Elsevier

Thrombosis Research

Volume 193, September 2020, Pages 160-165
Thrombosis Research

Full Length Article
Rivaroxaban or apixaban in fragile patients with acute venous thromboembolism

https://doi.org/10.1016/j.thromres.2020.06.035Get rights and content

Highlights

  • Fragile patients with VTE are at increased risk for bleeding during anticoagulation.

  • The use of DOACs in fragile patients with VTE is associated with better outcomes than standard therapy.

  • Rivaroxaban or apixaban at recommended doses was associated with a similar risk for VTE recurrences or major bleeding.

  • A substantial amount of patients using DOACs were prescribed non-recommended doses.

Abstract

Introduction

The efficacy and safety of the direct oral anticoagulants (DOACs) in fragile patients (age ≥ 75 years and/or creatinine clearance [CrCl] levels ≤50 mL/min and/or body weight ≤50kg) with venous thromboembolism (VTE) have not been consistently compared.

Material and methods

We used the RIETE database to compare the rates of the composite of VTE recurrences or major bleeding during anticoagulation in fragile patients with VTE, according to the use of rivaroxaban or apixaban for initial and long-term therapy.

Results

From January 2013 to October 2019, 36,889 patients were recruited, of whom 14,831 (40%) were fragile. Overall, 999 fragile patients (15%) received DOACs starting within the first 48 h: rivaroxaban 711 and apixaban 288. Median duration of therapy was: 113 vs. 111 days. A substantial amount of patients in both subgroups (25% vs. 40%) received non-recommended doses of DOACs. During anticoagulation, 13 patients developed VTE recurrences, 18 had major bleeding and 36 died. When only considering patients receiving recommended doses (n = 705), there were no differences between drugs in the rate of the composite outcome (rate ratio [RR]: 1.08; 95%CI: 0.35–3.30) or all-cause death (RR: 0.99; 95%CI: 0.32–3.08). On multivariable analysis, patients receiving rivaroxaban or apixaban at recommended doses had a similar risk for the composite outcome (hazard ratio: 1.34; 95%CI: 0.35–5.06).

Conclusion

The use of rivaroxaban or apixaban at recommended doses in fragile patients with VTE was associated with a similar risk for VTE recurrences or major bleeding.

Introduction

Subgroup analyses from randomized clinical trials suggested that the use of direct oral anticoagulants (DOACs) may have advantages over standard anticoagulant therapy in fragile patients (those aged ≥75 years, with creatinine clearance levels ≤50 mL/min or weighing ≤50 kg) with venous thromboembolism (VTE) [1,2]. The term fragile has been recently incorporated into the literature, and should not be confused with frail, which usually refers to elderly people with reduced physiologic reserve associated with increased susceptibility to disability. In a prior study using the RIETE registry, fragile patients with VTE had a 2-fold higher rate of major bleeding and half the rate of VTE recurrences during the first 3 months of anticoagulation compared with the non-fragile [3]. In a subsequent study, the use of DOACs in fragile patients with VTE was associated with a significantly lower risk of the composite of VTE recurrences or major bleeding compared with patients receiving standard anticoagulation [4].

The RIETE (Registro Informatizado de Enfermedad Trombo Embólica) registry is an ongoing, multicenter registry of consecutive patients with objectively confirmed VTE with 223 collaborating centers in the Americas, Asia and Europe (ClinicalTrials.gov identifier: NCT02832245). The aim of RIETE has always been to record data including the clinical characteristics, treatment and clinical outcomes in patients with VTE [[5], [6], [7], [8]]. In the current study, we compared the outcomes during anticoagulation in fragile patients with VTE, according to the use of rivaroxaban or apixaban.

Section snippets

Patients and methods

Consecutive patients with acute symptomatic deep vein thrombosis (DVT) or pulmonary embolism (PE) confirmed by objective testing (compression ultrasonography or contrast venography for DVT; helical CT-scan, ventilation-perfusion lung scintigraphy or angiography for PE) were enrolled in RIETE. Patients were excluded if they were currently participating in a therapeutic clinical trial with a blinded therapy. The rationale, design and methodology of RIETE have been reported elsewhere [9].

Results

From January 2013 to October 2019, 36,889 patients with acute VTE were recruited; of whom 14,831 (40%) were fragile. Overall, 999 fragile patients (15%) received DOACs starting <48 h after VTE diagnosis: rivaroxaban 711 and apixaban 288. Of these patients, 882 were aged ≥75 years, 370 had CrCl levels ≤50 mL/min and 92 weighed ≤50 kg (Table I). Forty-three patients had CrCl levels <30 mL/min. A substantial amount of patients in both subgroups (25% of patients receiving rivaroxaban vs. 40% of

Discussion

In the EINSTEIN-DVT and PE pivotal trials, the risk for major bleeding in fragile patients was significantly lower in those receiving rivaroxaban than in those on standard anticoagulant therapy [11,12]. This difference was not found in non-fragile patients. In the HOKUSAI trial, a higher efficacy was found in fragile patients receiving edoxaban than in those on warfarin [2]. In the AMPLIFY trial, there was no subgroup analysis comparing apixaban vs. standard therapy in fragile patients [13].

Acknowledgements

We express our gratitude to Sanofi Spain for supporting this Registry with an unrestricted educational grant. We also thank the RIETE Registry Coordinating Center, S&H Medical Science Service, for their quality control data, logistic and administrative support.

Authors contributions

Trujillo- Santos J, Moustafa F and Monreal M designed the study, collected data, analyzed the data, discussed the results, performed research and wrote the manuscript. Beroiz P, Alonso A, Morejon E, López-Reyes R, Casado I, Porras JA, Flores K and López-Núñez JJ collected data, discussed the results and revised the final version of the manuscript. The remaining doctors appearing as co-authors in the Appendix collected data, revised and approved the final version of the manuscript.

Source of funding and its roles

RIETE is an investigator-initiated registry. During the first 5 years, it was supported by Red Respira from the Instituto Carlos III, Spain (Red Respira-ISCiii-RTIC-03/11). It has been also supported with nonrestricted educational grants by Sanofi Spain (from 2002 to December 2019) and Bayer Pharma (from 2010 to December 2018) for the rest of the world.

There is no payment per recruited patient. The main incentive for patients and investigators participating in RIETE is to generate new knowledge

Declaration of competing interest

No potential conflicts of interest.

References (17)

There are more references available in the full text version of this article.

Cited by (9)

View all citing articles on Scopus
1

A full list of RIETE investigators is given in the appendix.

View full text