Updating clinical guidelines with limited evidence: case study of ASH/ISTH pediatric VTE treatment guidelines Open Access

TO THE EDITOR:

Venous thromboembolism (VTE) poses a significant health risk in both adult and pediatric populations.¹ The incidence of VTE in children has been steadily increasing but remains lower than that of adults.² This increase in pediatric VTE cases amplifies the need for evidence-based guidelines to inform optimal management strategies.

Clinical practice guidelines play a pivotal role in translating the latest scientific evidence into actionable recommendations for clinicians.³ The development process of evidence-based guidelines for uncommon and rare diseases is particularly challenging due to the relative scarcity of published research. This limitation often necessitates extrapolating data from indirect evidence, which may not accurately reflect the unique pathophysiology and treatment responses observed in the specific population. Nonetheless, guidelines in such fields provide evidence-based recommendations combined with expert consensus to guide clinical decision-making and allows for the identification of research gaps.

The American Society of Hematology (ASH) published its first set of comprehensive guidelines for pediatric VTE treatment in 2018. During the development of the 2018 guidelines, the panel acknowledged the limited pediatric data and significant reliance on adult data, calling for more research focused specifically on pediatric populations.⁴ Multiple studies addressing these gaps were published after the release of the guideline. Recognizing this, ASH/International Society on Thrombosis and Haemostasis (ISTH) decided to conduct an update for the pediatric VTE-treatment guidelines in 2024.⁵ 

The aim of this case study was to describe our experience while updating clinical practice guidelines for the treatment of VTE in pediatric patients, a field with scarce evidence. This is achieved by describing the changes in data informing the ASH recommendations between the 2018 and 2024 versions, focusing on the role of conducting guidelines for rare diseases with limited published literature.

In this study, we evaluated the changes in evidence between the 2018 ASH and 2024 ASH/ISTH guidelines for treatment of pediatric VTE. Both 2018 and 2024 involved similar methods for evidence synthesis and recommendation grading, such as the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach.⁴ We performed a comparative analysis for all prioritized outcomes in terms of the types of studies (eg, randomized controlled trials or observational studies), the number of studies and patients involved, and whether the data originated from adult or pediatric populations We additionally compared the recommendations that were updated noting any changes in direction, strength, or the certainty of evidence assigned. Finally, we identified the recommendations that transitioned from relying on adult comparative data in 2018 to depending solely on pediatric comparative data in 2024. All comparisons were conducted by 2 members of the evidence team for the 2024 iteration, who were involved in all steps of guideline development. We used count and percentages to describe the changes in outcomes and recommendations.

Nine panel members were members of both the original 2018 guideline panel and the 2024 iteration including the clinical co-chair. In the 2018 iteration 26 recommendations were made, of which 16 were selected to be addressed in the update. From the 16 recommendations, 2 changed in strength (from strong to conditional recommendation), 1 changed in direction (from conditional for the comparison to conditional for the intervention), and 1 changed in certainty of evidence (from very low to low certainty). Details on the changes in recommendations are described in Table 1.

Regarding changes in evidence, 45 outcomes out of 101 (44.5%) relied on higher certainty and more direct evidence. Thirty-two (31.6%) outcomes in 8 recommendations that relied on non-comparative data in the original guideline, relied on comparative data in the update. Four (3.9%) outcomes in three recommendations with no data in the original guidelines now relied on comparative data. Five (4.9%) outcomes in 2 recommendations that relied on adult comparative data in the original guidelines now relied on pediatric comparative data. Lastly, 4 (3.9%) outcomes in one recommendation changed from non-comparative to randomized control trials. Table 2 describes the changes in outcomes. Of the 16 recommendations that were updated, only 2 of 16 recommendations had no changes in the level of certainty of the evidence or directness of the evidence. On average, each recommendation relied on 2.1 additional comparative studies with a mean of 94.5 additional pediatric patients compared to the original 2018 guideline.

Of note, one significant change was the consideration of direct oral anticoagulants (DOACs) as therapeutic options in pediatric populations for all recommendations. In the 2018 guidelines DOACs were considered out of scope since DOAC use outside of trials could not be recommended due to lack of published pediatric specific data. In addition, in the 2024 guidelines, 2 specific recommendations related to DOAC use were included, both of which were informed by major trials that evaluated DOACs vs standard of care in VTE treatment in pediatric populations.^6-8 

Overall, our results showed advancement in the evidence that informed the updated guideline iteration with an increase in the number of pediatric specific comparative studies. These studies were reported after the publication of the 2018 guideline. Additionally, although data were not formally analyzed, numerous studies included in the updated version were conducted by panel members of the 2018 guidelines. The findings from this analysis underscore the importance of continued research efforts to strengthen the evidence base for pediatric VTE management, driven by research recommendations originating from the guideline effort.

Interestingly, 2 recommendations changed from strong recommendations for the intervention to conditional recommendations for the intervention. This change occurred because of these recommendations being previously driven by adult data; therefore, when primarily pediatric data was utilized certain group/conditions that may not benefit from the intervention were identified leading to this change.

This case study had a limited scope, focusing exclusively on 1 (ASH) published guidelines. However, we believe it is applicable for all fields of guideline research and appraisal. Examining recommendations from other clinical practice guidelines could provide a more comprehensive perspective on the evolution of evidence.

The 2024 ASH/ISTH guideline update for pediatric VTE treatment demonstrated a significant shift toward incorporating more pediatric-specific data. Although a limited number of recommendations changed, this progress highlighted that even in fields with scarce evidence, updates are critical to maintain clinical utility. However, persistent research gaps remain, underscoring the importance of continued research efforts. As new research emerges, updating clinical practice guidelines is crucial to ensure that recommendations reflect the most current and reliable evidence even if they do not lead to a change in overall recommendations.

Acknowledgements: This study was performed as part of the American Society of Hematology/International Society of Thrombosis and Haemostasis (ASH/ISTH) Clinical Practice Guidelines on venous thromboembolism in the pediatric population. This work was funded and supported by the ASH and ISTH. The authors thank the ASH and ISTH staff for their support during the guideline development process.

Contribution: A.C., A.A., M.A., H.K., M.B., L.R., S.K.V., R.B., P.M., and R.A.M. designed the research; A.C., A.A., M.A., and H.K. analyzed the data and wrote the manuscript; and M.B., L.R., S.K.V., R.B., P.M., and R.A.M. reviewed and edited the manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Reem A. Mustafa, Division of Nephrology and Hypertension, Department of Internal Medicine, The University of Kansas Medical Center, 3901 Rainbow Blvd MS3002, Kansas City, KS 66160; email: rmustafa@kumc.edu.