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, The Royal College of Surgeons of England.
Conclusion:
This small single-centre study investigated the role of intraoperative ATG injected directly to the coronary sinus during cardiac transplantation. Patients in both groups also received postoperative ATG infusion, to achieve the same total dose in both groups. The authors claim a significant reduction in the risk of acute rejection in the intraoperative ATG group, as well as a reduction in echocardiographic abnormalities and need of inotropic therapy. Whilst on the face of it, this sounds like a promising intervention, there are significant deficiencies in the methodology and reporting of this study. This study is described as randomised, but from the description in the manuscript it appears to be a sequential cohort study with all intraoperative ATG patients recruited at the end of the study. No power calculation is presented, and there is a real risk of type I error in the acute rejection results. I was unable to replicate the claim of a statistically significant increase in acute rejection – with 2/15 control and 0/15 study patients experiencing rejection, a Fisher exact test gives a p-value of 0.48, rather than the <0.05 reported in the manuscript. The claims of reduced inotrope use and improved echocardiographic function are not backed up with any data. In short, the data presented in the manuscript do not support the conclusion of the authors.
Expert Review
Reviewer:
Prof. Dr. Bart De Geest, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium
Conflicts of Interest:
No
Clinical Impact Rating
1
Review:
This prospective single center study was conducted in heart transplant patients receiving donor hearts procured after cardiocirculatory death (category III and category IV according to modified Maastricht classification). Thirty-two orthotopic heart transplant recipients were divided into 2 groups: group 1 included 17 patients who received retrograde antithymocyte globulin infusion via the coronary sinus intraoperatively and immediately after organ procurement and group 2 included 15 patients who received traditional antithymocyte globulin infusion after implantation. Two patients in group 1 were excluded due to early mortality resulting from a surgical complication (bleeding) and from acute renal failure. The first group had less acute rejection episodes than group 2 (0.0% vs 13.3%; P < .05) and graft function was better in these patients. The main limitation of this study is that group assignment was performed based on consecutive order, with group 1 being the last patients of the study period. The study is not a double-blind prospective study and no clear conclusions can be drawn. Furthermore, not all p-values are created equal and p-values obtained in small trials should be interpreted with greater caution.
Aims:
To identify the effects of intraoperative antithymocyte globulin administration on donor hearts following cardiocirculatory death.
Interventions:
Patients were randomized to receive retrograde antithymocyte globulin infusion via coronary sinus intraoperatively and immediately after organ procurement or traditional antithymocyte globulin infusion after implantation.
Participants:
30 patients with orthotropic heart transplants.
Outcomes:
Allograft rejection and graft function.
Follow Up:
30 days.
OBJECTIVES:
Our study was conducted to determine the effects of intraoperative antithymocyte globulin administration on donor hearts procured after cardiocirculatory death. We evaluated the impact of antithymocyte globulin on graft function and related parameters during isothermic blood cardioplegia.
MATERIALS AND METHODS:
In this prospective and randomized single center study, 30 patients with orthotropic heart transplant were divided into 2 groups: group 1 included 15 patients who received retrograde antithymocyte globulin infusion via coronary sinus intraoperatively and immediately after organ procurement and group 2 included 15 patients who received traditional antithymocyte globulin infusion after implantation.
RESULTS:
Study patients had a mean age of 33.8 years (range, 15-56 y). All patients had panel reactive antibody less than 10% except for 3 patients. The cluster of differentiation 3-positive cell count decrease was more than 20%. The inotropic therapy dose required and the myocardial pressure (stiffness) were less for group 1 patients. These patients had less acute rejection episodes than group 2 (0% vs 13.3%; P < .05).
CONCLUSIONS:
Favorable clinical outcomes were observed in terms of less acute rejection episodes and better graft function at least during the early posttransplant period. Intraoperative antithymocyte globulin treatment may have a preventive effect for acute cellular rejection in heart transplant patients.
Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This paper reports the long-term outcome from hearts randomised in the randomised PROCEED II study at a single centre. Previous publications of the PROCEED II study have already shown non-inferior short-term outcomes comparing perfusion on the OCS device to cold storage on ice. The study as a whole included 130 patients randomised in a 1:1 fashion, and this single-centre follow up reports on only 38. As such, this latest report is underpowered to identify all but the most obvious of clinical differences and the authors acknowledge this limitation. Follow-up in this cohort of 38 was acceptable, at 92%, which equates to 3 lost-to follow up. Recipients in the cold-storage arm were significantly older, by 8 years. There was no significant difference in overall survival at median follow up of 8.4 years and no difference in cardiac allograft vasculopathy. The study outcomes should be viewed in the context of a highly selected donor and recipient population, with any potential benefits more likely to show themselves when using extended criteria donors.
Expert Review
Reviewer:
Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Clinical Impact Rating
2
Review:
Utilisation of deceased donor cardiothoracic organs is typically lower than those of abdominal organs (1). This has led to interest in methods for ex-vivo preservation and viability assessment, which have the potential to prolong preservation times, recondition organs and improve outcomes by allowing assessment prior to transplantation. The first randomised controlled trial of normothermic ex-vivo cardiac preservation (PROCEED II) was reported in the Lancet in 2015 (2). The study randomised 130 transplant recipients to receive a heart either stored using conventional static cold storage (SCS) or preserved using the Organ Care System (OCS) perfusion device. The authors reported non-inferiority of perfused hearts, with no measurable difference in patient or graft survival despite longer overall preservation times in the OCS group. Of note, 5 hearts were discarded due to preservation parameters in the OCS group, but despite the potential advantages of discarding suboptimal organs, there was no measured clinical benefit (3). All hearts in the study had to be suitable for either arm and were relatively low-risk, meaning that any impact on organ utilisation cannot be assessed. In a recent paper published in Clinical Transplantation, Chen and colleagues report long-term outcomes in 38 patients from a single participating centre from the trial (4). Eight-year survival was numerically lower in the OCS group (57.9% vs. 73.7%, p=0.24) but not meeting statistical significance in this small sample. The apparent excess mortality in the OCS group seemed mainly related to events that are difficult to attribute to the preservation method (e.g. CMV infection or malignancy), supported by a lack of difference in the rate of graft-related mortality (84.2% in both groups). In contrast to the survival data, there was numerically higher freedom from coronary allograft vasculopathy (CAV; 89.5% vs. 67.8%) and non-fatal major cardiac events (89.5% vs. 67.5%) in the OCS group. Differences in CAV rate may relate to the shorter cold-ischaemic times in the OCS group, reducing ischaemia reperfusion injury. Overall, the small sample size means that firm conclusions are difficult to draw and this study is unlikely to have a significant impact on clinical practice. It would perhaps have been more useful to compile long-term outcomes from all patients in the original study to increase statistical power and see if the trends seen here were borne out in other centre’s data. Use of the OSC device is feasible and likely safe, but there is limited evidence of clinical benefit in standard-risk hearts. Whether ex-vivo perfusion will have a greater utility in preservation and viability assessment of hearts from more marginal donors remains to be seen. References 1. NHS Blood and Transplant. NHSBT Annual Activity Report 2020/21 [Internet]. [cited 2022 Apr 13] Available from: https://nhsbtdbe.blob.core.windows.net/umbraco-assets-corp/24053/activity-report-2020-2021.pdf 2. Ardehali A, Esmailian F, Deng M et al. Ex-vivo perfusion of donor hearts for human heart transplantation (PROCEED II): a prospective, open-label, multicentre, randomised non-inferiority trial. Lancet (London, England) 2015; 385: 2577. 3. Freed DH, White CW. Donor heart preservation: straight up, or on the rocks? The Lancet 2015; 385: 2552. 4. Chen Q, Singer-Englar T, Kobashigawa JA et al. Long-term outcomes after heart transplantation using ex vivo allograft perfusion in standard risk donors: A single-center experience. Clinical Transplantation 2022; : e14591.
Aims:
This study aimed to assess the long-term outcomes of heart transplant patients that received allografts preserved using the Organ Care System (OCS) versus standard cold storage (CS).
Interventions:
Participants were randomised to receive allografts preserved with either CS or OCS.
Participants:
38 heart transplant candidates.
Outcomes:
The primary outcomes were 8-year overall survival and freedom from cardiac allograft-related death up to 8 years. Secondary outcomes were 8-year freedom from cardiac allograft vasculopathy (CAV), freedom from non-fatal major adverse cardiac events and freedom from rejections.
Follow Up:
8 years
INTRODUCTION:
The Organ Care System (OCS) is an ex vivo perfusion platform for donor heart preservation. Short/mid-term post-transplant outcomes after its use are comparable to standard cold storage (CS). We evaluated long-term outcomes following its use.
METHODS:
Between 2011 and 2013, 38 patients from a single center were randomized as a part of the PROCEED II trial to receive allografts preserved with CS (n = 19) or OCS (n = 19). Endpoints included 8-year survival, survival free from graft-related deaths, freedom from cardiac allograft vasculopathy (CAV), non-fatal major adverse cardiac events (NF-MACE), and rejections.
RESULTS:
Eight-year survival was 57.9% in the OCS group and 73.7% in the CS group (p = .24). Freedom from CAV was 89.5% in the OCS group and 67.8% in the CS group (p = .13). Freedom from NF-MACE was 89.5% in the OCS group and 67.5% in the CS group (p = .14). Eight-year survival free from graft-related death was equivalent between the two groups (84.2% vs. 84.2%, p = .93). No differences in rejection episodes were observed (all p > .5).
CONCLUSIONS:
In select patients receiving OCS preserved allografts, late post-transplant survival trended lower than those transplanted with an allograft preserved with CS. This is based on a small single-center series, and larger numbers are needed to confirm these findings.
OBJECTIVES: The COVID-19 pandemic significantly affected the provisions of health services to necessary but deprioritised fields, such as transplantation. Many programmes had to ramp-down their activity, which may significantly affect transplant volumes. We aimed to pragmatically analyse measures of transplant activity and compare them by a country's income level and cumulative COVID-19 incidence (CCI). DESIGN, SETTING AND PARTICIPANTS: From June to September 2020, we surveyed transplant physicians identified as key informants in their programmes. Of the 1267 eligible physicians, 40.5% from 71 countries participated. OUTCOME: Four pragmatic measures of transplant activity. RESULTS: Overall, 46.5% of the programmes from high-income countries anticipate being able to maintain >75% of their transplant volume compared with 31.6% of the programmes from upper-middle-income countries, and with 21.7% from low/lower-middle-income countries (p<0.001). This could be because more programmes in high-income countries reported being able to perform transplantation/s (86.8%%-58.5%-67.9%, p<0.001), maintain prepandemic deceased donor offers (31.0%%-14.2%-26.4%, p<0.01) and avoid a ramp down phase (30.9%%-19.7%-8.3%, p<0.001), respectively. In a multivariable analysis that adjusted for CCI, programmes in upper-middle-income countries (adjusted OR, aOR=0.47, 95% CI 0.27 to 0.81) and low/lower-middle-income countries (aOR 0.33, 95% CI 0.16 to 0.67) had lower odds of being able to maintain >75% of their transplant volume, compared with programmes in high-income countries. Again, this could be attributed to lower-income being associated with 3.3-3.9 higher odds of performing no transplantation/s, 66%-68% lower odds of maintaining prepandemic donor offers and 37%-76% lower odds of avoiding ramp-down of transplantation. Overall, CCI was not associated with these measures. CONCLUSIONS: The impact of the pandemic on transplantation was more in lower-income countries, independent of the COVID-19 burden. Given the lag of 1-2 years in objective data being reported by global registries, our findings may inform practice and policy. Transplant programmes in lower-income countries may need more effort to rebuild disrupted services and recuperate from the pandemic even if their COVID-19 burden was low.
Dr. Liset Pengel, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion:
The study tested the hypothesis that reciprocal priming strategies increase organ donor registration intentions and behaviour compared to a control condition. 420 adult participants who were not registered as organ donors from England and Scotland were invited to complete an online survey and were randomised to the reciprocity prime condition or control condition. This sample provided sufficient power to detect a 10% increase in the number of participants who agreed to be taken to the U.K. organ donor registration and information pages. Intention to donate organs was assessed with the statements “I strongly intend to donate my organs when I die” and “I will definitely donate my organs when I die”. Participants in reciprocity prime condition displayed higher intention towards organ donation compared to controls however this did not result in an increase in the number of participants who signed up for organ donor registration. The authors conclude that more research is needed into changing organ donor registration behaviour.
Expert Review
Reviewer:
Prof Jeremy Chapman AC FRACP FRCP, Director of Medicine and Cancer, Westmead Hospital, Sydney, Australia.
Conflicts of Interest:
No
Clinical Impact Rating
1
Review:
Key Findings: This study of organ donation beliefs and, to a certain extent, also actions to commit to organ donation tested a single sentence reminding test subjects of the possibility that they might need an organ transplant (“If you needed an organ transplant would you have one? If so, please help others"). The control group had a bland statement in place of this sentence. Results of this study were that there was a marginal impact on stated intention to donate but no impact on action to increase the chance of donation since there was no impact on the likelihood that particpants would click on the link to the donor registry. It is very hard to see how a single sentence reminding individuals of reciprocal altruism could have a major impact despite the background media along the same lines from the national authority. Generalizability: The main impact is to emphasise again that beliefs and attitudes towards organ donation are strongly held and are not easily modified through community attitudinal modification through marketing approaches. This should encourage agencies seeking to modify attitudes to rely on behavioural modification or organisational systems rather than reciprocal altruism to increase organ donation. Implications for clinical practice: Organ donation activity is not decided on the streets or internet by appeal to reciprocal altruism.
Aims:
To assess if a digital reciprocity prime based on reciprocal altruism can effect intention attitudes to organ donation and organ donor registration.
Interventions:
Participants were randomized 1:1 to receive either a reciprocity prime statement (n=210) or control message (n=210) as part of a digital survey.
Participants:
420 participants (223 females; >18 years; had never previously donated an organ and not registered organ donors).
Outcomes:
After the survey, participants were asked to indicate their organ donation intentions by responding to two statements and whether or not they would like to be taken to an organ donation registration and information page.
Follow Up:
From September – October 2017
BACKGROUND:
Internationally the demand for organ transplants far exceeds the available supply of donated organs.
PURPOSE:
We examine if a digital reciprocity prime based on reciprocal altruism can be used to increase organ donor registration intentions and behavior.
METHODS:
Four hundred twenty participants (223 females) from England and Scotland aged 18+ who were not currently registered organ donors were randomized by block allocation using a 1:1 ratio to receive either a reciprocity prime or control message. After manipulation, they were asked to indicate their organ donation intentions and whether or not they would like to be taken to an organ donation registration and information page.
RESULTS:
In line with our previous work, participants primed with a reciprocity statement reported greater intent to register as an organ donor than controls (using a 7-point Likert scale where higher scores = greater intention; prime mean [SD] = 4.3 [1.6] vs. control mean [SD] = 3.7 [1.4], p ≤ .001, d = 0.4 [95% confidence interval [CI] = 0.21-0.59]). There was again however, no effect on behavior as rates of participants agreeing to receive the donation register web-link were comparable between those primed at 11% (n = 23/210) (95% CI = 7.4-16.0) and controls at 12% (n = 25/210) (95% CI = 8.1-17.1), X2 (1) = 0.09, p = .759.
CONCLUSIONS:
Reciprocal altruism appears useful for increasing intention towards joining the organ donation register. It does not, however, appear to increase organ donor behavior.
Mr John O'Callaghan, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion:
This is a very interesting study comparing T3 with T4 infusions in brain dead donors prior to cardiac allograft retrieval. Whilst the randomisation process was fair and the allocation concealment maintained, the infusions were not blinded to the study clinicians. The study was not powered for the number of hearts transplanted, but for the proportion of hearts with normalised Left Ventricular Ejection Fraction (LVEF) after infusion. Based on previous cases, the authors assumed a normalisation rate of 85% versus 44% using data from different time-periods to power their study. However, during the study, both arms had a normalisation rate of approximately 50%. During this study baseline T3 and T4 levels were not low in donors prior to infusions starting. More hearts from donors receiving T3 were ultimately transplanted, however there were significant differences in the baseline characteristics of the groups that may explain this phenomenon: younger donors, less with left ventricular hypertrophy, more blood group O donors. Overall this study is likely to be underpowered to test the hypothesis, and cardiac stunning seemed to resolve regardless of free T3 levels after infusion.
Expert Review
Reviewer:
David A. Baran, MD, FACC, FSCAI System Director, Advanced Heart Failure, Transplant and MCS Professor of Medicine, Eastern Virginia Medical School (Cardiology) Sentara Heart Hospital | 600 Gresham Dr | Norfolk, VA 23507 docbaran@gmail.com
Conflicts of Interest:
No
Clinical Impact Rating
4
Review:
Dhar and colleagues report the results of a prospective randomized trial of T3 versus T4 in the management of brain dead potential organ donors with hemodynamic instability despite protocol based fluid resuscitation. The authors are to be commended for performing donor research which is sorely lacking and is also quite challenging to perform. In all, they studied 37 donors out of 387 donors during a 2 year time period (9.6 %). The majority of donors were either too young or old (< 18 years or > 50 years old), or unable to randomize in less than 12 hours following brain death declaration. Of 387 donors, 71 were eligible for a run-in phase of the trial, and 52 % were actually randomized. Unfortunately, through the play of chance and small numbers, there were significant imbalances in baseline characteristics of the groups with the T3 group being younger with a better PaO2:FiO2 ratio. The authors found that hearts were more likely to be transplanted in the T3 group as well as lungs, but these differences did not meet statistical significance once adjusted for donor age and PaO2:FiO2 ratio. The improvement in left ventricular ejection fraction and reduction in vasopressor dose was comparable between groups as well. It is unclear why results on a cardiac trial would be adjusted for the PaO2:FiO2 ratio and in this case, it contributed to designating this a negative trial, perhaps avoidably so. Overall, the study was overtly underpowered especially to compare two treatments which both may have benefit compared to no hormonal therapy. The study illustrates the tremendous difficulty associated with donor research, even with an organ procurement organization that brings donors to a dedicated organ retrieval facility (so there is no variation between local donor hospitals). Future studies may consider removing the obstacles to enrollment such as the limitation of starting study drug within 12 hours of arrival at the procurement facility, and basing enrollment on donor left ventricular dysfunction rather than simply blood pressure and volume status. Other relevant questions remain including the utility of higher doses of T4 and T3, as well as a longer period of drug treatment. In conclusion, this intriguing study suggests that more work is warranted on the effect of thyroid hormone supplementation to increase the number of suitable donor hearts.
Aims:
To determine whether T3 infusion can improve cardiac performance, haemodynamic stability, and result in more hearts transplanted than standard T4 therapy in haemodynamically unstable heart-eligible brain dead (BD) organ donors.
Interventions:
Donors underwent echocardiography, within 12 hours of brain death and were randomised to T3 or T4 infusion for 8 hours.
Participants:
37 BD donors were randomised (n=16 T3 vs n=21 T4).
Outcomes:
Primary outcomes were assessed as incidence of myocardial dysfunction, improvement in left ventricular ejection fraction (LVEF) after 8 hours of treatment and proportion of donors with abnormal LVEF who achieve recovery to normal LVEF. Secondary outcomes comprised proportion of hearts that could be successfully transplanted, improvement in haemodynamic parameters and the change in free T3 and free T4 levels between groups after infusion.
Follow Up:
8 hours
RATIONALE:
Brain-dead (BD) organ donors frequently exhibit hemodynamic instability and/or reversible cardiac dysfunction. Retrospective studies have suggested that thyroid hormone may stabilize hemodynamics and enhance myocardial recovery. Intravenous levothyroxine (T4) is most frequently utilized but studies have suggested that triiodothyronine (T3) may be superior. We performed a randomized comparative-effectiveness trial to address this uncertainty in donor management.
METHODS:
All heart-eligible donors managed at a single OPO underwent standardized fluid resuscitation. If not weaned off vasopressors, donors underwent echocardiography (within 12 hours of BD) and were randomized to T3 or T4 infusion for eight hours.
RESULTS:
A total of 37 BD donors were randomized (16 T3 vs 21 T4). Baseline ejection fraction (EF) was comparable (median 38% vs 45%, P = 0.87) as was vasopressor dosage (6 vs 12 μg/min of norepinephrine, NE, P = 0.12). Reduction in NE dose and proportion weaned off vasopressors was similar and LVEF improved in both groups (repeat EF: 50% vs 52.5%, P = 0.38) with almost half attaining EF ≥55%. Although more hearts were transplanted in the T3 group (10/16 vs 6/21, P = 0.04), this difference did not persist after adjusting for baseline imbalances in age and PF ratio.
CONCLUSIONS:
Infusion of T3 does not appear to confer significant hemodynamic or cardiac benefits over T4 for hemodynamic unstable BD organ donors.
Mr Simon Knight, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion:
A recent study published in the NEJM suggested that hypothermia in the brain-dead donor has a protective effect on outcomes after renal transplantation. This study uses data from a previous RCT to investigate the role of donor hypothermia on the outcomes after cardiac transplantation. The authors find that lower donor core body temperature is associated with inferior heart allograft survival. This finding is potentially very important, as it suggests that what is best (in terms of donor management) for one organ may be detrimental to other organs. However, these data should only be regarded as exploratory in nature as this is a post-hoc analysis, and correction for confounders was very limited. Also, the core body temperature measurements were incidental rather than an intended therapeutic intervention and may not have been maintained over time.
Expert Review
Reviewer:
Maryl Johnson, MD, Professor of Medicine, Heart Failure and Transplant Cardiology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792.
Conflicts of Interest:
No
Clinical Impact Rating
3
Review:
This paper describes a post hoc analysis (with numerous limitations, as acknowledged by the authors) of a randomized trial of dopamine use in brain dead organ donors to evaluate the effect of donor core body temperature on outcomes following heart transplantation. The study showed that recipients of hearts from donors who were hypothermic had a worse outcome than those from donors with normal to slightly increased temperatures. This finding is the opposite of what was seen in a study evaluating the effects of donor hypothermia on outcomes following kidney transplantation where donor hypothermia resulted in decreased delayed graft function. This study suggests that at the present time therapeutic hypothermia should not be used routinely for donors who are also potential heart donors. Before this can be definitively stated, however, a study specifically evaluating the effect of donor hypothermia on heart transplant outcomes would have to be performed. The data suggest that what is good for the donated kidney may not always be good for the donor heart.
Aims:
To investigate the impact of the donor’s core body temperature (CBT) on the clinical results after heart transplantation.
Interventions:
Participants were randomized in the dopamine trial* to receive a dopamine infusion of 4 μg/kg per minute in the time window from brain death declaration to start of cold preservation. Statistical comparisons were made in tertiles of the donor’s CBT assessed by a temperature reading 4-20 hours before procurement (lowest, 32.0-36.2°C; middle, 36.3-36.8°C; highest, 36.9-38.8°C).
Participants:
224 donors from the heart transplant cohort of the multicenter randomised dopamine trial* who had a serum-creatinine <1.3 mg/dl on admission, and were stable under low-dose vasopressor support with norepinephrine at a dose of <0.4 μg/kg per minute.
Outcomes:
Measured outcomes included long-term graft survival, and events occurring after transplantation such as impaired left ventricular function on echocardiography, requirement of left ventricular assist device or hemofiltration, acute biopsy-proven rejection, and mortality at 3 months.
Follow Up:
3 years
BACKGROUND:
A previous donor intervention trial found that induction of mild therapeutic hypothermia in the brain-dead donor reduced the dialysis requirement after kidney transplantation. Consequences on the performance of cardiac allografts after transplantation were not explored to date.
METHODS:
Cohort study investigating 3-year heart allograft survival according to spontaneous core body temperature (CBT) assessed on the day of organ procurement. The study is nested in the database of the randomized trial of donor pretreatment with low-dose dopamine (ClinicalTrials.gov identifier: NCT000115115).
RESULTS:
Ninety-nine heart transplant recipients who had received a cardiac allograft from a multiorgan donor enrolled in the dopamine trial were grouped by tertiles of the donor's CBT assessed by a mere temperature reading 4 to 20 hours before procurement (lowest, 32.0-36.2°C; middle, 36.3-36.8°C; highest, 36.9-38.8°C). Baseline characteristics considering demographics of donors and recipients, concomitant donor treatments, donor hemodynamic, and respiratory parameters as well as underlying cardiac diseases in recipients, pretransplant hemodynamic assessments, including pretransplant inotropic/mechanical support, urgency, and waiting time were similar. A lower CBT was associated with inferior heart allograft survival (hazard ratio, 0.53; 95% confidence interval, 0.31-0.93, per tertile; P = 0.02, and hazard ratio, 0.68; 95% confidence interval, 0.50-0.93°C; P = 0.02) when CBT was included as continuous explanatory variable in the Cox regression analysis.
CONCLUSIONS:
A lower CBT in the brain-dead donor before procurement may associate with an unfavorable clinical course after heart transplantation. More research is required, before therapeutic hypothermia can routinely be used in multiorgan donors when a cardiac transplantation is intended.
Mr John O'Callaghan, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion:
This was an open-label, multicentre RCT in cardiac transplantation. Unfortunately, only 66% of those randomised went on to have matched intravascular ultrasound at both 12 and 36 months, the most common reason for dropout was logistical/technical issues. Patients in the everolimus arm had a greater risk of progression in cardiac allograft vasculopathy (CAV, as defined on intravascular ultrasound), and in multivariate analysis everolimus was an independent predictor of CAV progression, along with recipient sex and donor age. Worryingly there was a significantly higher risk of rejection graded ≥2R in the everolimus group (41% versus 13%), but there were no cases of humoral rejection or rejection with haemodynamic compromise and there were slightly more deaths in the ciclosporin arm (7 versus 3). Angiographic assessment of CAV progression did not show a significant difference between the two study arms, possibly due to the short follow-up period.
Expert Review
Reviewer:
Professor Peter Macdonald AM, Medical Director, Heart Transplant Unit, St Vincent's Hospital, Sydney
Conflicts of Interest:
No
Clinical Impact Rating
3
Review:
In their original report published in 2014, the Schedule Trial investigators reported 12 month outcomes of a prospective multicentre randomised trial comparing de novo everolimus plus early cyclosporine withdrawal (within the first 7-11 weeks) with standard cyclosporine-based immunosuppression in 115 heart transplant recipients. They reported that everolimus plus early cyclosprine withdrawal was associated with better preservation of renal function and less coronary allograft vasculopathy (CAV) as assessed by intravascular ultrasound at the cost of increased biopsy proven acute rejection (BPAR). The key findings of this follow-up report are that the beneficial impact of everolimus and early cyclosporine withdrawal on the development of CAV and renal function are sustained at 3 years. In addition, despite the higher rate of BPAR in the everolimus group, overall heart function and survival were similar in the 2 treatment groups at 3 years. While these are encouraging results, it should be noted that only 20% of the study population were on LVAD support - a group who are at increased risk of delayed wound healing. In addition, in a more recent publication, the investigators reported that there were substantial crossovers after the first 12 months so that by 5-7 years approximately 40% of the early withdrawal group and been recommenced on a CNI. Nonetheless, the Schedule Trial provides the strongest evidence to date for de novo initiation of everolimus combined with early minimisation and even withdrawal of CNI in heart transplantation.
Aims:
To evaluated whether initiation of everolimus and early cyclosporine elimination can reduce cardiac allograft vasculopathy (CAV) development in heart transplantation recipients.
Interventions:
Patients were randomized to everolimus with complete cyclosporine withdrawal 7 to 11 weeks after heart transplantation or standard cyclosporine-based immunosuppression. Intravascular ultrasound recordings were obtained at baseline, 12 and 36 months.
Participants:
115 de novo heart transplantation recipients were randomized. Seventy-six patients had matched intravascular ultrasound examinations at baseline, 12 and 36 months.
Outcomes:
Effect of everolimus initiation and CNI elimination on CAV at 12 and 36 months assessed by assessing percent atheroma volume (PAV) and total atheroma volume (TAV) (as alternative end points to maximal intimal thickness) as well as angiographic data. Inflammatory markers were measured in parallel. Plaque morphology was qualitatively assessed by virtual histology analysis at 12 and 36 months post randomization.
Follow Up:
36 months.
Background Cardiac allograft vasculopathy (CAV) limits survival after heart transplantation, and the effect of different immunosuppressive regimens on CAV is not fully understood. The randomized SCHEDULE trial (Scandinavian Heart Transplant Everolimus De Novo Study With Early Calcineurin Inhibitors Avoidance) evaluated whether initiation of the proliferation signal inhibitor everolimus and early cyclosporine elimination can reduce CAV development. Methods and Results The SCHEDULE trial was a multicenter Scandinavian trial, where 115 de novo heart transplantation recipients were randomized to everolimus with complete cyclosporine withdrawal 7 to 11 weeks after heart transplantation or standard cyclosporine-based immunosuppression. Seventy-six (66%) patients had matched intravascular ultrasound examinations at baseline and 12 and 36 months. Intravascular ultrasound analysis evaluated maximal intimal thickness, percent atheroma volume, and total atheroma volume. Qualitative plaque analysis using virtual histology assessed fibrous, fibrofatty, and calcified tissue as well as necrotic core. Serum inflammatory markers were measured in parallel. The everolimus group (n=37) demonstrated significantly reduced CAV progression as compared with the cyclosporine group (n=39) at 36 months (Δ maximal intimal thickness, 0.09±0.05 versus 0.15±0.16 mm [ P=0.03]; Δ percent atheroma volume, 5.3±2.8% versus 7.6±5.9% [ P=0.03]; and Δ total atheroma volume, 33.9±71.2 versus 54.2±96.0 mm3 [ P=0.34], respectively]. At 36 months the number of everolimus patients with rejection graded ≥2R was 15 (41%) as compared with 5 (13%) in the cyclosporine group ( P=0.01). Everolimus did not affect CAV morphology or immune marker activity during the follow-up period. Conclusions The SCHEDULE trial demonstrates that everolimus initiation and early cyclosporine elimination significantly reduces CAV progression at 12 months, and this beneficial effect is clearly sustained at 36 months. Clinical trial registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT01266148.
Mr Simon Knight, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion:
This industry-funded, multicentre study from Italy investigates the role of delayed initiation of everolimus compared to early initiation in heart transplant recipients. Patients in the delayed arm received MMF for 4-6 weeks prior to switching. All patients received cyclosporine maintenance. The primary endpoint, a composite safety outcome, was numerically but not significantly higher in the immediate arm, mainly driven by a significantly higher rate of pericardial effusions. Efficacy endpoints did not differ. The results suggest that delayed initiation of everolimus may help to prevent some of the early morbidity associated with everolimus in heart transplant recipients. There are, however, some issues to note. A lack of blinding raises the risk of treatment and measurement bias – possibly reflected in the higher use of induction therapy in the immediate arm. Baseline cyclosporine levels also differed between groups. Due to the fall in number of cardiac transplants in Italy over the study period, the study was underpowered and did not meet the required sample size.
Expert Review
Reviewer:
Dr Jayan Parameshwar, Royal Papworth Hospital, Papworth Everard, Cambridge, UK.
Conflicts of Interest:
No
Clinical Impact Rating
1
Review:
The study compared early (1-5 days) versus delayed (4-6 weeks) Everolimus in combination with Cyclosporine, and steroid (plus Induction therapy) in heart transplant recipients. The delayed group received Mycophenolate Mofetil from which they were switched. The key finding is that there were fewer pericardial effusions in the "delayed" group. There were also fewer episodes of CMV disease in the "early" group. There was no difference in rejection episodes between the two groups. The findings of this study are not generalizable to the majority of heart transplant recipients. The CNI of choice in most units today is Tacrolimus, not Cyclosporine which was used in this study. The study only included patients with eGFR>40 ml/min/1.7m2 in the first 5 days post-transplant; this would not be the case in a significant proportion of recipients in the current era. Because of the entry criteria, patients who were more ill are likely to have been excluded, these are the very patients where side effects like delayed wound healing and delayed recovery from acute tubular necrosis are most likely to be seen. This study is unlikely to have a significant impact on clinical practice. It would be unusual to use Everolimus (or Sirolimus) in combination with a CNI early post-transplant (within the first week) anyway.
Aims:
To compare the safety of delayed versus early everolimus initiation in heart transplant (HTx) recipients.
Interventions:
Participants were randomised to receive either immediate everolimus (dose initiation ≤144 h after graft reperfusion) or delayed everolimus (mycophenolate mofetil initiated within 144h after graft perfusion and replaced with everolimus at 4-6 weeks).
Participants:
182 de novo HTx recipients aged ≥18 years.
Outcomes:
The primary outcome was a composite of wound healing delays, pleural effusion, pericardial effusion, and acute renal insufficiency. Secondary outcomes included the cumulative incidence of biopsy-proven acute rejection, rejection with hemodynamic compromise, graft loss, and death.
Follow Up:
6 months
BACKGROUND:
Although everolimus potentially improves long-term heart transplantation (HTx) outcomes, its early postoperative safety profile had raised concerns and needs optimization.
METHODS:
This 6-month, open-label, multicenter randomized trial was designed to compare the cumulative incidence of a primary composite safety endpoint comprising wound healing delays, pericardial effusion, pleural effusion needing drainage, and renal insufficiency events (estimated glomerular filtration rate ≤30/mL/min per 1.73 m) in de novo HTx recipients receiving immediate everolimus (EVR-I) (≤144 hours post-HTx) or delayed everolimus (EVR-D) (4-6 weeks post-HTx with mycophenolate mofetil as a bridge) with reduced-dose cyclosporine A. Cumulative incidence of biopsy-proven rejection ≥ 2R, rejection with hemodynamic compromise, graft loss, or death was the secondary composite efficacy endpoint.
RESULTS:
Overall, 181 patients were randomized to the EVR-I (n = 89) or EVR-D (n = 92) arms. Incidence of primary safety endpoint was higher for EVR-I than EVR-D arm (44.9% vs 32.6%; P = 0.191), mainly driven by a higher rate of pericardial effusion (33.7% vs 19.6%; P = 0.04); wound healing delays, acute renal insufficiency events, and pleural effusion occurred at similar frequencies in the study arms. Efficacy failure was not significantly different in EVR-I arm versus EVR-D arm (37.1% vs 28.3%; P = 0.191). Three patients in the EVR-I arm and 1 in the EVR-D arm died. Incidence of clinically significant adverse events leading to discontinuation was higher in EVR-I arm versus EVR-D arm (P = 0.02).
CONCLUSIONS:
Compared with immediate initiation, delayed everolimus initiation appeared to provide a clinically relevant early safety benefit in de novo HTx recipients, without compromising efficacy.
CET Conclusion