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.