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

Design

Subgroup analysis of an open-label, randomized, phase 2b/3 trial (DIVERSITY) and a secondary venous thromboembolism (VTE) prevention, single-arm, cohort study

N= 480

Objective

To evaluate the efficacy and safety of dabigatran in children with thrombophilia versus those with negative/unknown thrombophilia status

Study Groups

DIVERSITY (N= 267)

Documented thrombophilia (n= 62)

Thrombophilia-negative/unknown status (n= 205)

Secondary VTE prevention study (N= 213)

Documented thrombophilia (n= 106)

Thrombophilia-negative/unknown status (n= 107)

Inclusion Criteria

DIVERSITY: Age <18 years with a diagnosis of VTE objectively confirmed by compression ultrasound, computed tomography, or magnetic resonance imaging; initially treated for 5 to 21 days with standard of care (SOC), with parenteral anticoagulation therapy expected to last for ≥3 months

Secondary VTE prevention study: Aged 3 months to <18 years with an objectively confirmed diagnosis of VTE; treated for acute VTE with SOC for ≥3 months or completed dabigatran or SOC treatment in a prior acute VTE treatment study; unresolved clinical thrombosis risk factor requiring further anticoagulation for secondary prevention of VTE

Exclusion Criteria

Key criteria from both studies: Conditions associated with increased bleeding risk; renal dysfunction

Methods

Patients from the DIVERSITY trial and secondary VTE prevention study were assessed for thrombophilia status and were classified as "thrombophilia positive" or "thrombophilia status negative/unknown". In DIVERSITY, patients were randomized (2:1) to receive open-label dabigatran or SOC for 3 months. In the secondary VTE prevention study, patients were treated with dabigatran for up to 12 months. Dabigatran was dosed according to an age- and weight-adjusted nomogram derived from estimated renal function, with the goal of achieving exposure comparable to that of adults treated with dabigatran.

The information presented in this table is specific to patients with factor V Leiden (FVL) mutations.

Duration

DIVERSITY: treatment for 3 months, follow-up for an additional month

Secondary VTE prevention study: treatment for 12 months

Outcome Measures

DIVERSITY: Composite of thrombus resolution, freedom from recurrent VTE, and freedom from VTE-related death; thrombus progression; VTE recurrence; bleeding

Secondary VTE prevention study: VTE recurrence at 12 months; postthrombotic syndrome (PTS); bleeding

Baseline Characteristics

DIVERSITY

Thrombophilia documented

FVL

Prothrombin (PT) mutation

FVL homozygous

FVL heterozygous

FVL heterozygous + PT mutations heterozygous

In both studies, patients with documented thrombophilia were ∼2.5 years older, on an average, than patients with negative/unknown thrombophilia status. Patients with thrombophilia, and in particular, major thrombophilia, were predominantly male. 

Results

DIVERSITY: 

In patients with documented thrombophilia, dabigatran was found to be noninferior to SOC for the primary composite endpoint (35.9% vs. 21.7%; noninferiority p= 0.0014). The same occurrence was observed for those with negative/unknown thrombophilia status (48.5% vs. 49.3%; noninferiority p= 0.0033). For the subgroup of patients with major thrombophilia (n= 37), 25% treated with dabigatran and 29.4% treated with SOC met the primary end point (noninferiority p= 0.1806).

Thrombus progression was experienced by 8.1% of patients with documented thrombophilia, of whom most had major thrombophilia (6.3% of patients with confirmed inherited thrombophilia [FVL and PT mutations]), and by 2% of patients with negative/unknown thrombophilia status. The VTE recurrence rate was 12.9% among patients with thrombophilia (mostly those with major thrombophilia) and 2.9% for those with negative/unknown thrombophilia status. In patients with thrombophilia, 5.1% of patients treated with dabigatran and 13% treated with SOC experienced thrombus progression, and 7.7% and 21.7%, respectively experienced VTE recurrence.

Within the thrombophilia subgroup, there was no difference between dabigatran and SOC for bleeding events (17.9% vs. 26.1%; p= 0.66).

Secondary VTE prevention study: 

Recurrence of VTE at 12 months was reported for 2.8% of patients with thrombophilia compared to 0% with negative/unknown thrombophilia status, with no remarkable difference between major and minor thrombophilia subgroups. Of note, VTE recurrence at 12 months was reported for 2.7% of patients with major thrombophilia.

Newly identified or worsening of baseline PTS was observed in 2.8% of patients with thrombophilia and 0 patients without thrombophilia.

There was no difference in the proportion of patients with any bleeding while on treatment between patients with thrombophilia and those with negative/unknown thrombophilia status (27.4% vs. 17.8%). Bleeding incidence was similar between major and minor thrombophilia subgroups (26% and 30% at 12 months, respectively).

Adverse Events

DIVERSITY: Rates of adverse events (AEs), serious AEs, and AEs leading to treatment discontinuation were similar across subgroups. Most common AEs included headache, nasopharyngitis, alopecia, and epistaxis.

Secondary VTE prevention study: Rates of AEs, serious AEs, and AEs leading to treatment discontinuation were higher among patients with thrombophilia. Most common AEs included headache, nasopharyngitis, dyspepsia, and upper respiratory tract infection.

Study Author Conclusions

Given that thrombophilia is associated with a higher risk of long-term complications of VTE, it is important to establish appropriate and stable treatments for prolonged duration in this patient group. The exploratory findings of this study suggest that dabigatran could potentially have improved efficacy in these higher risk patients with thrombophilia compared with those without thrombophilia, who are at lower risk. Taken together, these data suggest that dabigatran could be appropriate for long-term anticoagulation in pediatric patients with thrombophilia. Future studies might add to the evidence on the treatment effects of DOACs, such as dabigatran vs SOC.

InpharmD Researcher Critique

These findings lack statistical power, and the analysis was not exclusive to patients with FVL mutations. Thus, the data within this analysis should be interpreted with caution.

Direct oral anticoagulants in pediatric venous thromboembolism: Experience in specialized pediatric hemostasis centers in the United States

Design

Multi-center, retrospective and prospective cohort, chart review

N= 233

Objective

To investigate the use of direct oral anticoagulants (DOACs) at 15 different American Hemostasis and Thrombosis Network (ATHN)-affiliated specialized pediatric hemostasis centers with an emphasis on safety and effectiveness

Study Groups

ATHN 15 patients (N= 233)

Inclusion Criteria

Patients aged 0 to 21 years at the time of DOAC treatment for anticoagulation management of acute venous thromboembolism (VTE) or secondary prevention of VTE

Exclusion Criteria

Did not sign informed consent or provide authorization for ATHNdataset network inclusion

Methods

The ATHNdataset was reviewed for study participants and divided into two cohorts. The retrospective cohort included patients who completed DOAC treatment ≥6 months before study enrollment, with the prospective cohort including patients who started a DOAC at the time of enrollment. Analyzed data consisted of demographic characteristics, baseline medical history, and use of hormonal therapy (use of any combined estrogen and progestin oral or transdermal contraceptives within 4 weeks before VTE onset). Identification of congenital thrombophilia conditions was based upon cutoff determination values of reported protein C, protein S, and antithrombin deficiencies set at the investigator's discretion.

Treatment-related bleeding events were classified as major, clinically relevant nonmajor bleeding (CRNMB), or minor. Major bleeding consisted of fatal, clinically overt (hemoglobin ≥2 mg/dL within 24 hours and/or bleeding was retroperitoneal, pulmonary, intracranial, or central nervous system), or required surgical intervention. CRNMB consisted of any overt bleeding required blood product, not attributed to patient's underlying condition, and required medical or surgical intervention, to restore hemostasis, administered other than in an operating room. Heavy menstrual bleeding (HMB) was also reported for females aged >12 years. 

Duration

Enrollment: January 2015 to June 2021

Follow-up: 3 and 6 months post-DOAC initiation

Outcome Measures

VTE progression and recurrence, treatment-related bleeding, and mortality status 

Baseline Characteristics

ATHN 15 patients (N= 233)

Patient age at start of DOAC therapy

0 to <13

13 to <18

18 to 21

Unknown

23 (9.9%)

164 (70.4%)

45 (19.3%)

1 (0.4%)

Female

White

No prior history of thrombosis

Medical risk factor(s) present at VTE diagnosis

Antiphospholipid syndrome

Autoimmune disorder

Cancer 

Recent hospital admission (>7 days within 30 days before VTE)

Obesity

Trauma (within 30 days before VTE requiring casting or ICU admission)

Sepsis (within 7 days before VTE)

Other^∗

6 (2.6%)

12 (5.2%)

9 (3.9%)

263 (11.2%)

53 (22.7%)

15 (6.4%)

8 (3.4%)

47 (20.2%)

Thrombophilia condition present at VTE diagnosis

Antithrombin deficiency

Factor V Leiden mutation (heterozygous)

Factor V Leiden mutation (homozygous)

Protein C deficiency

Protein S deficiency

Prothrombin G20210A mutation (heterozygous)

Other

6 (2.6%)

22 (9.4%)

4 (1.7%)

13 (5.6%)

12 (5.2%)

11 (4.7%)

3 (1.3%)

Initially prescribed DOAC

Apixaban

Dabigatran

Edoxaban

Rivaroxaban

90 (38.8%)

3 (1.3%)

2 (0.9%)

137 (59.1%)

Initiated on ≥1 standard anticoagulant and/or thrombolytic therapy

203 (87.5%)

^∗Includes congenital heart disease, COVID-19/SARS-CoV-2, inborn errors of metabolism/mitochondrial disease, inflammatory bowel disease, nephrotic syndrome, pregnancy, sickle cell disease, and others.

ICU, intensive care unit

Results

Endpoint

ATHN 15 patients (N= 225)†

Thrombosis recurrence‡

Patients with bleeding events

Type of reported bleeding events

Minor

CRNMB

Major

Minor and CRNMB

n= 31

25 (80.6%)

2 (6.5%)

1 (3.2%)

3 (9.7%)

†Among the total 233 patients enrolled in this study, 225 completed at least 1 follow-up form. 

‡No patients reporting thrombosis recurrence had previously reported congenital thrombophilia diagnosis. 

Adverse Events

Common Adverse Events: epistaxis and reproductive tract bleeding; HMB associated with DOAC use was seen in 35 of 98 (35.7%) eligible females overall, with apixaban use in 7 patients (18.9%) and rivaroxaban use in 26 patients (45.6%)

Serious Adverse Events: One patient receiving apixaban had a major bleeding event of the gastrointestinal tract, but resumed DOAC therapy 48 hours following resolution of bleeding with no additional complications. 

Percentage that Discontinued due to Adverse Events: A total of 15 (6.7%) patients discontinued DOAC therapy due to treatment-related bleeding events, with 8 patients restarting DOAC therapy without further bleeding complications.

Study Author Conclusions

Pediatric hematologists at specialized hemostasis centers in the United States have been using DOACs for the treatment and prevention of VTEs, primarily in adolescents and young adults. Reported DOAC use showed adequate safety and effectiveness rates.

InpharmD Researcher Critique

Study limitations include a retrospective lens, which is reliant upon accurate reporting of outcomes such a minor bleeding in patient chart, as well as study participants only from ATHN-affiliated specialized sites with higher levels of expertise in pediatric VTE management present, limiting generalizability. No subgroup analyses evaluated DOAC use for safety and efficacy outcomes in patients with factor V Leiden mutations.