Discussion:
The optimal first-line treatment for children with asymptomatic CVC-related VTE is unknown. We surveyed pediatric hematologists and oncologists in Saudi Arabia using specific cases. The results of the surveys demonstrate a wide variation in the management approaches between physicians. While the majority agreed to initiate anticoagulation therapy for the incidentally found asymptomatic CVC-related VTE, there was significant variation observed in the duration of anticoagulation: around 20% treated for 6 weeks, 40% for 12 weeks and 30% treated until the CVC was removed regardless of the length of therapy. We observed a wide variation as well in the use of secondary prophylaxis when the patient needed a new CVC placed.
A lack of published and definitive evidence may explain this heterogenicity of clinical practice and the variety in the recommendations for antithrombotic therapy in children with asymptomatic VTE. However, the current guidance based on a low level of certainty in the evidence about the benefits of treatment14.
Adult data show that asymptomatic VTE may have a favorable outcome without anticoagulation therapy17. It is common for pediatricians to hesitate to extrapolate recommendations from adult-literature, given the anatomical and pathophysiological differences in children18–20. The treatment decision of asymptomatic CVC-related VTE is affected by the presence of provoked thrombogenic factors and the risk of long-term sequelae that may impact the child’s quality of life. Lack of definitive evidence may justify why more than 71% of physicians treated the asymptomatic CVC-related VTE with anticoagulation, which is in keeping with the previous recommendation from the 2012 Chest guideline11.
The majority of surveyed physicians did not send a thrombophilia workup on the initial presentation. Interestingly, 20% would use thrombophilia testing to guide secondary prophylaxis, despite the Chest 2012 and ASH 2018 guidelines recommending against thrombophilia workup in children with CVC- related thrombosis11,14. A prospective Canadian study assessed 245 children who had CVC- related VTE with their first CVC, had a thrombophilia workup, and subsequently had a second CVC placed. The study showed 107 recurrent CVC-related VTE in 84 children, highlighting this is a high-risk group for developing recurrence of CVC-related VTE13. The study could not find an association between thrombophilia and recurrence of CVC-related VTE, which again supports the current recommendation against sending thrombophilia workup for CVC- related VTE13.
Variation in treatment duration between the current guidelines and the respondents may be due to a lack of pediatric clinical trials that specifically address treatment duration. The KIDS-DOTT is a randomized controlled trial investigating the safety and efficacy of limited treatment duration (6 weeks vs. 12 weeks) in the setting of a provoked DVT in pediatric patients. This study will provide meaningful answers to the ongoing clinical questions21. (ClinicalTrials.gov Identifier: NCT00687882)
The resolution of the clot on the subsequent US follow up did not seem to have a significant influence on the duration of proposed anticoagulation management by respondents. However, 35% of the physicians would consider prophylactic dosing after the resolution of the clot. Interestingly, all the physicians who elected to treat for the duration of CVC placement preferred to step down to prophylactic dosing for the CVC placement period. A limited number of pediatric studies have reported rates of resolution for asymptomatic VTE, and the impact of the resolution on the long-term outcome is currently unestablished. A recent Australian prospective study assessed the long-term consequences of asymptomatic VTE in 189 children with un-tunneled CVCs (CVC in jugular or femoral veins for more than 24 hours) in the pediatric intensive care unit (PICU). One hundred forty-six underwent US screening. 22% (32/146) had asymptomatic CVC-related VTE and were followed up two years later with repeat imaging. Thirty-one children had persistent asymptomatic CVC-related thrombus; however, despite no treatment, only one child had mild PTS at 2 years follow up3. Larger studies are needed to understand the clinical significance of these findings.
There was a wide variation in the reported use of anticoagulation prophylaxis for subsequent CVC insertion. With another CVC placement 6 months later, the majority of respondents, 57%, would not initiate anticoagulation prophylaxis. Interestingly, 20% of the respondents would use thrombophilia testing to guide secondary prophylaxis, despite as previously mentioned, the Chest 2012, ASH 2018 guidelines, and ASH-ASPHO Choosing Wisely® recommending against thrombophilia workup in children with CVC- related thrombosis11,14. A previous survey of the members of the American Pediatric Hematology and Oncology (ASPHO) demonstrated that 24.4% of the respondents used thrombophilia testing to guide their decision for secondary prophylaxis22 which is consistent with our study observation.
Three randomized controlled trials (RCTs) and a recent systematic review did not prove the benefit of primary anticoagulation prophylaxis for children with CVC23–27. However, none of the guidelines addressed secondary prophylaxis in a rather common clinical scenario, i.e., subsequent CVC insertion following CVC-RT. In the aforementioned prospective Canadian study13, they used prophylactic anticoagulation for the subsequent CVC placement. When they compared no anticoagulation vs. anticoagulation (prophylactic dose or treatment dose), the study showed an increase in the risk of VTE recurrence among the non-anticoagulation group13. This may support the rationale of prophylactic anticoagulation for secondary CVC placement, with an ongoing clinical question surrounding optimal dosing.
Limitations to this study include that only 60 (25%) providers responded and completed the forum posting, which may represent a biased, small sample and not fully represent the current management of asymptomatic CVC-related VTE in children in Saudi Arabia. Other limitations of self-reporting with a hypothetical scenario, is that decisions may vary from their actual management. This is the first survey that has explicitly focused on evaluating the practices of hematologists and oncologists on the management of asymptomatic CVC-related VTE in children in Saudi Arabia.
Our study has demonstrated that there is considerable variability in management, particularly in the duration of treatment and the use of secondary prophylaxis for pediatric patients with an asymptomatic CVC-related VTE. Further clinical trials are needed to provide evidence-based treatment guidelines.