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Clinical Trial
. 2022 Nov 22;6(22):5908-5923.
doi: 10.1182/bloodadvances.2021005681.

Dabigatran in the treatment and secondary prophylaxis of venous thromboembolism in children with thrombophilia

Leonardo R Brandão  1   2 , Igor Tartakovsky  3 , Manuela Albisetti  4 , Jacqueline Halton  5 , Lisa Bomgaars  6 , Elizabeth Chalmers  7 , Matteo Luciani  8 , Paola Saracco  9 , Judy Felgenhauer  10 , Olga Lvova  11   12 , Monika Simetzberger  13 , Zhichao Sun  14 , Lesley G Mitchell  15
Affiliations
Clinical Trial

Dabigatran in the treatment and secondary prophylaxis of venous thromboembolism in children with thrombophilia

Leonardo R Brandão et al. Blood Adv. .

Abstract

In the phase 2b/3 DIVERSITY trial, 3 months treatment with dabigatran was noninferior to standard of care (SOC) for acute venous thromboembolism (VTE) in children. In a single-arm, phase 3, secondary VTE prevention study, up to 12 months dabigatran use was associated with favorable safety. Dabigatran is approved by the European Medicines Agency and US Food and Drug Administration for pediatric indications. We assessed primary composite efficacy (complete thrombus resolution and freedom from VTE recurrence/VTE-related death) in subgroups with thrombophilia vs those with negative/unknown thrombophilia status in the DIVERSITY trial and safety in both studies. Thrombophilia types were similar between the DIVERSITY trial (total population) and secondary prevention studies: factor V Leiden, 42% vs 33%; prothrombin mutation (G20210A), 19% vs 17%; antithrombin deficiency, 15% vs 20%; protein C/S deficiency, 23% vs 25%; and antiphospholipid antibodies, 18% vs 20% of patients, respectively. In DIVERSITY, 36% and 22% of thrombophilia subgroup patients treated with dabigatran and SOC, respectively, met the primary end point (Mantel-Haenszel-weighted rate difference, -0.135; 95% confidence interval, -0.36 to 0.08; noninferiority P = .0014); comparable to the total DIVERSITY trial population (46% vs 42%) showing dabigatran noninferiority to SOC. Within this subgroup, numerically fewer patients experienced VTE recurrence or progression of index thrombus in the dabigatran treatment group vs SOC. In the secondary prevention study, VTE recurrence at 12 months occurred in 2.8% of patients with thrombophilia vs 0% with negative/unknown thrombophilia. Safety profiles were consistent with those reported previously. Although they should be interpreted with caution, these exploratory findings suggest dabigatran could be an appropriate long-term anticoagulant for children with thrombophilia. These trials were registered at www.clinicaltrials.gov as #NCT01895777 and #NCT02197416.

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Conflict of interest statement

Conflict-of-interest disclosure: L.R.B. is a member of a pediatric advisory board for Boehringer Ingelheim, and reports fees to his institution from Boehringer Ingelheim. I.T., M.S., and Z.S. are employees of Boehringer Ingelheim. M.A. is a member of a pediatric advisory board for Boehringer Ingelheim and has received advisory board fees from Daiichi Sankyo. J.H. is a member of a pediatric advisory board for Boehringer Ingelheim and has received honoraria from Boehringer Ingelheim for congress presentation. L.B. is a member of a pediatric advisory board for Boehringer Ingelheim and reports fees to her institution from Janssen Pharmaceuticals. E.C. is a member of a pediatric advisory board for Boehringer Ingelheim and reports personal fees from Roche, Sobi, Bristol Myers Squibb, CSL Behring, and Shire/Takeda. M.L. is a member of a pediatric advisory board for Boehringer Ingelheim. P.S. and J.F. significantly contributed to the enrollment of patients with thrombophilia in the program in their role as investigators (pediatric hematologists). O.L. significantly contributed to the enrollment of patients with thrombophilia in the program (investigator; pediatric hematologist) and has an Investigator Agreement with Bristol Myers Squibb, Novartis, and UCB. L.G.M. is a member of a pediatric advisory board for Boehringer Ingelheim and has received a research grant from Bristol Myers Squibb.

A complete list of the DIVERSITY and Secondary VTE Prevention Study Group investigators appears in the supplemental data.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Dispositionof patients in the acuteVTE treatment study and secondary VTE prevention study by thrombophilia status. In the acute VTE treatment study, 267 patients were randomized and all but 1 patient randomized to dabigatran were treated; 176 patients received dabigatran and 90 received SOC. In the secondary VTE prevention study, 213 of 221 enrolled patients received dabigatran.
Figure 2.
Figure 2.
Kaplan-Meier curves of freedom from recurrent VTE by study, thrombophilia status, and treatment.
Figure 3.
Figure 3.
Forest plot for the acute VTE treatment study of the Mantel-Haenszel–weighted rate difference for composite primary efficacy end point (complete VTE resolution, freedom from recurrent VTE, and freedom from VTE-related death) by subgroup. DE, dabigatran etexilate.
Figure 4.
Figure 4.
Kaplan-Meier curves of freedom from bleeding by study, thrombophilia status, and treatment.
See this image and copyright information in PMC

References

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