risk Scores in Predicting Non–Vitamin K Antagonist Oral Anticoagulants-Associated Bleeding in Patients With Atrial Fibrillation. Am J Cardiol. 2017;120(9):1549–56. https://doi.org/10.1016/j.amjcard.2017.07.051 .
doi: 10.1016/j.amjcard.2017.07.051
pubmed: 28844514
R Core Team. R: A language and environment for statistical computing. R Foundation for statistical computing Vienna, Austria: 2021. Available from: https://www.R-project.org/ .
Ho D, Imai K, King G, Stuart EA. MatchIt: nonparametric preprocessing for parametric causal inference. J Stat Softw. 2011;42(8):1–28. https://doi.org/10.18637/jss.v042.i08 .
doi: 10.18637/jss.v042.i08
Therneau TM, Grambsch PM. A package for survival analysis in R: 2020. Available from: https://CRAN.R-project.org/package=survival .
Camm AJ, Cools F, Virdone S, Bassand JP, Fitzmaurice DA, Arthur Fox KA, et al. Mortality in patients with atrial fibrillation receiving nonrecommended doses of direct Oral anticoagulants. J Am Coll Cardiol. 2020;76(12):1425–36. https://doi.org/10.1016/j.jacc.2020.07.045 .
doi: 10.1016/j.jacc.2020.07.045
pubmed: 32943160
Steinberg BA, Shrader P, Thomas L, Ansell J, Fonarow GC, Gersh BJ, et al. Off-label dosing of non-vitamin K antagonist Oral anticoagulants and adverse outcomes: the ORBIT-AF II registry. J Am Coll Cardiol. 2016;68(24):2597–604. https://doi.org/10.1016/j.jacc.2016.09.966 .
doi: 10.1016/j.jacc.2016.09.966
pubmed: 27978942
Kang F, Ma Y, Cai A, Cheng X, Liu P, Kuang J, et al. Meta-analysis evaluating the efficacy and safety of low-intensity warfarin for patients >65 years of age with non-Valvular atrial fibrillation. Am J Cardiol. 2021;142:74–82. https://doi.org/10.1016/j.amjcard.2020.12.001 .
doi: 10.1016/j.amjcard.2020.12.001
pubmed: 33307015
Lee KN, Choi JI, Boo KY, Kim DY, Kim YG, Oh SK, et al. Effectiveness and safety of off-label dosing of non-vitamin K antagonist anticoagulant for atrial fibrillation in Asian patients. Sci Rep. 2020;10(1):1801. https://doi.org/10.1038/s41598-020-58665-5 .
doi: 10.1038/s41598-020-58665-5
pubmed: 32019993
pmcid: 7000392
Reinecke H, Jürgensmeyer S, Engelbertz C, Gerss J, Kirchhof P, Breithardt G, et al. Design and rationale of a randomised controlled trial comparing apixaban to phenprocoumon in patients with atrial fibrillation on chronic haemodialysis: the AXADIA-AFNET 8 study. BMJ Open. 2018;8(9):e022690. https://doi.org/10.1136/bmjopen-2018-022690 .
doi: 10.1136/bmjopen-2018-022690
pubmed: 30206088
pmcid: 6144324
Vranckx P, Valgimigli M, Eckardt L, Tijssen J, Lewalter T, Gargiulo G, et al. Edoxaban-based versus vitamin K antagonist-based antithrombotic regimen after successful coronary stenting in patients with atrial fibrillation (ENTRUST-AF PCI): a randomised, open-label, phase 3b trial. Lancet. 2019;394(10206):1335–43. https://doi.org/10.1016/S0140-6736(19)31872-0 .
doi: 10.1016/S0140-6736(19)31872-0
pubmed: 31492505
Riesinger L, Strobl C, Leistner DM, Gori T, Akin I, Mehr M, et al. Apixaban versus PhenpRocoumon: Oral AntiCoagulation plus antiplatelet tHerapy in patients with acute coronary syndrome and atrial fibrillation (APPROACH-ACS-AF): rationale and design of the prospective randomized parallel-group, open-label, blinded-endpoint, superiority, multicenter-trial of a triple therapy versus a dual therapy in patients with atrial fibrillation and acute coronary syndrome undergoing coronary stenting. Int J Cardiol Heart Vasc. 2021;35:100810. https://doi.org/10.1016/j.ijcha.2021.100810 .
doi: 10.1016/j.ijcha.2021.100810
pubmed: 34258380
pmcid: 8256176
Ferner M, Wachtlin D, Konrad T, Deuster O, Meinertz T, von Bardeleben S, et al. Rationale and design of the RE-LATED AF—AFNET 7 trial: REsolution of left atrial-appendage Thrombus—effects of dabigatran in patients with atrial fibrillation. Clin Res Cardiol. 2016;105(1):29–36. https://doi.org/10.1007/s00392-015-0883-7 .
doi: 10.1007/s00392-015-0883-7
pubmed: 26109251
Di Biase L, Callans D, Hæusler KG, Hindricks G, Al-Khalidi H, Mont L, et al. Rationale and design of AXAFA-AFNET 5: an investigator-initiated, randomized, open, blinded outcome assessment, multi-Centre trial to comparing continuous apixaban to vitamin K antagonists in patients undergoing atrial fibrillation catheter ablation. Europace. 2017;19(1):132–8. https://doi.org/10.1093/europace/euw368 .
doi: 10.1093/europace/euw368
pubmed: 28130378
Mantha S, Ansell J. Indirect comparison of dabigatran, rivaroxaban, apixaban and edoxaban for the treatment of acute venous thromboembolism. J Thromb Thrombolysis. 2015;39(2):155–65. https://doi.org/10.1007/s11239-014-1102-5 .
doi: 10.1007/s11239-014-1102-5
pubmed: 24989022
Ufer M. Comparative efficacy and safety of the novel oral anticoagulants dabigatran, rivaroxaban and apixaban in preclinical and clinical development. Thromb Haemost. 2010;103(3):572–85. https://doi.org/10.1160/TH09-09-0659 .
doi: 10.1160/TH09-09-0659
pubmed: 20135071
Freemantle N, Marston L, Walters K, Wood J, Reynolds MR, Petersen I. Making inferences on treatment effects from real world data: propensity scores, confounding by indication, and other perils for the unwary in observational research. BMJ. 2013;347:f6409. https://doi.org/10.1136/bmj.f6409 .
doi: 10.1136/bmj.f6409
pubmed: 24217206
Camm AJ, Fox KAA. Strengths and weaknesses of 'real-world' studies involving non-vitamin K antagonist oral anticoagulants. Open Heart. 2018;5(1):e000788. https://doi.org/10.1136/openhrt-2018-000788 .
doi: 10.1136/openhrt-2018-000788
pubmed: 29713485
pmcid: 5922572
Angelow A, Reber KC, Schmidt CO, Baumeister SE, Chenot J-F. Untersuchung der Prävalenz kardiologischer Risikofaktoren in der Allgemeinbevölkerung: Ein Vergleich ambulanter ärztlicher Abrechnungsdaten mit Daten einer populationsbasierten Studie. Das Gesundheitswesen. 2019;81(10):791–800. https://doi.org/10.1055/a-0588-4736 .
doi: 10.1055/a-0588-4736
pubmed: 29864769