Secondary Anticoagulation Use in Patients < 21 Years Old following Primary Anticoagulant Treatment for Provoked Venous Thromboembolism: Findings from the Kids-DOTT Trial

Over 90% of venous thromboembolism (VTE) in children are provoked by transient risk factors and are associated with a very low risk for recurrence (∼1%).[ 1 ] Nevertheless, children with a history of VTE and persistent prothrombotic risk factors such as, but not limited to, central venous catheters (CVCs), thrombophilia, and cancer, have an increased risk for recurrent VTE,[ 2 ] [ 3 ] [ 4 ] [ 5 ] ranging from 16 to 29% in previous studies.[ 3 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ] [ 8 ] Prospective multicenter data on the use of secondary anticoagulation in patients with a first provoked VTE and persistent or recurrent risk factors are limited. The objective of this study was to characterize secondary anticoagulation use and clinical outcomes in children < 21 years old with provoked VTE. We conducted a secondary analysis of the National Institutes of Health (NIH)-sponsored, multinational Kids-DOTT parallel-cohort randomized controlled trial (RCT; NCT00687882)[ 1 ] on duration of anticoagulation for the treatment of acute provoked VTE in patients < 21 years old. The trial was approved by the local institutional review board or research ethics committee at each of the 42 participating sites in Australia, Austria, Canada, the Netherlands, and the United States. The Kids-DOTT trial enrolled 532 children ages 0 to <21 years with a first provoked VTE from 2008 to 2021. Full details of the trial design and eligibility criteria have been previously published.[ 1 ] The trial protocol permitted the use of secondary anticoagulation at prophylactic dosing at the discretion of the treating clinician for persistent prothrombotic risk factors following the randomized duration of primary anticoagulation (“extended secondary anticoagulation”) or for episodes of transient recurrence of prothrombotic risk factors over the course of the 2-year follow-up period (“episodic secondary anticoagulation”). For this study, we defined extended secondary anticoagulation as any continuation of anticoagulation after the completion of primary anticoagulation treatment. Episodic secondary anticoagulation was defined as anticoagulation that began ≥ 2 weeks after primary anticoagulation was completed. We reviewed all anticoagulant treatment case report forms and extracted details specific to secondary anticoagulant use. Data were summarized as counts and percentages for categorical variables and medians with interquartile ranges (IQR) for continuous variables. To compare groups who did, versus who did not, receive secondary anticoagulation, Mann–Whitney U test was used for continuous variables and chi-square or Fisher's exact test for categorical variables. A p- value of ≤0.05 was considered significant. Statistical analyses were performed using R version 4.1.2 (R Core Team, 2021) and SAS software version 9.4 (Cary, NC). Among 532 participants enrolled in the Kids-DOTT parallel-cohort RCT, 13 (2.4%) were prescribed secondary anticoagulation. Characteristics of participants who did versus did not receive secondary anticoagulation are shown in [ Table 1 ]. Participants who received secondary anticoagulation were older than those who did not (median: 12.8 years [IQR: 7.5–14.18] vs. 7.84 years [0.95–15.1], p = 0.3), but the difference was not statistically significant. Sex, race, and ethnicity did not differ significantly between groups. Table 1 Characteristics of patients in the Kids-DOTT study (including randomized population and parallel cohorts) who did versus did not receive secondary anticoagulation Variable Overall N = 532[ a ] No secondary anticoagulation N = 519[ a ] Secondary anticoagulation N = 13[ a ] p -Value[ b ] Age (y) 0.3 Mean 8.26 8.2 10.6 Median (IQR) 7.97 (0.02–20.91) 7.84 (0.95–15.1) 12.77 (7.5–14.18) Sex 0.96 Female 249 (47%) 243 (47%) 6 (46%) Male 283 (53%) 276 (53%) 7 (54%) Race 0.48 American Indian or Alaskan Native 2 (0.4%) 2 (0.4%) 0 (0%) Asian 16 (3.0%) 16 (3.1%) 0 (0%) Black or African American 69 (13%) 68 (13%) 1 (8%) White or Caucasian 385 (72%) 374 (73%) 11(85%) Multiple 5 (9%) 4 (1%) 1 (8%) Other 14 (2.4%) 14 (3%) 0 (0%) Unknown/not reported 41 (7.7%) 41(8%) 0 (11%) Index VTE anatomical site 0.01 Cerebral sinovenous thrombosis 75 (14%) 73 (14%) 2 (15%) 0.70 Lower extremity DVT ± PE 242 (45%) 240 (46%) 2 (15%) 0.04 Renal vein thrombosis 2 (0.4%) 1 (0.2%) 1(8%) 0.05 Right atrial thrombosis 2 (0.4%) 2 (0.4%) 0 (0%) 1.00 Splanchnic vein thrombosis 7 (13%) 6 (1%) 1(8%) 0.16 Upper extremity DVT ± PE 157 (30%) 150 (29%) 7 (54%) 0.07 Other VTE site 46 (9%) 46 (9%) 0 (0%) 0.62 Not reported 1(0.2%) 1 (0.2%) 0 (0%) 1.00 Provoking factor for index VTE Central venous catheter 237 (44%) 229 (49%) 8 (73%) 0.22 Infection 145 (27%) 141 (27%) 4 (31%) 0.69 Trauma or surgery within previous 30 d 92 (17%) 90 (17%) 2 (15%) 0.65 Unspecified 52 (10%) 52 (10%) 0(0%) 0.29 Other 48 (9%) 47 (9%) 1 (8%) 0.70 Hospitalization within last 30 d 6 (1%) 6 (1%) 0 (0%) 0.65 Estrogen or other prothrombotic medication use 29 (5%) 28 (5%) 1(8%) 0.46 Flare of autoimmune/chronic inflammatory condition 16 (3%) 14 (3%) 2 (15%) 0.70 Congenital heart or acquired cardiac disease 3 (0.5%) 3 (0.6%) 0 (0%) 0.63 Abbreviations: DVT, deep vein thrombosis; IQR, interquartile range; PE, pulmonary embolism; VTE, venous thromboembolism. a n (%). b Mann–Whitney U test; Pearson's chi-squared test; Fisher's exact test. When compared with those who received no secondary anticoagulation, patients who received secondary anticoagulation were more likely to have an upper extremity deep vein thrombosis (150/519 [29%] vs. 7/13 [54%]) or a CVC (229/513 [44%] vs. 8/13 [62%]). Eighty-six percent (6/7) of upper extremity deep vein thrombosis in the secondary anticoagulation group were associated with a CVC. As shown in [ Table 2 ], low molecular weight heparins were the most frequently used anticoagulant (85%) for secondary anticoagulation, followed by vitamin K antagonists (15%). Episodic secondary anticoagulation was administered in 85% (11/13) of cases, with a median interval of 123 days (IQR: 31–168) from end of primary anticoagulation for VTE treatment to initiation of episodic secondary anticoagulation. The median duration of episodic secondary anticoagulation was 8 days (IQR: 6–20) and 383 days (IQR: 72–693) for extended secondary anticoagulation. The most common indication for episodic secondary anticoagulation was the presence of a CVC (50%, N = 4), followed by infection (25%, N = 2). Table 2 Characteristics of secondary anticoagulation use in the Kids-DOTT study ( n = 13) Variable n (%) Agent used for secondary anticoagulation Low molecular weight heparin 11 (85%) Vitamin K antagonist 2 (15%) Interval from end of treatment to start of secondary anticoagulation (d, n = 12) Median (IQR) 123 (31–168) Modality of secondary anticoagulation Extended 2 (15%) Episodic 11 (85%) Duration of secondary anticoagulation (d) Median (IQR)—overall 9 (6.5–52) Median (IQR)—extended 383 (72–693) Median (IQR)—episodic 8 (6–20) Indication for secondary anticoagulation ( n = 8) Central venous catheter 4 (50%) Infection 2 (25%) Trauma or surgery within previous 30 d 1 (13%) Prothrombotic medication 0 (0%) Flare of autoimmune disease 0 (0%) Hospitalization within previous 30 d 0 (0%) Congenital or acquired cardiac disease 0 (0%) Persistent thrombus 0 (0%) Other indication[ a ] 2 (25%) Abbreviation: IQR, interquartile range. a Melody valve replacement, renal transplant. Despite the presence of persistent or recurrent prothrombotic risk factors, none of the participants who received secondary anticoagulation experienced recurrent VTE and none had clinically relevant bleeding related to secondary anticoagulation. Overall, we found a low frequency (2.4%) of secondary anticoagulation usage among the 532 participants < 21 years old with an initial provoked VTE enrolled in the multinational Kids-DOTT trial. Our findings are consistent with prior reports of low use of secondary anticoagulation for VTE prevention in children at risk for recurrent VTE.[ 9 ] [ 10 ] Comparable to results from the phase 3 dabigatran etexilate for the treatment of acute VTE in children (DIVERSITY) trial (NCT02197416, n = 203),[ 2 ] there were no recurrent VTE events in the Kids-DOTT trial among patients with prothrombotic risk factors (persistent or recurrent) who received secondary anticoagulation. Although children with cancer (in remission) were eligible for enrollment, there was only one such patient enrolled. Therefore, although cancer is a known risk factor for VTE, none were in our study population. Strengths of this study include its prospective multicenter design with blinded, central adjudication of clinical outcomes, as well as its delineation of episodic and extended subtypes of secondary anticoagulation. A notable limitation of the study is the rather small sample size of patients receiving secondary anticoagulation, such that estimates of subpopulation characteristics and outcomes should be interpreted with caution. This sample size reflects both the low frequency of, and the limited published guidance on, use of secondary anticoagulation in pediatric VTE patients. A second limitation is the lack of details regarding provider decision for or against the use of secondary anticoagulation. Additionally, we were unable to ascertain the proportion of children with persistent or recurrent prothrombotic risk factors who did not receive secondary anticoagulation as these elements were only collected for participants with documented receipt of secondary anticoagulation. Additional limitations lie within the Kids-DOTT dataset itself. It did not capture the indication for CVC, a common provoking factor for DVT and found in a high proportion of patients in the Kids-DOTT trial with DVT of the upper extremities. Comorbid medical conditions were also not captured in the Kids-DOTT dataset, which themselves may represent a hypercoagulable state, predisposing to VTE. These limitations present opportunities for more detailed data collection in future dedicated studies of secondary anticoagulation use in children with provoked VTE. Notwithstanding these limitations, findings from this study contribute important new knowledge to the paucity of evidence on use, modalities, and clinical outcomes of secondary anticoagulation in children with provoked VTE. Publication History Article published online: 19 September 2024 © 2024. Thieme. All rights reserved. Thieme Medical Publishers, Inc. 333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

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