Rivaroxaban Compared with Standard Anticoagulants for the Treatment of Acute Venous Thromboembolism in Children: a Randomised, Controlled, Phase 3 Trial

Background: Treatment of venous thromboembolism in children is based on data obtained in adults with little direct documentation of its efficacy and safety in children. The aim of our study was to compare the efficacy and safety of rivaroxaban versus standard anticoagulants in children with venous thromboembolism. Methods: In a multicentre, parallel-group, open-label, randomised study, children (aged 0–17 years) attending 107 paediatric hospitals in 28 countries with documented acute venous thromboembolism who had started heparinisation were assigned (2:1) to bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20-mg equivalent dose or standard anticoagulants (heparin or switched to vitamin K antagonist). Randomisation was stratified by age and venous thromboembolism site. The main treatment period was 3 months (1 month in children <2 years of age with catheter-related venous thromboembolism). The primary efficacy outcome, symptomatic recurrent venous thromboembolism (assessed by intention-to-treat), and the principal safety outcome, major or clinically relevant non-major bleeding (assessed in participants who received ≥1 dose), were centrally assessed by investigators who were unaware of treatment assignment. Repeat imaging was obtained at the end of the main treatment period and compared with baseline imaging tests. This trial is registered with ClinicalTrials.gov, number NCT02234843 and has been completed. Findings: From Nov 14, 2014, to Sept 28, 2018, 500 (96%) of the 520 children screened for eligibility were enrolled. After a median follow-up of 91 days (IQR 87–95) in children who had a study treatment period of 3 months (n=463) and 31 days (IQR 29–35) in children who had a study treatment period of 1 month (n=37), symptomatic recurrent venous thromboembolism occurred in four (1%) of 335 children receiving rivaroxaban and five (3%) of 165 receiving standard anticoagulants (hazard ratio [HR] 0·40, 95% CI 0·11–1·41). Repeat imaging showed an improved effect of rivaroxaban on thrombotic burden as compared with standard anticoagulants (p=0·012). Major or clinically relevant non-major bleeding in participants who received ≥1 dose occurred in ten (3%) of 329 children (all non-major) receiving rivaroxaban and in three (2%) of 162 children (two major and one non-major) receiving standard anticoagulants (HR 1·58, 95% CI 0·51–6·27). Absolute and relative efficacy and safety estimates of rivaroxaban versus standard anticoagulation estimates were similar to those in rivaroxaban studies in adults. There were no treatment-related deaths. Interpretation: In children with acute venous thromboembolism, treatment with rivaroxaban resulted in a similarly low recurrence risk and reduced thrombotic burden without increased bleeding, as compared with standard anticoagulants. Funding: Bayer AG and Janssen Research & Development. © 2020 Elsevier Ltd

The Impact of Tacrolimus as Rescue Therapy in Children Using a Double Immunosuppressive Regimen After Heart Transplantation

Background. Organ transplant recipients with refractory rejection or intolerance to the prescribed immunosuppressant may respond to rescue therapy with tacrolimus. We sought to evaluate the clinical outcomes of children undergoing heart transplantation who required conversion from a cyclosporine-based, steroid-free therapy to a tacrolimus-based regimen. Methods. We performed a prospective, observational, cohort study of 28 children who underwent conversion from cyclosporine-based, steroid-free therapy to a tacrolimus-based therapy for refractory or late rejection or intolerance to cyclosporine. Results. There was complete resolution of refractory rejection episodes and adverse side effects in all patients. The incidence rate (X100) of rejection episodes before and after conversion was 7.98 and 2.11, respectively (P &lt;= .0001). There was a 25% mortality rate in patients using tacrolimus after a mean period of 60 months after conversion. Conclusion. Tacrolimus is effective as rescue therapy for refractory rejection and is a therapeutic option for pediatric patients

Long-Term Survivors Following Pediatric Heart Transplantation: A PHTS Database Analysis

Short-term outcomes following pediatric heart transplantation have improved over time with 1-year survival of over 90%, but comparable improvements in longer-term survival continues to have important barriers. We sought to investigate long-term outcomes following pediatric heart transplantation and to identify favorable factors associated with long-term survival. The Pediatric Heart Transplant Society (PHTS) database was queried for pediatric heart transplant recipients from 1993-2010. Patients with graft survival ≥10 years were compared to the general cohort and to patients with follow up ≥3 but <10 years. Kaplan-Meier analysis was used to evaluate overall survival and 3-year conditional survival. Factors associated with graft loss after 3-year conditional survival were identified using Cox proportional hazard modeling. 3,436 patients were transplanted between 1993-2010, of whom 1355 (39.4%) had ≥10 years of follow up (median 13.7 years (range 10.0-27.5)). Of those surviving to 10 years post-transplant, 84.4% and 74.3% survived to 15 and 20 years, respectively. Of the complete PHTS cohort, overall survival at 15 years was 53.3%. Patients <1 year at transplant who survived to 10 years had improved survival compared to other age groups (Figure). In 10-year survivors, the leading cause of subsequent mortality was cardiac allograft vasculopathy (CAV). Risk factors for graft loss after 3 years post-transplant were age, female gender, African American race, use of steroids at 2 years, rejection (particularly with hemodynamic compromise) and CAV (p-value for all <0.05). Use of mTORi was not associated with long-term survival. Heart transplantation remains an effective therapy in pediatric patients with a growing number of long-term survivors. Of modifiable risk factors, cessation of steroids may provide long-term survival benefit. Additional studies on social determinants of health are warranted to address increased mortality among African Americans

Waitlist and Post-Transplant Outcomes for Children with Myocarditis Listed for Heart Transplantation over Three Decades: A Multi-Institutional Analysis

Outcomes on children with myocarditis listed for heart transplantation (HT) is sparse and conflicting. Our study aims to determine if this population of listed patients have better outcomes pre- and post-HT in the current era given the advent of ventricular assist devices (VADs). We queried the Pediatric Heart Transplant Society (PHTS) database from 1993-2019 to identify patients with myocarditis and dilated cardiomyopathy (DCM). Patients were divided into two eras: earlier (1993-2008) and current era (2009-2019). Clinical characteristics were compared. Kaplan-Meier method with log-rank test and adjusted using multiphase parametric hazard modeling to examine outcomes. During the study period, of the 9755 patients listed for HT, 323 (3%) had myocarditis and 3279 (34%) DCM. A higher proportion of myocarditis patients in the current era were status 1A (85% vs 58% earlier era), have lower AST (mean 195 vs. 560 U/L), ALT (mean 109 vs. 277 U/L) and higher eGFR (mean 96 vs. 75 ml/min/1.73m2) (p<0.05 for all) at listing. VAD use was higher in myocarditis patients in the current era at listing (28 vs. 8%; p<0.001) and at time of HT (38 vs. 12%; p<0.001). Waitlist and post-transplant survival has not improved for patients with myocarditis over time (Figure a-b). In the current era, 5 year survival post-HT was higher in patients with DCM vs. myocarditis (88 vs. 79.5%, p=0.058). On multivariate analysis, myocarditis patients have increased post-HT mortality [HR 6.9, 95% CI 3.0-15.6; p<0.0001]. Patients with myocarditis in the current era have better renal and hepatic function at listing and increased VAD use at listing and at HT. Overtime, however, there have been no improvements in waitlist or post-transplant outcomes for patients with myocarditis and post-transplant survival continues to be worse in patients with myocarditis compared to those with DCM

The impact of heart failure severity at time of listing for cardiac transplantation on survival in pediatric cardiomyopathy

BACKGROUND: The survival benefit of heart transplantation in adult heart failure is greatest for the sickest patients and negligible for patients not requiring inotropic or mechanical support. We hypothesized a similar survival benefit of heart transplantation for childhood cardiomyopathies with heart failure. METHODS: A merged dataset of children registered in both the Pediatric Cardiomyopathy Registry and the Pediatric Heart Transplant Study was used to assess differences in mortality before and after transplant in patients with different levels of heart failure severity. Severity was scored 2 if mechanical ventilatory or circulatory support was required, 1 if intravenous inotropes were required, or 0 if no support was required. RESULTS: For 332 eligible children, 12-month mortality after listing was 9% for those with a severity score of 0 (n=105), 16% with a score of 1 (n=118), and 26% with a score of 2 (n=109; P=0.002) with a 3%, 8%, and 20% mortality with severity scores at listing of 0, 1, and 2, respectively, occurring before transplant. Patients listed with a score of 0 frequently deteriorated: 50% were transplanted or died prior to transplant with severity scores of 1 or 2. The risk of deterioration increased with previous surgery (relative risk, 3.84; P=0.03) in the short-term and with lower left ventricular mass z-score at time of presentation (relative risk, 1.74; P=0.003) in the longer-term. CONCLUSION: Pediatric cardiomyopathy patients who require high levels of support receive a survival benefit from heart transplantation that is not shared by patients not requiring intravenous inotropic or mechanical support