Deborah de SĂĄ Pereira Belfort, Bruno Biselli, MĂ´nica Samuel Ăvila, Renata Lopes Hames ¡ 18 authors
Background: In middle-income countries, costs limit widespred use of left ventricular assist device (LVAD) as a strategy for end-stage heart failure. We aim to describe the experience of a LVAD program in a middle-income country in a hub-and-spoke model. Methods: Patients fulfilling strict inclusion and exclusion criteria were referred from different centers in Brazil for LVAD implantation through a philanthropy program financed via a Brazilian Federal Government tax exemption structure. LVAD implantation was performed in a hub-and-spoke model with a single implanting center. Data were collected retrospectively using hospital records and telephone contact with other centers. Patients who received LVAD implants external to the philanthropic program, either at this or other Brazilian centers, were not included. Results: Between January 1, 2013 and December 31, 2020, 20 adult patients underwent long-term continuous flow LVAD implantation with decentralization of postimplant patient care in regional centers. Patients were referred from 11 centers from 7 states in Brazil and underwent LVAD implantation through a philanthropy program. The median age was 52.5 years and 85% were Interagency Registry for Mechanically Assisted Circulatory Support profile 3 patients. Two patients had Chagas cardiomyopathy. The overall survival censored for competing risks at 1 and 2 years were 90% and 84%, respectively. Three patients (15%) underwent heart transplantation in the first 2 years after LVAD implantation. Twelve patients returned to their original centers and were followed remotely. Conclusions: This study presents a successful LVAD implantation program in a hub-and-spoke model in Brazil. Centralization of LVAD implantation with decentralization of postimplant patient care in regional centers is feasible and safe, enabling optimal allocation of resources in middle-income countries.
This industry update covers the period from January 1 through January 31, 2022, and is based on information sourced from company press releases, scientific literature, patents and news websites. January 2022 saw Janssen and Midatech expand their collaboration on bioresorbable polymer microsphere technology for drug delivery. Takeda announced its plans to acquire UK-based Adaptate Biotherapeutics and Gandeeva raised further investment funds to support its drug discovery and development platform focused on the evaluation of proteinâdrug interactions. Biogen announced that it will sell its stake in a biosimilars joint venture and ABL Bio and Sanofi announced a collaboration around a novel treatment for Parkinson's disease. New regulatory announcements this month included US FDA approvals of a new insomnia treatment for Idorsia and a treatment for atopic dermatitis developed by Pfizer. Insulet gained FDA clearance for a closed-loop insulin pump and Ascendis Pharma followed up its United States approval last year for a once-weekly treatment for growth hormone deficiency with European approval. Pfizer and Ionis announced the discontinuation of the clinical development of a novel cardiovascular drug. In terms of collaborations, Novartis and Alnylam announced they will work together to explore targeted therapies to restore liver function; Scorpion Therapeutics partnered with AstraZeneca to develop novel cancer treatments and Nutriband Inc. and Kindeva Drug Delivery will work together to develop a transdermal fentanyl patch. Collaborations were also announced between Century Therapeutics and Bristol Myers Squibb and Lilly and Entos Pharmaceuticals in the areas of stem cell therapies for cancer treatment and neurology, respectively. A team from the Massachusetts Institute of Technology reported progress in developing oral mRNA treatments and West Pharmaceutical Services published a blog describing the development of a proof-of-principle system for a closed-loop feedback system targeting opioid overdose. A report on the BBC website highlighted the benefits of more sustainable inhalers.
Patent ductus arteriosus (PDA) is a common finding in preterm infants. Some PDAs will close spontaneously but those that remain open can be associated with significant morbidities and mortality.1-4 The current standard of care to treat a hemodynamically significant PDA (hsPDA) is to use either intravenous (IV) ibuprofen or IV indomethacin. These medicines have a nonselective mechanism of COX inhibition which can lead to side effects.5-7 To avoid this, researchers have explored using acetaminophen, which has COX-2 selectivity.8, 9 Recent studies using enteral acetaminophen for PDA closure have suggested that it is safe and effective.5, 6, 10, 11 The diagnosis of a hsPDA is confirmed by echocardiogram which evaluates size of the PDA and stress on the heart. B-type natriuretic peptide (BNP) levels produced in the ventricles of the heart rise in response to stretch from volume overload and have been used in previous studies to help determine the efficacy of ibuprofen treatment for a hsPDA.12-14 Studies evaluating the efficacy of enteral acetaminophen for PDA closure have not reported BNP levels. The efficacy of intravenous acetaminophen for closure of a hsPDA is unknown. We developed a proof of concept study to assess whether IV acetaminophen can be effective at closing a hsPDA using echocardiogram and BNP data as outcome measures. Infants 23 0/7 weeks through 29 6/7 weeks at birth with a hsPDA diagnosed by echocardiogram within the first 2 weeks of life were recruited in the neonatal intensive care unit at the Bernard and Millie Duker Children's Hospital at Albany Medical Center in Albany, NY. Written parental consent was obtain prior to randomization. This study was approved by the Institutional Review Board and registered on clinicaltrials.gov (NCT03008876). Five infants were randomized to each treatment group (10 infants total). The IV ibuprofen group received three doses: a loading dose of 10 mg/kg/dose on the first day followed by 5 mg/kg/dose on the second and third day. The IV acetaminophen group received 12 doses: 15 mg/kg/dose administered every 6 hours (total 3 days). Infants with any of the following were excluded: sepsis and/or meningitis, necrotizing enterocolitis, intestinal perforation, major congenital heart disease, major congenital malformations or disorders, fetal hydrops, pulmonary hypertension, grade 3 or 4 intraventricular hemorrhage, evidence of acute renal injury, thrombocytopenia, prior treatment with a prostaglandin, or of their aspartate transaminase (AST) and alanine transaminase (ALT) levels were twice the upper limits of normal. The primary outcome was PDA closure. Echocardiograms were performed for initial diagnosis and then 1 day after study drug completion. The ductus was graded as large, moderate, small, or closed, taking into consideration the LA: Ao ratio, the ductal diameter, and the doppler flow pattern through the PDA. The secondary outcome was BNP level. BNP levels were obtained before and after treatment on the same day that the echocardiogram was performed and were not known to the medical team. Serum chemistries, complete blood count (CBC), AST/ALT, and bilirubin levels were performed before, during, and after the study drug was administered. If values were abnormal, the attending neonatologist could halt the medication administration. Group sizes were too small for statistical analysis of change in PDA size. BNP levels were analyzed using both a repeated measures ANOVA and Wilcoxon signed rank tests. Nineteen infants were eligible from January 2017 through May 2019. Ten infants were ultimately randomized after informed consent was obtained: five received IV acetaminophen and five received IV ibuprofen (Figure 1). Demographic characteristics were similar in each group (Table 1). PDA closure was observed in two of the five infants in the IV acetaminophen group vs zero of five infants in the IV ibuprofen group. An additional infant in the IV acetaminophen group had a PDA that became smaller post study drug and then received two additional courses of IV ibuprofen. After the third course, the PDA was still present; however, it was closed on the echocardiogram prior to discharge. Of the remaining two infants in the IV acetaminophen group, one received two additional courses without improvement and underwent a PDA ligation, and the other infant did not undergo any additional treatment and the ductus was closed on a later echocardiogram (see Table 2). In the IV ibuprofen group, two of the five infants were noted to have smaller PDAs after the initial course. However, all five infants received additional courses of medication. Three infants had two additional courses of treatment (two of those received one course each of IV acetaminophen and IV ibuprofen and the third infant received two courses of IV ibuprofen), one infant had three additional courses (two IV ibuprofen, one IV acetaminophen), and the last infant had one additional course (IV ibuprofen) (see Table 2). Five infants in the ibuprofen group and two in the acetaminophen group, required subsequent pharmacologic therapy. The hsPDA closure rate at discharge (not including those that underwent PDA ligation), for infants in the IV acetaminophen group was higher compared to the IV ibuprofen group. A repeated measures ANOVA analysis on BNP levels showed a significant decrease in BNP levels pre and post-treatment, regardless of the study group (P = .01). There was a greater decrease in median BNP level after treatment in the IV acetaminophen group as compared to the IV ibuprofen group (P = .07 vs P = .17, respectively) (Figure 2). Creatinine, AST/ALT, and fractionated bilirubin levels were all found to be within normal limits before, during, and after the study drug course in both groups. There were no cases of NEC or GI bleeding. In this study the efficacy of acetaminophen in closing a PDA was evaluated. IV acetaminophen was used in our study, in comparison to many of the previous studies which used an enteral form, as we theorized a preterm infant's immature digestive system may alter enteral absorption and lead to lower serum concentrations and possible decreased efficacy in closing a PDA. Our results suggest that IV acetaminophen can successfully close a hsPDA. It was interesting to note that we saw no hsPDA closures from IV ibuprofen. The mean start day of treatment in this study was greater than previous studies which may explain lack of closure seen here as those infants who were treated earlier may have had a hsPDA that would have closed on its own. Since many are now using a watchful waiting approach to PDA management, the results in this study may be more reflective of the current outcomes with medical management.15 There was a decrease in cardiac stress (as measured by BNP level) in both groups, although greater in the acetaminophen group. To our knowledge, this is the first study to include BNP levels to assess the efficacy of acetaminophen on PDA closure. This study suggests that IV acetaminophen can be used as an alternative medication to close a hsPDA without adverse effects. The major limitation to this study was its small sample size and large scale studies are needed but will be challenging due to the current watchful waiting trend leading to decreased numbers of infants being treated. In addition to a larger number of patients, it would useful to address the optimal dose and duration of IV acetaminophen for PDA closure as well as the long-term safety and potential effects on neurodevelopment. Bin-Nun et al16 reported that a serum acetaminophen concentration > 20 mg/L was 100% sensitive and specific for ductal closure in their small cohort of preterm infants. However, McPherson et al17 found no correlation between serum concentration and ductal size post-treatment. The authors want to express their appreciation to James Cummings, MD, MA, and Joaquim Pinheiro, MD, MPH, for their help in preparing this manuscript. This work was funded by grants from The Gerber Foundation and Quidel, Inc. The funders did not have a role in the study design or implementation, running of the samples, analysis of the data, or writing of this manuscript. The authors declare no conflicts of interest. Conceptualization: Kate A. Tauber, Ronnelle King, Michael Colon Formal Analysis: Kate A. Tauber, Ronnelle King, Michael Colon Funding Acquisition: Kate A. Tauber Investigation: Kate A. Tauber, Ronnelle King, Michael Colon Methodology: Kate A. Tauber, Ronnelle King, Michael Colon Project Administration: Kate A. Tauber Supervision: Kate A. Tauber Visualization: Kate A. Tauber Writing â original draft preparation: Kate A. Tauber Writing â review and editing: Kate A. Tauber, Ronnelle King, Michael Colon All authors have read and approved the final version of this manuscript. Kate A. Tauber had full access to all of the data in the study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis. Kate A. Tauber affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained. Deidentified data from this study will be shared following publication with those individuals who have approval from an institutional review board (IRB) from their institution and approval from the IRB at our institution. Persons requesting data will need to sign a data access agreement. If interested in obtaining the data from this study please contact tauberk@amc.edu.