Mr Keno Mentor, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
CMV infection which is refractory to standard treatment is a challenging clinical problem, resulting in patient morbidity and increased healthcare costs, mainly due to prolonged and repeat admissions. In the SOLSTICE trail, Maribavir was shown to be more effective than standard treatment protocols for refractory CMV infection in post-transplant patients. This post-hoc analysis of the SOLISTICE trial used trial data to calculate the reduction in healthcare costs that could be achieved by using Maribavir in this patient population. The analysis demonstrated a third to two thirds reduction in costs over an 8-week period when using Maribavir. Healthcare cost analyses are complex and subject to many assumptions, which the authors acknowledge introduces significant bias. However, the most striking omission from the analysis is the cost of the Maribavir treatment itself, which is significantly higher than standard therapy. With the additional limitation of a short duration of study, the reliability and applicability of the reported cost savings cannot be readily determined.
Aims:
The aim of this study was to use the data from the randomised controlled trial, SOLSTICE, to estimate the cytomegalovirus (CMV) related health care resource utilization (HCRU) costs of maribavir (MBV) versus investigator-assigned therapy (IAT), among hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) recipients.
Interventions:
Participants in the SOLSTICE trial were randomised to either receive IAT or MBV therapy.
Participants:
352 patients that had either HSCT (40%) or SOT (60%).
Outcomes:
The key outcomes were the cost of hospitalisation with IAT versus MBV therapy, and cost difference (i.e. cost savings) with MBV.
Follow Up:
N/A
BACKGROUND:
Cytomegalovirus (CMV) infections among hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) recipients impose a significant health care resource utilization (HCRU)-related economic burden. Maribavir (MBV), a novel anti-viral therapy (AVT), approved by the United States Food and Drug Administration for post-transplant CMV infections refractory (with/without resistance) to conventional AVTs has demonstrated lower hospital length of stay (LOS) versus investigator-assigned therapy (IAT; valgancilovir, ganciclovir, foscarnet, or cidofovir) in a phase 3 trial (SOLSTICE). This study estimated the HCRU costs of MBV versus IAT.
METHODS:
An economic model was developed to estimate HCRU costs for patients treated with MBV or IAT. Mean per-patient-per-year (PPPY) HCRU costs were calculated using (i) annualized mean hospital LOS in SOLSTICE, and (ii) CMV-related direct costs from published literature. Probabilistic sensitivity analysis with Monte-Carlo simulations assessed model robustness.
RESULTS:
Of 352 randomized patients receiving MBV (n = 235) or IAT (n = 117) for 8 weeks in SOLSTICE, 40% had HSCT and 60% had SOT. Mean overall PPPY HCRU costs of overall hospital-LOS were $67,205 (95% confidence interval [CI]: $33,767, $231,275) versus $145,501 (95% CI: $62,064, $589,505) for MBV and IAT groups, respectively. Mean PPPY ICU and non-ICU stay costs were: $32,231 (95% CI: $5,248, $184,524) versus $45,307 (95% CI: $3,957, $481,740) for MBV and IAT groups, and $82,237 (95% CI: $40,397, $156,945) MBV versus $228,329 (95% CI: $94,442, $517,476) for MBV and IAT groups, respectively. MBV demonstrated cost savings in over 99.99% of simulations.
CONCLUSIONS:
This analysis suggests that Mean PPPY HCRU costs were 29%-64% lower with MBV versus other-AVTs.
Mr John Fallon, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This large multi-centre double-blinded randomised trial demonstrated a higher vaccine response using MF59-adjuvanated and high-dose influenza vaccines compared with standard vaccine, but this did not lead to improved clinical outcomes, with no difference in the incidence of influenza. Overall, the trial is robustly designed with clear outcome measures, though choosing the main clinically relevant outcome, clinical efficacy, as a secondary measure due the samples size this would require. The vaccine response in standard vaccine was 42%, 60% in MF-59-adjuvanted and 66% in the high dose group, while these differences are significant, if it does not translate to clinical outcome it is more difficult to make a case for their use given the increased cost and potential side effect burden. Adverse events occurred in 84% and 86% in the MF59-adjuvanted and high dose cohorts and only 59% for the standard vaccine, but all were mild side effects, such as: pain, redness, swelling, arthralgia, fatigue, and headache. De novo anti-HLA antibodies and biopsy-proven acute rejection was rare across all groups. Despite the vaccine response rate differences, when scrutinising seroprotection by strains within the trivalent vaccine (H1N1, H3N2 & B), one can see the potential cause for the lack of clinical efficacy. Across all three groups baseline protection is around 60% for H1N1 and around 30% for the other strains, likely due to the large number of participants (83%) who have previously received an influenza vaccine, and given the majority of participants are primary recipients, they are likely to have been immunocompetent at the time of the previous vaccine. They have demonstrated MF59-adjuvanted and high-dose vaccines to be safe in the solid organ transplant population, and given pervious evidence of clinical benefit in high risk populations such as the elderly, these vaccine could provide clinical benefit in transplant populations, but definitive evidence to alter practice is not provided here.
Aims:
They aimed to evaluate whether MF59-adjuvanated or high-dose influenza vaccines elicited better immunogenicity, were safe had better clinical efficacy compared to standard vaccine.
Interventions:
Intervention vaccines were MF59-adjuvanated and high-dose influenza vaccine versus control, standard influenze vaccine.
Participants:
598 adults who received a solid organ transplant >3 months prior to enrolment.
Outcomes:
The primary outcome was antibody response rate at day 2 post-vaccine. The secondary clinical outcomes were influenza confirmed on PCR and vaccine reactogenicity. The secondary immunogenicity outcomes were: geometric mean titres of haemagglutination inhibition, seroproctection rates, seroconversion rates, seroconversion factors for each strain.
Follow Up:
180 days
BACKGROUND:
The immunogenicity of the standard influenza vaccine is reduced in solid-organ transplant (SOT) recipients, so new vaccination strategies are needed in this population.
METHODS:
Adult SOT recipients from 9 transplant clinics in Switzerland and Spain were enrolled if they were >3 months after transplantation. Patients were randomized (1:1:1) to a MF59-adjuvanted or a high-dose vaccine (intervention), or a standard vaccine (control), with stratification by organ and time from transplant. The primary outcome was vaccine response rate, defined as a ≥4-fold increase of hemagglutination-inhibition titers to at least 1 vaccine strain at 28 days postvaccination. Secondary outcomes included polymerase chain reaction-confirmed influenza and vaccine reactogenicity.
RESULTS:
A total of 619 patients were randomized, 616 received the assigned vaccines, and 598 had serum available for analysis of the primary endpoint (standard, n = 198; MF59-adjuvanted, n = 205; high-dose, n = 195 patients). Vaccine response rates were 42% (84/198) in the standard vaccine group, 60% (122/205) in the MF59-adjuvanted vaccine group, and 66% (129/195) in the high-dose vaccine group (difference in intervention vaccines vs standard vaccine, 0.20; 97.5% confidence interval [CI], .12-1); P < .001; difference in high-dose vs standard vaccine, 0.24 [95% CI, .16-1]; P < .001; difference in MF59-adjuvanted vs standard vaccine, 0.17 [97.5% CI, .08-1]; P < .001). Influenza occurred in 6% of the standard, 5% in the MF59-adjuvanted, and 7% in the high-dose vaccine groups. Vaccine-related adverse events occurred more frequently in the intervention vaccine groups, but most of the events were mild.
CONCLUSIONS:
In SOT recipients, use of an MF59-adjuvanted or a high-dose influenza vaccine was safe and resulted in a higher vaccine response rate.
Mr Keno Mentor, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
Potential brain-dead organ donors are frequently lost to cardiac arrest prior to organ retrieval. This unblinded randomised trial investigated the efficacy of employing an ICU-based checklist to optimise donor physiology to reduce the rate of donor loss. The checklist included various aspects of critical care management and was randomised to 743 patients (vs. 792 controls). Although there was a numerical improvement in the intervention group, there was no significant difference in rate of donor loss between the two groups. There are several important confounders that are not controlled for in this trial, but the most important limitation is due to the lack of blinding. ICU units in the control arm could have improved their practice in response to being included in such a trial, negating any potential effect due to the intervention.
Aims:
This study aimed to investigate the whether an evidence-based, goal-directed checklist was effective in delaying cardiac arrest in brain-dead potential donors in the intensive care unit (ICU).
Interventions:
At cluster level, eligible hospitals were randomised to provide either checklist guidance or usual care. At individual level, potential organ donors were randomised to receive either checklist guidance or usual care.
Participants:
At cluster level, hospitals with a mean number of ≥ 10 brain-dead potential donors annually over the previous 2 years were eligible. At individual level, brain dead organ donors in the ICU (aged 14 to 90 years) were enrolled.
Outcomes:
The primary endpoint was the loss of brain-dead potential donors to cardiac arrest. The secondary endpoints included the conversion of brain-dead potential donors to actual organ donors and the number of solid organs recovered per actual organ donor.
Follow Up:
14 days or until transfer from the ICU to the operating room
IMPORTANCE:
The effectiveness of goal-directed care to reduce loss of brain-dead potential donors to cardiac arrest is unclear.
OBJECTIVE:
To evaluate the effectiveness of an evidence-based, goal-directed checklist in the clinical management of brain-dead potential donors in the intensive care unit (ICU).
DESIGN, SETTING, AND PARTICIPANTS:
The Donation Network to Optimize Organ Recovery Study (DONORS) was an open-label, parallel-group cluster randomized clinical trial in Brazil. Enrollment and follow-up were conducted from June 20, 2017, to November 30, 2019. Hospital ICUs that reported 10 or more brain deaths in the previous 2 years were included. Consecutive brain-dead potential donors in the ICU aged 14 to 90 years with a condition consistent with brain death after the first clinical examination were enrolled. Participants were randomized to either the intervention group or the control group. The intention-to-treat data analysis was conducted from June 15 to August 30, 2020.
INTERVENTIONS:
Hospital staff in the intervention group were instructed to administer to brain-dead potential donors in the intervention group an evidence-based checklist with 13 clinical goals and 14 corresponding actions to guide care, every 6 hours, from study enrollment to organ retrieval. The control group provided or received usual care.
MAIN OUTCOMES AND MEASURES:
The primary outcome was loss of brain-dead potential donors to cardiac arrest at the individual level. A prespecified sensitivity analysis assessed the effect of adherence to the checklist in the intervention group.
RESULTS:
Among the 1771 brain-dead potential donors screened in 63 hospitals, 1535 were included. These patients included 673 males (59.2%) and had a median (IQR) age of 51 (36.3-62.0) years. The main cause of brain injury was stroke (877 [57.1%]), followed by trauma (485 [31.6%]). Of the 63 hospitals, 31 (49.2%) were assigned to the intervention group (743 [48.4%] brain-dead potential donors) and 32 (50.8%) to the control group (792 [51.6%] brain-dead potential donors). Seventy potential donors (9.4%) at intervention hospitals and 117 (14.8%) at control hospitals met the primary outcome (risk ratio [RR], 0.70; 95% CI, 0.46-1.08; P = .11). The primary outcome rate was lower in those with adherence higher than 79.0% than in the control group (5.3% vs 14.8%; RR, 0.41; 95% CI, 0.22-0.78; P = .006).
CONCLUSIONS AND RELEVANCE:
This cluster randomized clinical trial was inconclusive in determining whether the overall use of an evidence-based, goal-directed checklist reduced brain-dead potential donor loss to cardiac arrest. The findings suggest that use of such a checklist has limited effectiveness without adherence to the actions recommended in this checklist.
Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This interesting study from the US randomised 10 VA transplant centres, at a centre level, to use of a computerised alert dashboard designed to identify recipients at risk of non-adherence, drug interactions and abnormal/missing lab values. The authors found that use of the dashboard significantly reduced the incidence of hospital admissions (by 12.3%) and emergency department visits (by 11.3%), although the incidence of registry-reported acute rejection episodes was increased. There are potential issues with cluster randomisation in this type of study. When the number of centres is small, cluster randomisation can lead to imbalances in the groups in terms of baseline demographics and standard care levels. There is some evidence of this – ED visits and hospitalisations differed significantly in the year preceding the study between the control and intervention groups, and there are demographic and transplant mix differences as well. All of these may affect the risk of the outcomes. It is likely that the intervention was not used optimally by the participating pharmacists, with delays in responding to alerts and a lack of response to many. The key to successful implementation is therefore likely to be in optimising the workflow to ensure that alerts are acted upon in a timely fashion to achieve maximum benefit.
Aims:
This study aimed to report the outcomes of the cluster-randomised ISTEP trial, which aimed to examine the effectiveness of a bioinformatics-driven dashboard to guide pharmacist-led medication therapy management intervention in solid organ transplant recipients.
Interventions:
Participants were randomised to either standard care combined with the pharmacist-led, bioinformatics dashboard intervention or standard care alone.
Participants:
1982 veterans receiving 2196 transplants.
Outcomes:
The primary endpoints were the overall rate of veterans affairs (VA) emergency department (ED) visits and VA hospitalisations. Secondary endpoints included patient survival, graft survival and acute rejection episodes.
Follow Up:
24 months
An ambulatory medication safety dashboard was developed to identify missing labs, concerning labs, drug interactions, nonadherence, and transitions in care. This system was tested in a 2-year, prospective, cluster-randomized, controlled multicenter study. Pharmacists at 5 intervention sites used the dashboard to address medication safety issues, compared with usual care provided at 5 control sites. A total of 2196 transplant events were included (1300 intervention vs 896 control). During the 2-year study, the intervention arm had a 11.3% (95% confidence interval, 7.1%-15.5%) absolute risk reduction of having ≥1 emergency department (ED) visit (44.2% vs 55.5%, respectively; P < .001, respectively) and a 12.3% (95% confidence interval, 8.2%-16.4%) absolute risk reduction of having ≥1 hospitalization (30.1% vs 42.4%, respectively; P < .001). In those with ≥1 event, the median ED visit rate (2 [interquartile range (IQR) 1, 5] vs 2 [IQR 1, 4]; P = .510) and hospitalization rate (2 [IQR 1, 3] vs 2 [IQR 1, 3]; P = .380) were similar. Treatment effect varied by comorbidity burden, previous ED visits or hospitalizations, and heart or lung recipients. A bioinformatics dashboard-enabled, pharmacist-led intervention reduced the risk of having at least one ED visit or hospitalization, predominantly demonstrated in lower risk patients.
Mr John Fallon, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This modest sized double-blinded, placebo-controlled RCT was robustly designed, with sound methodology, and demonstrated liraglutide treatment to the donor reduced circulating IL-6 and prevented increase in IL-10. While IL-6 is a pro-inflammatory cytokine which induces the expression of various transcription factors related to inflammation, in this study its reduction in the donor did not translate into any altered gene expression within the liver tissue. They also found no significant differences in their other inflammatory cytokines. In terms of correlation with outcome, the study was severely limited by the number transplanted in their own centre, resulting in a small cohort of recipients they were able to follow-up, they do not specifically report the rates of EAD, however on looking at the results, by Olthoff criteria the rates of EAD, were low and comparable. While the trial is not groundbreaking it is mechanistically interesting with the effects of the GLP-1 agonist measurable within the donors. It is also ethically interesting considering little research is done in donors currently, which could be a valuable window of opportunity to deliver therapies to improve organ outcomes.
Aims:
To assess if delivery of liraglutide to brainstem death donors reduced donor inflammation prior to organ donations with correlation to liver transplant outcomes.
Interventions:
The intervention group donors received 3mg of liraglutide subcutaneously (0.5mL) at the point of randomisation and then every 6 hours until donation. The placebo group received 0.5mL of normal saline.
Participants:
50 adult DBD donors, of which 12 livers went on to be transplanted in the study centre.
Outcomes:
The primary outcome measure was IL-6 levels in the donor prior to first dose and immediately prior to retrieval. The secondary outcomes were donor plasma levels of IL-1β, IL-10, IFN-γ, TNF and BCL-2. Assessment of liver tissue for inflammation related gene expression and immunohistochemistry. The exploratory outcomes were the utilisation rate of the livers and early allograft dysfunction in the livers transplanted in the study centre.
Follow Up:
The organ donation period
Brain death triggers an inflammatory cascade that damages organs before procurement, adversely affecting the quality of grafts. This randomized clinical trial aimed to compare the efficacy of liraglutide compared to placebo in attenuating brain death-induced inflammation, endoplasmic reticulum stress, and oxidative stress. We conducted a double-blinded, placebo-controlled, randomized clinical trial with brain-dead donors. Fifty brain-dead donors were randomized to receive subcutaneous liraglutide or placebo. The primary outcome was the reduction in IL-6 plasma levels. Secondary outcomes were changes in other plasma pro-inflammatory (IL-1β, interferon-γ, TNF) and anti-inflammatory cytokines (IL-10), expression of antiapoptotic ( BCL2 ), endoplasmic reticulum stress markers ( DDIT3/CHOP , HSPA5/BIP ), and antioxidant ( superoxide dismutase 2 , uncoupling protein 2 ) genes, and expression TNF, DDIT3, and superoxide dismutase 2 proteins in liver biopsies. The liraglutide group showed lower cytokine levels compared to the placebo group during follow-up: Δ IL-6 (-28 [-182, 135] vs. 32 [-10.6, 70.7] pg/mL; p = 0.041) and Δ IL-10 (-0.01 [-2.2, 1.5] vs. 1.9 [-0.2, 6.1] pg/mL; p = 0.042), respectively. The administration of liraglutide did not significantly alter the expression of inflammatory, antiapoptotic, endoplasmic reticulum stress, or antioxidant genes in the liver tissue. Similar to gene expression, expressions of proteins in the liver were not affected by the administration of liraglutide. Treatment with liraglutide did not increase the organ recovery rate [OR = 1.2 (95% CI: 0.2-8.6), p = 0.82]. Liraglutide administration reduced IL-6 and prevented the increase of IL-10 plasma levels in brain-dead donors without affecting the expression of genes and proteins related to inflammation, apoptosis, endoplasmic reticulum stress, or oxidative stress.
Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This randomised study from New York recruited adult Hispanic residents and delivered an online survey to elicit their knowledge and views on organ donation. Participants were randomised to watch an emotive video on deceased donation either before answering the survey, or after. The authors found that participants who watched the video before answering the survey showed more willingness to register as a donor (OR 2.05) and greater awareness as to how to sign up. The study is well designed and interesting, demonstrating how simple information provision may impact donation decisions in diverse populations. It is worth noting that the study did not measure actual registrations, just intent, and future studies should look at impact on actual registration rates as a closer proxy to real-world benefit.
Aims:
The aim of this study was to evaluate whether an educational video was effective in improving organ donation intent among Hispanic New York residents.
Interventions:
Participants were randomised to either view a short educational video on organ donation prior to the survey or to view the same video following the survey.
Participants:
365 Hispanic New York City (NYC) residents.
Outcomes:
The main outcomes of interest were to assess the impact of the emotional video on willingness to donate, and to identify driving factors for organ donation.
Follow Up:
N/A
BACKGROUND:
The Hispanic community has a high demand for organ donation but a shortage of donors. Studies investigating factors that could promote or hinder organ donation have examined emotional video interventions. Factors acting as barriers to organ donation registration have been classified as: (1) Bodily integrity; (2) medical mistrust; (3) "ick"-feelings of disgust towards organ donation; and (4) "jinx"-fear that registration may result in one dying due to premeditated plans. We predict that by providing necessary information and education about the donation process via a short video, individuals will be more willing to register as organ donors.
AIM:
To determine perceptions and attitudes regarding barriers and facilitators to organ donation intention among Hispanic residents in the New York metro politan area.
METHODS:
This study was approved by the Institutional Review Board at Northwell Health. The approval reference number is No. 19-0009 (as presented in Supplementary material). Eligible participants included Hispanic New York City (NYC) residents, 18 years of age and above, who were recruited voluntarily through Cloud Research and participated in a larger randomized survey study of NYC residents. The survey an 85-item Redcap survey measured participant demographics, attitudes, and knowledge of organ donation as well as the intention to register as an organ donor. Attention checks were implemented throughout the survey, and responses were excluded for those who did fail. Participants were randomly assigned two-between subject conditions: To view a short video on organ donation and then proceed to complete the survey (i.e., video first) and view the same video at the end of the survey (video last). No intra-group activities were conducted. This study utilized an evidenced-based emotive educational intervention (video) which was previously utilized and was shown to increase organ donation registration rates at the Ohio Department of Motor Vehicles. Results were analyzed using Jamovi statistical software. Three hundred sixty-five Hispanic individuals were included in the analysis. Once consent was obtained and participants entered the survey (the survey sample is presented in Supplementary material), participants were asked to report on demographic variables and their general impression of organ donation after death. The video depicted stories regarding organ donation after death from various viewpoints, including from the loved ones of a deceased person who died waiting for a transplant; from the loved ones of a deceased person whose organs were donated upon death; and, from those who were currently waiting for a transplant.
RESULTS:
Using a binomial logistic regression, the analysis provides information about the relationship between the effects of an emotive video and the intention to donate among Hispanic participants who were not already registered as donors. The willingness to go back and register was found to be significantly more probable for those who watched the emotive video before being asked about their organ donation opinions (odds ratio: 2.05, 95% confidence interval: 1.06-3.97). Motivations for participation in organ donation were also captured with many stating the importance of messages coming from "people like me" and a message that highlights "the welfare of those in need". Overall, the findings suggest that using an emotive video that addresses organ donation barriers to prompt organ donation intentions can be effective among the Hispanic populous. Future studies should explore using targeted messaging that resonates with specific cultural groups, highlighting the welfare of others.
CONCLUSION:
This study suggests that an emotive educational intervention is likely to be effective in improving organ donation registration intent among the Hispanic population residing in NYC.
Reshma Rana Magar, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This study aimed to establish whether factors such as anticipated regret, the deceased wishes and next-of-kin attitudes could predict next-of-kin approval for organ donation, and to develop a model of next-of-kin decision making regarding organ donation in Wales, UK, which has an opt-out system. A total of 808 participants were randomly assigned to imagine whether a deceased relative had either opted-in, opted-out or had not registered a decision (deemed consent). The authors concluded that anticipated regret significantly influenced the next-of-kin approval for organ donation, and also that if the next-of kin had negative beliefs towards organ donation, they were less likely to follow the deceased wishes to donate. It is possible that the participants may have underestimated the influence of their emotions on future decision-making process; thus, how they believed they would act may be different from how they behave in real life. The authors do a good job of acknowledging this. However, the study did not assess ethnicity or religion, both of which have been found to affect the decision of the next-of-kin on organ donation. These could have acted as potential confounders in the analyses. Perhaps another factor the authors could have also considered is the type of relationship between the deceased donor and the next-of-kin. It would have been interesting to see if relatives with negative attitude towards organ donation were able to override their beliefs and follow the deceased donor’s wishes to donate if the deceased donor was an authority figure or a final decision maker when alive. For example, in cultures where fathers are the main decision makers, there may be a higher chance of sons/daughters respecting their deceased father’s wishes to donate despite their negative affective attitudes, in comparison to fathers respecting their deceased children’s wishes.
Aims:
This study aimed to investigate how the deceased donor’s wishes, negative affective attitudes, perceived benefits and anticipated regret had an effect on the next-of-kin’s approval of organ donation under opt-out legislation.
Interventions:
Participants were randomised to imagine if their deceased relative had either opted in, opted-out or not registered a decision (deemed consent).
Participants:
Adults (≥18 years) living in Wales.
Outcomes:
The outcome variables of interest included previous health-based philanthropy, uncertainty, anticipated regret, intention of next-of-kin to approve donation of organs, negative affective attitudes and perceived benefits.
Follow Up:
Not reported
RATIONALE:
Family, and sometimes longstanding friends, have considerable influence over organ donation, through agreeing or disagreeing to the donation of a deceased individual's organs. To date, most research has been undertaken within opt-in systems.
OBJECTIVE:
This study advances on previous research by assessing next-of-kin approval under opt-out legislation. We tested whether next-of-kin approval varies when the deceased is a registered donor (opted-in), registered non-donor (opted-out) or has not registered a decision under an opt-out policy (deemed consent). We also tested if the deceased's wishes influenced next-of-kin approval through relatives anticipating regret for not donating and feelings of uncertainty. Finally, we assessed whether next-of-kin's own beliefs about organ donation influenced whether they followed the deceased's wishes.
METHODS:
Participants (N = 848) living in a country with opt-out legislation (Wales, UK) were asked to imagine a relative had died under an opt-out system and decided if their relatives' organs should be donated. Participants were randomly allocated to imagine the deceased had either (i) opted-in, (ii) opted-out or (iii) not registered a decision (deemed consent). The outcome variable was next-of-kin approval, with uncertainty and anticipated regret as potential mediators and next-of-kin's beliefs about organ donation as moderators.
RESULTS:
Next-of-kin approval was lower when the deceased had opted-out than under deemed consent. This was due to next-of-kin anticipating more regret for not donating under deemed consent than opt-out. Further analyses revealed the deceased's wishes influence next-of-kin approval, via anticipated regret, when next-of-kin did not hold negative beliefs about organ donation.
CONCLUSIONS:
The deceased's wishes were less likely to be followed when next-of-kin had negative beliefs towards donation. Developing large-scale campaigns to improve these beliefs in the general public should make people more likely to follow the deceased's wishes. As a result, these campaigns should improve the availability of donor organs.
Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This multicentre RCT investigated the use of Maribavir (a UL97 protein kinase inhibitor) in post-transplant (HCT or SOT) patients with refractory CMV infection. Maribavir was compared to investigator assigned treatment with either valganciclovir/ganciclovir, foscarnet, or cidofovir. CMV clearance was significantly more likely in the Maribavir group (55.7% vs 23.9%) and demonstrated less nephrotoxicity than foscarnet, and less myelosuppression than valganciclovir/ganciclovir. Whilst unblinded, the study is pragmatic and well designed. There is some variability in included patients (“refractory” patients had to have failed to respond to one first line therapy, but this was not specified in detail) and in the investigator assigned comparator group, but this likely reflects real-world variations in practice. The results encouraging for the use of Maribavir as an alternative, potentially less toxic, alternative to existing therapies in this setting.
Expert Review
Reviewer:
Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Clinical Impact Rating
4
Review:
Treatment of refractory cytomegalovirus (CMV) infection in solid organ transplant recipients is challenging, with existing therapies limited by toxicity and drug resistance. Ganciclovir resistance is frequently seen, and foscarnet is associated with renal dysfunction in around 50% of patients treated (1). Safer, more effective treatments are needed to improve outcomes. Avery and colleagues have recently reported the outcomes of a multicentre, phase 3 randomised controlled trial of Maribavir, a novel UL97 protein kinase inhibitor that interferes with CMV DNA replication and encapsidation (2). The study randomised solid organ or stem cell transplant recipients with refractory CMV infection to Maribavir or investigator assigned treatment (IAT; valganciclovir/ganciclovir, foscarnet or cidofovir). Maribavir-treated patients demonstrated significantly higher clearance of viraemia after 8 weeks of treatment compared to IAT (55.7% vs. 23.9%). This response also appeared more sustained with Maribavir, with more patients achieving viraemia clearance and symptom control through to week 16. Perhaps as importantly, Maribavir also appeared to have an improved safety profile compared to other agents. Incidence of renal dysfunction was lower than with foscarnet, and neutropenia was less frequent than valganciclovir/ganciclovir. Dysguesia was the most frequently reported side effect in Maribavir-treated patients. Overall, fewer patients discontinued therapy due to side effects than in the IAT group. The study is pragmatic and well designed. It is not blinded, although this would be challenging give n the different routes of administration of the various agents. There is some variability in included patients (“refractory” patients had to have failed to respond to one first line therapy, but this was not specified in detail) and in the investigator assigned comparator group, but this likely reflects real-world variations in practice. Overall, the results are very encouraging and suggest that Maribavir offers an effective, better tolerated alternative to existing therapies for refractory CMV. References 1. Avery RK, Arav-Boger R, Marr KA et al. Outcomes in Transplant Recipients Treated With Foscarnet for Ganciclovir-Resistant or Refractory Cytomegalovirus Infection. Transplantation 2016; 100: e74. 2. Avery RK, Alain S, Alexander BD et al. Maribavir for Refractory Cytomegalovirus Infections With or Without Resistance Post-Transplant: Results from a Phase 3 Randomized Clinical Trial. Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America 2021; : ciab988.
Aims:
This study aimed to investigate the safety and efficacy of maribavir compared to investigator-assigned therapy (IAT) for the treatment of with or without resistance cytomegalovirus (R/R CMV) infection in solid-organ transplant (SOT) and hematopoietic-cell transplant (HCT) recipients.
Interventions:
Participants were randomised to either the maribavir group or the IAT group.
Participants:
352 HCT and SOT recipients.
Outcomes:
The primary outcome was confirmed CMV viremia clearance. Secondary outcomes included achievement of CMV clearance and symptom control.
Follow Up:
16 weeks
BACKGROUND:
Therapies for refractory cytomegalovirus infections (with or without resistance [R/R]) in transplant recipients are limited by toxicities. Maribavir has multimodal anti-cytomegalovirus activity through the inhibition of UL97 protein kinase.
METHODS:
In this phase 3, open-label study, hematopoietic-cell and solid-organ transplant recipients with R/R cytomegalovirus were randomized 2:1 to maribavir 400 mg twice daily or investigator-assigned therapy (IAT; valganciclovir/ganciclovir, foscarnet, or cidofovir) for 8 weeks, with 12 weeks of follow-up. The primary endpoint was confirmed cytomegalovirus clearance at end of week 8. The key secondary endpoint was achievement of cytomegalovirus clearance and symptom control at end of week 8, maintained through week 16.
RESULTS:
352 patients were randomized (235 maribavir; 117 IAT). Significantly more patients in the maribavir versus IAT group achieved the primary endpoint (55.7% vs 23.9%; adjusted difference [95% confidence interval (CI)]: 32.8% [22.80-42.74]; P < .001) and key secondary endpoint (18.7% vs 10.3%; adjusted difference [95% CI]: 9.5% [2.02-16.88]; P = .01). Rates of treatment-emergent adverse events (TEAEs) were similar between groups (maribavir, 97.4%; IAT, 91.4%). Maribavir was associated with less acute kidney injury versus foscarnet (8.5% vs 21.3%) and neutropenia versus valganciclovir/ganciclovir (9.4% vs 33.9%). Fewer patients discontinued treatment due to TEAEs with maribavir (13.2%) than IAT (31.9%). One patient per group had fatal treatment-related TEAEs.
CONCLUSIONS:
Maribavir was superior to IAT for cytomegalovirus viremia clearance and viremia clearance plus symptom control maintained post-therapy in transplant recipients with R/R cytomegalovirus. Maribavir had fewer treatment discontinuations due to TEAEs than IAT. Clinical Trials Registration. NCT02931539 (SOLSTICE).
Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This donor intervention study randomised 199 deceased brain dead donors to 4 groups – levothyroxine, methylprednisolone, both or control. Primary outcome was the vasoactive inotropic score (VIS), a measure of inotropic requirement at various time points prior to procurement. Both per-protocol and ITT analyses are presented due to relatively high rates of crossover to the combination arm. VIS improved in the methylprednisolone and combination groups, and was worse in the levothyroxine alone group, suggesting that methylprednisolone is the main driver of improved donor stability. Importantly in a donor intervention study, the authors looked at organ utilisation and outcomes following transplantation. These outcomes did not differ significantly between groups, although the study is not powered to these outcomes. These findings are interesting and do question the role of levothyroxine in donor management. The one main caveat is the lack of blinding – this may have increased the crossover rate and impacted inotrope administration, introducing the potential for treatment bias.
Expert Review
Reviewer:
Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Clinical Impact Rating
3
Review:
The haemodynamic instability seen in many brain dead (DBD) donors is thought in part to result from disruption in the hypothalamo-pituitary axis, resulting in reduced levels of thyroid hormone and vasopressin (1). For this reason, donor management often includes supplementation of thyroid hormones and vasopressin, and use of corticosteroids. Existing evidence as to the benefits of hormone replacement in the DBD donor is conflicting, with potential benefits of thyroid hormone and desmopressin administration seen in observational registry studies not borne out in prospective randomised controlled trials (2,3). In a recent issue of Transplantation, Van Bakel and colleagues report the results of a prospective randomised controlled trial of donor management in 199 brain-dead organ donors (4). Donors were randomised to four groups: high-dose levothyroxine, high-dose methylprednisolone, combination therapy and no hormonal therapy. Vasopressor requirements were assessed using a validated score (the vasoactive-inotropic score; VIS). The reduction in VIS from baseline was significant in the methylprednisolone and combination groups, but no improvement was seen in the levothyroxine alone or control groups. Unlike many donor intervention studies, the investigators were careful to report organ utilisation and graft outcomes for all groups. No differences were found between groups, although the study was not powered for these outcomes. Of note, the study was not blinded and this may have contributed to significant crossover from other arms to the combination arm and possibly impacted inotrope use. However, the findings above were confirmed in both intent-to-treat and per-protocol analyses. Overall, these results support the existing RCT evidence that thyroid hormone replacement alone does not improve cardiovascular stability in DBD donors, and that the largest impact on stability comes from corticosteroid use. References 1. Howlett TA, Keogh AM, Perry L, Touzel R, Rees LH. Anterior and posterior pituitary function in brain-stem-dead donors. A possible role for hormonal replacement therapy. Transplantation 1989; 47: 828. 2. Macdonald PS, Aneman A, Bhonagiri D et al. A systematic review and meta-analysis of clinical trials of thyroid hormone administration to brain dead potential organ donors. Critical Care Medicine 2012; 40: 1635. 3. Rech TH, Moraes RB, Crispim D, Czepielewski MA, Leitão CB. Management of the brain-dead organ donor: a systematic review and meta-analysis. Transplantation 2013; 95: 966. 4. Van Bakel AB, Hino SA, Welker D et al. Hemodynamic Effects of High-dose Levothyroxine and Methylprednisolone in Brain-dead Potential Organ Donors. Transplantation : 10.1097/TP.0000000000004072
Aims:
The aim of this study was to examine whether high-dose levothyroxine, high-dose methylprednisolone, or a combination of the two hormones, when administered early in the course of donor management, would lead to improvements in donor hemodynamics, allowing significant reduction in vasopressor support.
Interventions:
Participants were randomly assigned to receive high-dose levothyroxine, high-dose methylprednisolone, a combination of both, or no hormonal therapy (control).
Participants:
199 consecutive adult organ donors.
Outcomes:
The primary outcome was the difference in vasopressor requirement to maintain goal hemodynamics among the four treatment groups. Secondary mechanistic outcomes included the assessment of thyroid hormone (TH) levels, cortisol levels and markers of inflammation (C-reactive protein [CRP] and multiple cytokines). Secondary clinical outcomes were the number, types, and proportion of organs procured versus consented, rate of transplantation of procured organs, and patient and graft outcomes of organ recipients exposed to the various treatments.
Follow Up:
120 days
BACKGROUND:
Hormonal replacement therapy is administered to many brain-dead organ donors to improve hemodynamic stability. Previous clinical studies present conflicting results with several randomized studies reporting no benefit.
METHODS:
Consecutive adult donors (N = 199) were randomized to receive high-dose levothyroxine, high-dose methylprednisolone, both (Combo), or no hormonal therapy (Control). Vasopressor requirements using the vasoactive-inotropic score (VIS) were assessed at baseline, 4 h, and at procurement. Crossover to the Combo group was sufficient to require separate intention-to-treat and per-protocol analyses.
RESULTS:
In the intention-to-treat analysis, the mean (±SD) reduction in VIS from baseline to procurement was 1.6 ± 2.6, 14.9 ± 2.6, 10.9 ± 2.6, and 7.1 ± 2.6 for the levothyroxine, methylprednisolone, Combo, and Control groups, respectively. While controlling for the baseline score, the reduction in VIS was significantly greater in the methylprednisolone and Combo groups and significantly less in the levothyroxine group compared with controls. Results were similar in the per-protocol analysis.
CONCLUSIONS:
High-dose methylprednisolone alone or in combination with levothyroxine allowed for significant reduction in vasopressor support in organ donors. Levothyroxine alone offered no advantage in reducing vasopressor support. Organ yield, transplantation rates, and recipient outcomes were not adversely affected.
Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This small single-centre study from Japan investigates the role of common hepatic artery reconstruction in pancreas transplantation. 29 pancreas transplant recipients were randomised to reconstruction of the common hepatic artery or not. No differences in graft or patient survival, complication rate or graft function were seen between groups. Despite a sample size calculation performed on a non-inferiority basis, in reality the study is underpowered to show any difference between groups. The authors set a lower limit of non-inferiority in graft survival at 80%, which is a large difference from the baseline of 93.2% in their historic cohort. Randomisation was undertaken in blocks of two, meaning that there was no allocation concealment. Due to differences in national organ retrieval protocols, it is unlikely that reconstruction in this way would be possible in a lot of settings. In most regions, the splenic artery and SMA are reconstructed with a y-graft to allow the coeliac axis to be kept with the liver. This study suggests that reperfusion of the GDA is not usually required to provide adequate blood supply to the head of the pancreas.
Aims:
This study aimed to assess the efficacy and effects of common hepatic artery (CHA) reconstruction in pancreas transplantation.
Interventions:
Participants were randomised to either the non-reconstructed group or the reconstructed group.
Participants:
25 patients who underwent pancreas transplantation.
Outcomes:
The primary outcomes were 1-year graft survival. The secondary outcomes were the incidence of perioperative complications, 1-year graft survival, 1-month and 1-year patient survival, graft endocrine function, and tissue perfusion.
Follow Up:
1 year
Maintenance of postoperative graft flow is important in pancreas transplantation. In Japan, reconstruction of the common hepatic artery is performed primarily to increase perfusion in the pancreatic head. We investigated the effects of common hepatic artery reconstruction on patient and graft survival and endocrine functions. Twenty-nine cases of pancreas transplantation were registered in the clinical trial. Of the 29 cases, four were excluded because of the risk of ischemia without reconstruction or complicated reconstruction due to a narrow artery. A total of 25 cases were randomized into two groups: 13 in the non-reconstructed group and 12 in the reconstructed group. The 1-year patient survival and graft survival rates of the non-reconstructed and reconstructed groups were 92.3% and 83.3%, and 91.7% and 82.5%, respectively. The incidence of complications in the two groups was comparable, with 38.5% (5/13 cases) in the non-reconstructed group and 33.3% (4/12 cases) in the reconstructed group. The results of the glucagon stimulation test and oral glucose tolerance test at 1 month and 1 year post-transplantation were comparable. Common hepatic artery reconstruction is not essential unless there is risk of ischemia. This study was registered at the University Hospital Medical Information Network Clinical Trials Registry under UMIN000027213.
CET Conclusion