SCCM Resource Library-Twice-Daily Enoxaparin as Primary Thromboprophylaxis in Pediatric Patients Hospitalized for COVID-19

Video Transcription

My name is Anthony Sauchet. I am an Associate Professor of Anesthesiology and Critical Care Medicine through Johns Hopkins University,  but located down in beautiful St. Petersburg, Florida, not too far from what would have been the 51st Congress in Puerto Rico, but now excited still  to give this lecture through a virtual format. I participate through SCCM. I've been a member since I finished my training. I'm actually the president of our Florida chapter,  and I'm a member of the board of trustees  and I'm a clinical and translational scientist involved in a variety of lines of inquiry that I'm happy to discuss offline. But today I have a presentation that I'll be giving  that's entitled, Twice Daily Anoxaprint as Primary Thromboprophylaxis in Pediatric Patients Hospitalized for COVID-19, which is actually represents the primary findings  for the COVAC-TP clinical trial.  I have no disclosures. This project was funded by the Johns Hopkins All Children's Foundation.  I don't think I have to spend too much time going over the background on the COVID-19 pandemic as we have all been living through it,  but it has absolutely impacted how we deliver healthcare, how we think about translational science and research work in this era, and also emphasizes the importance of guidelines  that are based and derived from clinical trial data rather than just observational study.  Early on in the pandemic, it was unclear whether or not the severity of illness that was witnessed and reported in the adult populations would also be true for pediatrics.  In fact, this is a publication early on in Pediatrics by Dong et al from China that really showed only mild or moderate disease, largely asymptomatic disease  in many of the subgroups of interest.  However, we have found that COVID-19 and variants to follow  were in fact absolutely a pediatric problem. And here is some surveillance data through 2020 through mid-2021 that show that an increasing incidence across all subgroups.  And obviously these data do not incorporate even Omicron and Delta variants, although it does show the spike there at the end of the August period.  And when we look at hospitalizations related to pediatrics during that same time period,  not surprisingly, 16% of those hospitalized children required respiratory support, and even 8% of them required some type of vasoactive support  underscoring that these children did get sick and that COVID-19 did in fact impact them.  Switching gears a little bit, we're gonna talk about venous embolism.  Many of us in a traditional training understand the concept of virtual triad where you have this combination of hemostasis or immobility  combined with a hypercoagulable state and endothelial injury. And in critical illness in children, these things can be acquired, they can be congenital,  they can be molecularly based. And there are certainly comorbid primary admission diagnoses that may put them at more or greater risk as compared to other children.  In the general population, the risk of thrombosis for hospitalized children is about 0.9% and it's 2% in most recent reports in critical illness.  And when we look from the CHAT consortium data, which is coordinated out of Children's Hospital of Los Angeles with Julie Jaffrey,  that the risk factors echo previous risk modeling that have been reported. And I'll underscore that their biggest risk factors have not changed.  Their central venous catheterization, a Braden Q score indicating immobility and the duration of illness. And if that illness is in fact hyperinflammatory,  results in multiple portions of that virtual triad  that may be combined to add to risk of venous thromboembolism later on during the hospitalization. And when we look at adult data  that looks at hospital acquired venous thromboembolism and COVID-19, sure enough, the rates of venous thromboembolism are extremely high,  as with even the initial reports regarding COVID-19. In this report from Journal of Thrombosis and Thrombolysis, 31% of those who presented with SARS-CoV-2  have also had a thromboembolism during their hospitalization. And our data for pediatrics is somewhat more limited. This is a publication out of Blood that was coordinated out of,  I believe seven or eight different pediatric facilities that supplied retrospective data regarding COVID-19 hospitalizations. And as you can see,  the rates of thrombosis were not negligible. In fact, in the MIS-C group, the rates of thromboembolism were not negligible. In fact, in the MIS-C group  that were greater than 12 years of age were as high as almost 20%.  And even then, our management of those patients, in particular, our prophylaxis  to prevent these events were significantly varied by institution and within institution.  And with a predominant number of patients receiving twice daily enoxaprine as a treatment,  as thromboprophylaxis, if they did receive it.  And so the complete absence of trial data, in particular in pediatrics in general, but also regarding COVID-19 and the absence of prospectively calibrated  and validated hospital-acquired VTE models in pediatrics really makes it difficult for the clinician to determine, is it safe for me to give a drug  that puts them at risk for clinically relevant bleeding if that risk of bleeding is no different perhaps than the risk of clotting? And so this is the conundrum  that we are faced with as clinical providers. And this is also what we hope to address. There was a call to action by the International Society of Thrombosis and Hemostasis  that recommended thromboprophylaxis for COVID-19, in particular children who had elevated D-dimers or also some superimposed risk factors.  Within that same publication, as with other guidelines, research priorities were outlined, including a rapid call for activation of clinical trials to assess the efficacy and safety  of pharmacologic thromboprophylaxis. And ta-da, and here we are in April of 2020,  where we reached out to the existing infrastructure of the KidsDOT trial, anticoagulation trial, to rapidly activate eight sites within the United States  to address this concern regarding venous-term vandalism among children hospitalized with COVID-19.  The primary aim of this study was to conduct a phase two multi-center perspective open-label single-arm clinical trial to evaluate the safety, dose finding, and efficacy  of twice-daily enoxaprin subcutaneous as primary anticoagulant thromboprophylaxis for children less than 18 years of age who were hospitalized for COVID-19.  And that did include children who were hospitalized for primary acute respiratory-based COVID-19 infection or multisystem inflammatory syndrome in children, MIS-C.  The central hypothesis was very straightforward. It's that bleeding events were rare.  So the specific aims were as itemized are to determine the cumulative incidence of ISTH to define clinically relevant bleeding, assess enoxaprin dosing requirements  to achieve a goal level of 0.2 to 0.5, and identify cumulative incidence of VTE within a 30-day follow-up post-discharge.  We did so by leading this trial at eight sites within the United States from June of 2020 through June of 2021. Obviously, we included children zero to 17.  They had to be hospitalized for COVID-19. And when they were enrolled into study, they received throughout their entire hospitalization  twice a subcutaneous enoxaprin. The starting dose was 0.5 milligrams per kilo. The maximum dose was 60 milligrams. And that is relevant as we get into the descriptive data.  The primary exclusion criteria were children that were expected to be hospitalized for less than two days. Early on in the pandemic, as many of you know,  it was very unclear where to board these patients, in the ICU where there may be better monitoring and the general pediatric floors. And these things changed and evolved over time.  If the providers really expected that the patients were gonna go home in less than two days, we did not want them incorporated in the study per se.  Obviously, if the patients were receiving therapeutic anticoagulation, high doses of aspirin,  or had already bled, then we didn't need them to be part of the study. And the laboratory criteria were actually just standard criteria used for the decision-making  regarding the exposure to enoxaprin.  Obviously, if you have a renal insufficiency or you're already very coagulopathic, then perhaps that's not the right patient to continue to expose to an anticoagulant.  The primary study endpoint was the cumulative incidence of clinically relevant bleeding, which was assessed using clock or piercing confidence intervals.  And exploratory analyses were performed using comparative statistics in a priori groups, including those defined by age greater than or less than 12 years,  which is a known risk factor for the development of venous thromboembolism, as well as the clinical presentation of COVID-19 defined by groups that had MIS-C  versus primary acute COVID-19 infection.  This is a concert flow diagram. We did assess 302 children for eligibility for the study and eventually did enroll the goal of 38 subjects.  Predominant reason that people were excluded for a study was actually just expected length of stay less than two days or having insufficient lab dairy  or enrollment time windows were not met.  Here are the general characteristics for the participants of the COVECT-TP trial divided by groups that either had COVID-19 primary infection versus MIS-C.  Some things that you can note are that the age groups actually are pretty well defined here and correspond with the less than or greater than 12 years of age analysis,  which was not gonna be shown in the slide deck. The children that had MIS-C were generally speaking less than 12 years of age and those that had primary COVID-19  were greater than 15 years of age. Some other things to note that we did not see any significant differences in gender, ethnicity, or race.  The patients who had primary COVID-19 were obese and were significantly larger by weight than those who had MIS-C, something that I think we have seen anecdotally  and in other reports regarding pediatric COVID-19 infection and that patients who had MIS-C had a largely elevated D-dimer compared to those with primary COVID-19.  There was no differences in the presence of a central venous catheterization or non-invasive ventilatory support prior to enrollment.  Of the study participants that received anticoagulation with anoxaprin, 35 to 38 did achieve goal anti-tenning levels. Of the remaining who did not,  they simply were discharged prior to a dosing adjustments that could be provided. A majority of the patients did achieve the goal  anti-tenning level without any adjustment in the dosing. Anoxaprin dose requirements were higher amongst those who had MIS-C as compared to those with COVID-19,  but this actually may reflect the obesity that was depicted on the previous descriptive table. There were no clinically relevant bleeding events  recorded throughout the study period. There were no serious adverse events that were related to the study intervention, including one mortality.  Two participants during the study did develop a hospital-acquired venous thromboembolism that was central venous catheter related. And this was despite having  targeted prophylactic anti-tenning levels.  So in conclusion, by performing this phase two clinical trial, we were able to determine that subcutaneous anoxaprin as primary thromboprophylaxis  among children hospitalized for COVID-19 was in fact safe without any evidence of clinically relevant bleeding or other serious adverse events.  We're excited to report that this is one of the few prospective pediatric investigations of thromboprophylaxis in children. At the same time, we're a little disappointed  that this is one of the few prospective pediatric clinical trials in children for thromboprophylaxis. And so I wanna emphasize an opportunity here  to go after several large knowledge gaps that exist in our field, not related necessarily to COVID-19. The presence of venous thromboembolism in our study  despite treatment suggests that the intensity of exposure may actually have been insufficient  and or that the ISTH guidelines that the intensity was based on are also insufficient. So this is highlighting some great opportunities for us to collaborate  and potentially answer some larger questions.  As with all research, there are so many people to thank and not enough time to thank them. However, I would like to highlight and thank specifically my primary research mentor,  Dr. Neil Goldenberg, as well as the PIs, three at each of the participating sites, as well as their coordinating staff at each of those sites, our data coordinating center  and clinical trials coordinating center at Johns Hopkins All Children's Hospital and the Institute for Clinical and Translational Research at Johns Hopkins All Children's Hospital.  I am looking forward to answering some questions, taking some constructive feedback and perhaps engaging and collaborating with you in the future. Thank you so much.  Thank you.

Video Summary

Dr. Anthony Sauchet presented the primary findings of the COVAC-TP clinical trial, which aimed to evaluate the safety, efficacy, and dose requirements of twice-daily enoxaparin as primary thromboprophylaxis in pediatric patients hospitalized for COVID-19. The trial found that subcutaneous enoxaparin was safe and did not result in any clinically relevant bleeding or serious adverse events. However, two participants did develop hospital-acquired venous thromboembolism despite the prophylactic treatment. The study highlighted the need for further investigation to improve thromboprophylaxis guidelines for pediatric patients. Overall, the trial contributes valuable insights into thromboprophylaxis in children, particularly in the context of COVID-19.

Asset Subtitle

Pharmacology, Infection, Pediatrics, 2022

Asset Caption

INTRODUCTION: Evidence is limited on the safety or efficacy of anticoagulant thromboprophylaxis (TP) against hospital-associated venous thromboembolism (HA-VTE) in children hospitalized with COVID-19 and multisystem inflammatory syndrome in children (MIS-C). We aimed to assess: (1) the cumulative incidence of ISTH-defined clinically-relevant (major plus clinically-relevant non-major) bleeding (primary endpoint); (2) enoxaparin dose-requirements to achieve a goal anti-Xa activity of 0.2-0.49 U/mL (secondary endpoint); and (3) the cumulative incidence of VTE within 30-days post-discharge from hospital (exploratory efficacy). METHODS: We performed a multicenter, open-label, phase 2 clinical trial of twice-daily enoxaparin as primary TP for children 0-17 years of age hospitalized for COVID-19-related illness. The study was approved by the Johns Hopkins single IRB and required informed consent. Children received twice-daily subcutaneous enoxaparin (starting dose, 0.5mg/kg; maximum=60mg/dose) throughout hospitalization. Descriptive statistics were employed. The observation of ≤1 primary safety event was prespecified as demonstrating safety with regard to bleeding for n=38. RESULTS: Forty children were enrolled, of which 38 met criteria for analyses. Children with MIS-C (n=19) were younger (9.8 [IQR:6.9.11.7] vs 15.4 [12.5,17.1] years of age, p < 0.001) compared to those without MIS-C. No clinically relevant differences in demographics or clinical outcomes were noted (data not shown). Prophylactic anti-Xa levels were achieved in 35 children (92%). Median (interquartile range, IQR) enoxaparin dose required to achieve goal anti-Xa levels were as follows: age ≥ 12 years (n=18), 0.5 (IQR:0.43,0.52) mg/kg; < 12 years (n=17), 0.52 (IQR:0.49,0.55) mg/kg. There were no clinically-relevant bleeds. No SAEs were judged to be related to study intervention, including one death from COVID-19 illness. HA-VTE developed in two children (5.2%). CONCLUSIONS: In children hospitalized for COVID-19 related illness, primary TP with subcutaneous enoxaparin twice-daily at a starting dose of 0.5 mg/kg is safe and achieves target anti-Xa levels during hospitalization in >90% of patients. Future phase 3 trials of primary TP are warranted in hospitalized children with proinflammatory conditions such as COVID-19, for which HA-VTE risk is increased.

Meta Tag

Content Type Presentation

Knowledge Area Pharmacology

Knowledge Area Infection

Knowledge Area Pediatrics

Knowledge Level Intermediate

Knowledge Level Advanced

Membership Level Select

Tag Pharmacology

Tag Pediatrics

Tag COVID-19

Tag Infectious Diseases

Year 2022

Keywords

Dr. Anthony Sauchet

COVAC-TP clinical trial

enoxaparin

thromboprophylaxis

pediatric patients

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