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 John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion:
This paper presents post hoc analyses from a previously published RCT. The original RCT investigated inhaled liposomal ciclosporin-A in the prevention of Bronchiolitis Obliterans Syndrome (BOS) after lung transplantation. 10-year follow up is now available for all 130 of the included patients. A strong association was found between baseline FEV1 and mortality risk and each 1% drop from baseline FEV1 was associated with 3.5% increased risk for mortality. The individual trajectories in lung function were highly variable between patients, however it seems that post-transplant FEV1 is a valid predictor of mortality and could be used to institute pre-emptive treatment.
Expert Review
Reviewer:
Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Review:
This paper presents some long term follow up from a previously published RCT of inhaled liposomal cyclosporine A in lung transplantation. The original study closed prior to reaching the target patient inclusion due to very slow accumulation of cases (Neurohr et al 2022). The paper by Kneidinger et al presents post hoc analyses from the RCT. The authors used the collected data to explore the relationship between decline in FEV1 and mortality in patients with single and double lung transplant. Whilst patients were included in the trial they had FEV1 measurements every 2 months, and for this analysis they were requested every 6 months up to ten years from inclusion. Complete data was retrieved for 91% of included patients, and reduced data for the remaining patients, censored at the last study visit. Mean follow up was 61 months. On average, FEV1 deteriorated over time but the trajectory for showed a great deal of diversity between patients. A highly significant correlation was found between the relative drop in FEV1 compared to baseline and mortality. In broad terms a 1% reduction in FEV1 compared to baseline, related to 3.4% higher mortality risk. In cox regression analysis, type of transplant was the only significant independent predictor of mortality; with recipients of single lung transplants having increased risk of progression. A significant amount of lung function must be lost before chronic lung allograft dysfunction can be diagnosed. Understanding the decline in FEV1 might allow early intervention and improvement in patient care through modification of the underlying process. Decline in FEV1 from baseline could also be used as a reliable surrogate outcome for mortality in clinical trials. References Neurohr, C. ; Kneidinger, N. ; Ghiani, A. ; et al. A randomized controlled trial of liposomal cyclosporine A for inhalation in the prevention of bronchiolitis obliterans syndrome following lung transplantation. American Journal of Transplantation. 2022;22(1):222-229
Aims:
This study aimed to determine the association between forced expiratory volume in one second (FEV1) and risk of mortality in patients following lung transplantation, using the 10-year follow up data from the PARI Study No. 12011.201.
Interventions:
Participants in the original trial were randomised to receive either liposomal Cyclosporine A inhalation (L-CsA-i) or placebo.
Participants:
130 lung transplant recipients.
Outcomes:
The main outcomes of interest were the association between the course of post-transplant FEV1 over time and the risk of mortality, time to progression to allograft dysfunction and survival.
Follow Up:
10 years
BACKGROUND:
Chronic lung allograft dysfunction (CLAD) is defined by a progressive loss of FEV1 and is associated with premature mortality. The aim of this study was to investigate the direct association between FEV1 decline and risk of mortality in patients after lung transplantation (LTx).
METHODS:
10-year follow up data from lung transplant recipients participating in randomized placebo-controlled clinical trial investigating the role of liposomal Cyclosporine A for inhalation (L-CsA-i) in the prevention of bronchiolitis obliterans syndrome (NCT01334892) was used. The association between the course of FEV1 over time and the risk of mortality was assessed using joint modeling and Cox regression analysis.
RESULTS:
A total of 130 patients were included. Predictors of FEV1 decline were a higher absolute FEV1 at baseline and male sex. The joint model analysis indicated a significant association of change of FEV1 and risk of mortality (p < 0.001), with a predicted 3.4% increase in mortality risk for each 1% decline in FEV1. Significant predictors of a progressive phenotype were single LTx and treatment with placebo (as opposed to L-CsA-i). At the end of follow-up, 82 patients (63.1%) were still alive. Cox regression analyses for mortality identified only single LTx as a predictor of higher risk.
CONCLUSION:
Based on our observation of a close association between FEV1 and mortality over a period of 10 years we suggest FEV1 as a valid predictor of mortality and a suitable surrogate endpoint in the investigation of early interventions.
Mr Simon Knight, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion:
This muticentre, placebo-controlled study investigated the use of IV naloxone in brain-dead organ donors as a strategy to reduce neurogenic pulmonary oedema. The study demonstrated no difference in the primary outcome of improvement in PaO2:FiO2 ratio, and no difference in transplant rates from the donors recruited. The study is well designed, and it appears that there is no benefit to this intervention in this subset of donors with all-cause hypoxaemia. Interestingly, reversal of hypoxaemia through other donor management protocols was significantly associated with increased chance of transplant, highlighting the importance of interventions to improve this in donors. It should also be noted that no transplant outcomes were assessed: it is important that in any donor intervention the transplant rates and outcomes of all transplanted organs from the donors are documented, as what is good for one organ may be detrimental to the outcomes of another.
Expert Review
Reviewer:
Lorraine B. Ware M.D. Professor of Medicine and Pathology, Immunology and Microbiology Vanderbilt University School of Medicine
Conflicts of Interest:
No
Clinical Impact Rating
4
Review:
Naloxone has been postulated to improve donor oxygenation by reducing the rise in cardiac output that accompanies herniation and leads to neurogenic pulmonary edema. This hypothesis was derived from a sheep model and data from a single uncontrolled human donor study; nonetheless, naloxone has been incorporated into many donor management protocols. To better define the potential utility of naloxone in donor management, Dhar and colleagues tested the effect of IV naloxone in a multicenter prospective randomized controlled clinical trial in 199 hypoxemic deceased organ donors. Contrary to the hypothesis, they found no beneficial effect of naloxone on oxygenation or rate of lung utilization. The findings of this study have two important clinical implications. First, the findings suggest that there is no role for naloxone in management of deceased organ donors; routine use in donor management is not indicated. Second, despite the inherent challenges, it is critical that we continue to design and implement randomized clinical trials in the deceased donor population to better inform the clinical practice of donor management.
Aims:
To evaluate whether naloxone is able to improve oxygenation in brain dead (BD) lung donors with hypoxemia.
Interventions:
Eligible donors were randomized to naloxone (8 mg IV) or saline placebo as soon as possible after the initial arterial blood gas (ABG). ABGs were collected as per standard Organ Procurement Organizations practices (approx. every 6-8 hours) with a final ABG collected prior to organ procurement.
Participants:
199 lung-eligible BD donors were randomized (naloxone, n=98; placebo, n=101). Eligible patients were age 13-70 years without established lung disease who had hypoxemia, defined as PaO2:FiO2 ratio (PFR) <300 on arterial blood gas (ABG) performed after BD declaration.
Outcomes:
The primary outcome was change in PFR from baseline to final ABG. The secondary efficacy outcome was proportion of donors enrolled who had lungs transplanted. Primary analyses were performed using intention-to-treat principles. Outcomes were also evaluated in a per protocol analysis.
Follow Up:
Median total time from BD to procurement was 41 hours (IQR 32-47).
BACKGROUND:
Persistent hypoxemia is the principal reason lungs from otherwise eligible brain dead (BD) organ donors are not transplanted. Experimental models and retrospective studies have suggested that naloxone attenuates neurogenic pulmonary edema and reverses hypoxemia after brain death. We undertook a multisite, randomized, placebo-controlled trial to evaluate whether naloxone is able to improve oxygenation in BD donors with hypoxemia.
METHODS:
BD organ donors at 4 organ procurement organizations were randomized in a blinded manner to naloxone 8 mg or saline placebo if lung were being considered for allocation but exhibited hypoxemia (partial pressure of oxygen in arterial blood to fraction of inspired oxygen ratio [PFR] below 300 mm Hg). The primary outcome was change in PFR from baseline to final arterial blood gas. Secondary outcomes included early improvement in PFR and proportion of lungs transplanted.
RESULTS:
A total of 199 lung-eligible BD donors were randomized to naloxone (n = 98) or placebo (n = 101). Groups were comparable at baseline. Both groups exhibited similar improvements in oxygenation (median improvement in PFR of 81 with naloxone versus 80 with saline, P = 0.68), with 37 (39%) versus 38 (40%) exhibiting reversal of hypoxemia. There was no difference in the rate of lungs transplanted (19% in both groups, P = 0.97) although it was significantly higher in those with reversal of hypoxemia (32/69 versus 2/111, P < 0.001).
CONCLUSIONS:
Naloxone does not improve oxygenation more than placebo in hypoxemic organ donors. However, reversal of hypoxemia was a powerful predictor of lung utilization regardless of drug therapy. Further organ procurement organization-led research is needed to assess optimal interventions to improve oxygenation in BD donors with hypoxemia.
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.
Dr Liset Pengel, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion:
This pilot, double-blind randomised controlled trial investigated the feasibility, acceptability and safety of daily omega-3 fish oil to prevent skin cancers in adult lung transplant recipients who were at least 1 year posttransplant. Patients were randomised based on a computer-generated randomisation sequence to either omega-3 fish oil or placebo capsules that looked identical and were stored in identical containers. No sample size calculation was conducted and 49 patients were included. Six patients withdrew from the study and 86% completed the follow up. Groups were similar at baseline although there were more patients with skin prone to sunburn in the placebo group (71% versus 40%) and less patients in the placebo group that never applied sunscreen to the head/neck area (8% versus 32%). The study showed that the supplementation is feasible and safe. A sufficiently powered study will need to be conducted to evaluate the efficacy of omega-3 fish oil in reducing skin cancers.
Expert Review
Reviewer:
Dr Lianne G Singer, MD, FRCPC Clinical Researcher
Conflicts of Interest:
No
Clinical Impact Rating
2
Review:
This is a randomized, placebo-controlled pilot trial to assist in planning of a future definitive clinical trial to assess the efficacy of omega-3 fatty acid supplementation at prevention of skin cancers in lung transplant recipients. Lung transplant recipients are at particularly high skin cancer risk due to the high intensity of lifelong immunosuppression, and are also at a greatly increased risk of aggressive skin cancers. Therefore effective prevention would have significant clinical impact at reducing morbidity and mortality after lung transplantation and the proposed effect of omega-3 fatty acid supplementation appears biologically plausible. The study was conducted in Brisbane, Australia. Adult lung transplant recipients more than one year post transplant were randomly assigned to 4 g-omega 3 fatty acids or 4 g placebo (olive oil) daily and followed for 12 months. Full skin examinations were done at enrolment and at the end of the study. Primary endpoints related to feasibility and safety, but incident skin cancers were also assessed. Half of eligible patients agreed to participate, of whom 86% completed the trial. Adherence appeared adequate based on blood samples of omega-3 fatty acids , and no safety issues were identified. There was an apparent lower skin cancer rate observed in the treated group although the study was not powered to detect a significant difference in this end point. This study indicates that a definitive clinical trial is feasible and that omega-3 fatty acid supplementation is worthy of further study. The design of a future clinical trial should consider that this pilot study may overestimate the efficacy of omega-3 fatty acids due to unequal randomization of sunburn-prone subjects and subjects with more prolonged immunosuppression to the placebo group, and the generally increased incidence of skin cancer in Australia compared with regions with less sun exposure. Given the pilot nature of this study, it does not constitute sufficient evidence to change practice.
Aims:
To assess the feasibility and acceptability, and safety of daily supplementation with omega-3 fatty acids (FA) to prevent skin cancers in lung transplant recipients.
Interventions:
Participants were randomly allocated to daily supplements containing either 4g omega-3 FA (3.36g eicosapentaenoic acid (EPA) + docosahexaenoic acid) or placebo (4g olive oil) for 12 months.
Participants:
49 lung transplant recipients randomised into two groups (n=25 omega-3 FA intervention) (n=24 placebo group).
Outcomes:
Primary outcomes were assessed as rates of recruitment, retention, adherence (assessed by plasma omega-3 FA) and safety. Secondary outcomes were assessed as the incidence of skin cancers.
Follow Up:
12 months
BACKGROUND:
Lung transplant recipients (LTRs) are at very high risk of skin cancer. Omega-3 fatty acids (FAs) are anti-inflammatory and immune-modulating and could potentially reduce this risk. We assessed the feasibility of omega-3 FA supplementation to reduce skin cancer among these patients.
METHODS:
LTRs aged 18+ years, at least 1 year post-transplant, were recruited from the outpatient clinic of The Prince Charles Hospital, Brisbane. Participants were randomly allocated to 4-times-daily supplements containing either omega-3 FA (3.36 eicosapentaenoic acid [EPA] + docosahexaenoic acid) or placebo (4 g olive oil) for 12 months. Primary outcomes were rates of recruitment, retention, adherence (assessed by plasma omega-3 FA), and safety. Secondary outcomes were incident skin cancers.
RESULTS:
Among 106 eligible lung transplant recipients, 49 consented to take part (46%) with 25 allocated to omega-3 FA and 24 to placebo supplements. Of these, 22 (88%) and 20 (83%), respectively, completed the trial. After 12 months, median plasma EPA increased substantially in the intervention group (125.0 to 340.0 µmol/L), but not the placebo group (98.0 to 134.5 µmol/L). In the intervention group, 6 patients developed skin cancers compared with 11 in the placebo group, giving an odds ratio (95% confidence interval) of 0.34 (0.09 to 1.32). There were no serious, active intervention-related adverse events.
CONCLUSIONS:
This pilot trial among LTRs showed acceptable recruitment and high retention and adherence. We demonstrated a signal for reduction of new skin cancer cases in those taking omega-3 FA supplements, which supports the notion that a larger, more definitive trial is warranted.
Dr. Richéal Burns, Health Economics and Policy Analysis Centre, NUI Galway, Ireland; Affiliate Health Economics Researcher, Nuffield Department of Surgical Sciences, University of Oxford.
Conflicts of Interest:
No
Clinical Impact Rating
3
Review:
This study is the first to assess the benefits of introducing a supervised exercise programme for upper limb rehabilitation (ULR) following lung transplantation as part of a randomised controlled trial. For the 80 patients recruited, the trial measured overall bodily pain, shoulder flexion, abduction strength and health-related quality of life (HRQOL) using the validated SF-36 measure at 6 and 12 weeks and at the end of the 6 month follow-up. The intervention highlighted significant improvements in HRQOL at 12 weeks but no statistically significant difference was evidenced across all outcomes at 6 months. Therefore, the trial concludes that ULR may yield short term improvements in pain and muscle strength, thus having a positive impact on HRQOL; however, longer term impacts were not supported by the evidence presented. Although a single centre trial with a relatively small sample size, these findings highlight potential benefits of ULR to patients who received lung transplantation without any adverse events, and as such have implications for clinical practice internationally. It would be beneficial to undertake a more detailed account of resource utilisation and associated costs during follow-up which may highlight further benefits to the patient, the healthcare payer and society.
OBJECTIVE:
To investigate the effect of a supervised upper limb (UL) program (SULP) compared to no supervised UL program (NULP) after lung transplantation (LTx).
DESIGN:
Randomized controlled trial.
SETTING:
Physiotherapy gym.
PARTICIPANTS:
Participants (N=80; mean age, 56±11y; 37 [46%] men) were recruited after LTx.
INTERVENTIONS:
All participants underwent lower limb strength thrice weekly and endurance training. Participants randomized to SULP completed progressive UL strength training program using handheld weights and adjustable pulley equipment.
MAIN OUTCOME MEASURES:
Overall bodily pain was rated on the visual analog scale. Shoulder flexion and abduction muscle strength were measured on a hand held dynamometer. Health related quality of life was measured with Medical Outcomes Study 36-item Short Form health Survey and the Quick Dash. Measurements were made at baseline, 6 weeks, 12 weeks, and 6 months by blinded assessors.
RESULTS:
After 6 weeks of training, participants in the SULP (n=41) had less overall bodily pain on the visual analog scale than did participants in the NULP (n=36) (mean VAS bodily pain score, 2.1±1.3cm vs 3.8±1.7cm; P<.001) as well as greater UL strength than did participants in the NULP (mean peak force, 8.4±4.0Nm vs 6.7±2.8Nm; P=.037). At 12 weeks, participants in the SULP better quality of life related to bodily pain (76±17 vs 66±26; P=.05), but at 6 months there were no differences between the groups in any outcome measures. No serious adverse events were reported.
CONCLUSIONS:
UL rehabilitation results in short-term improvements in pain and muscle strength after LTx, but no longer-term effects were evident.
Sir Peter Morris, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion:
Post-operative cognitive dysfunction is common after lung transplantation and occurs in more than half of recipients of a lung transplant. In this study the authors have selected from a randomised control trial (INSPIRE) a cohort of patients in whom they have measured a battery of neuro cognitive tests at six months after transplantation. These tests include assessments of executive function, processing speed and verbal memory. During a thirteen-year follow-up, two-thirds of the participants died. The authors observed a greater neuro-cognition in those who survived longer and this association was the strongest in tests assessing processing speed and executive function. Thus declines in executive function tended to be predictive of worse survival and obviously these preliminary findings do suggest that cognitive function should be assessed where possible after lung transplantation, and the authors say there is need for further studies in this area and these should include neuro-imaging.
Expert Review
Reviewer:
REVIEW1 Professor Allan R Glanville, Department of Thoracic Medicine, St.Vincent's Hospital, Darlinghurst, NSW, Australia. REVIEW2 Dr. Maria Monteagudo Vela and Mr André R Simon, Department of Cardiothoracic Transplantation and Mechanical Circulatory Support, Royal Brompton & Harefield NHS Foundation Trust, London, UK.
Conflicts of Interest:
No
Clinical Impact Rating
4
Review:
REVIEW1 Professor Allan R Glanville: This 13-year follow up analysis of data collected as part of the INSPIRE trial (a telephone based survey assessment) demonstrates evidence to support a survival benefit for patients with better neurocognitive function before and after lung transplantation. The results are at once intuitive and thereby not surprising, as long-term lung transplant survival is critically dependent on maintenance of allograft function, one major adverse risk factor for which is mal-adherence to therapy and follow up. Given the pill burden, complexities of dosage changes and issues with therapeutic drug monitoring, it is understandable at a grass roots level. Nevertheless, the study is both interesting and important and underscores the value of assessment for neurocognitive dysfunction at 6 months after lung transplant. Abnormal scores should then raise concerns, which should be addressed proactively by the introduction of supportive measures. One issue of course is that only one time point was selected post-transplant (6 months), but that should not invalidate generalising the principle to later time points. Closer to transplant, there are numerous metabolic, steroid related and post-surgical issues that may confound analysis, especially if cardiopulmonary bypass or ECMO are employed. Armed with this knowledge, the challenge remains to effect meaningful change, which may depend on resources available. REVIEW2 Dr. Maria Monteagudo Vela and Mr André R Simon: Postoperative cognitive dysfunction (POCD) is a commonly encountered outcome after lung transplantation. In the study of Smith et al, longer survival was seen in those patients with better neurocognition 6 months post-surgery, whilst a decline in executive function was associated with higher mortality. In transplanted patients, adherence to the treatment plays a vital role in survival and is strongly associated with mortality. According to the authors, impaired executive function and memory may be important predictors of non-adherence leading on to worse outcomes. Although small, the cohort of patients in the paper by Smith et al includes a broad spectrum of different lung diseases (39% COPD, 24% cystic fibrosis and 22% of pulmonary fibrosis). Their average age was 49.6 years. This differs from a standard cohort that could be represented by the ISHLT data (1). A major problem of this paper is the lack of intra-operative data such as the use of cardiopulmonary bypass (CPB). Use of CPB implies per se neurological dysfunction (2). Therefore, in the authors’ final Cox regression model, when attempting to identify whether cognitive dysfunction is an independent predictor of outcome, use of CPB as well as surgical technique should have been one of the confounders adjusted for. As CPB might be, it self, an independent predictor of cognitive dysfunction. The study by Smith et al highlights that POCD is associated with not only a worse quality of life, but also that it impacts on long-term survival. This is an important finding, as after successful transplantation and when all surgical issues have been dealt with, what is important for patients and families is their cognitive and functional status. 1. Lund LH, et al. The Registry of the International Society for Heart and Lung Transplantation: Thirty-fourth Adult Heart Transplantation Report-2017; Focus Theme: Allograft ischemic time. J Heart Lung Transplant. 2017; 36(10): 1037-1046. 2. Ganushchak YM, et al. Neurological complications after coronary artery bypass grafting related to the performance of cardiopulmonary bypass. Chest. 2004; 125(6): 2196-205.
Aims:
To examine the impact of postoperative cognitive dysfunction (POCD) on long-term survival in lung transplant recipients.
Interventions:
Using data collected as part of the previous Investigational Study of Psychological Intervention in Recipients of Lung Transplant (INSPIRE)* trial, a battery of neurocognitive assessment tests were completed 6 months post-transplantation including assessments of processing speed, executive function and verbal memory. Mortality was assessed at 13 years.
Participants:
49 lung transplant recipients who participated in the previous INSPIRE trial.
Outcomes:
Measured outcomes included neurocognitive test perfomance, posttransplant survival, chronic lung allograft dysfunction, neurocognition and mortality, and neurocognitive decline and mortality.
Follow Up:
6 months and 13 years
Preliminary evidence suggests that postoperative cognitive dysfunction (POCD) is common after lung transplantation. The impact of POCD on clinical outcomes has yet to be studied. The association between POCD and longer-term survival was therefore examined in a pilot study of posttransplantation survivors. Forty-nine participants from a prior randomized clinical trial underwent a neurocognitive assessment battery pretransplantation and 6 months posttransplantation, including assessments of the domains of Executive Function (Trail Making Test, Stroop, Digit Span), Processing Speed (Ruff 2 and 7 Test, Digit Symbol Substitution Test), and Verbal Memory (Verbal Paired Associates, Logical Memory, Animal Naming, and Controlled Oral Word Association Test). During a 13-year follow-up, 33 (67%) participants died. Greater neurocognition was associated with longer survival (hazard ratio [HR] = 0.49 [0.25-0.96], P = .039), and this association was strongest on tests assessing Processing Speed (HR = 0.58 [0.36-0.95], P = .03) and Executive Function (HR = 0.52 [0.28-0.97], P = .040). In addition, unadjusted analyses suggested an association between greater Memory performance and lower risk of CLAD (HR = 0.54 [0.29-1.00], P = .050). Declines in Executive Function tended to be predictive of worse survival. These preliminary findings suggest that postoperative neurocognition is predictive of subsequent mortality among lung transplant recipients. Further research is needed to confirm these findings in a larger sample and to examine mechanisms responsible for this relationship.
Sir Peter Morris, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion:
This is a carefully done feasibility study of adherence to Mediterranean or low fat diet among 41 heart and lung transplant recipients. Patients were randomised to one or the other diet (n=41) but did receive a quite intensive diet specific education at base-line. Adherence, which was assessed by a questionnaire, was higher for the Mediterranean diet than the low fat diet, but was impressive. Over 12 months the adherence rate remained high and there was a significant reduction in BMI and serum triglycerides as well as mean weight. What was impressive was that the change from base-line eating habits was maintained over 12 months. Thus, this trial would seem to suggest that with appropriate educational support a Mediterranean diet or a low fat diet was readily able to be implemented in thoracic transplant patients.
Expert Review
Reviewer:
Professor Christiane Kugler, University of Freiburg, Faculty of Medicine, Institute of Nursing Science, Germany.
Conflicts of Interest:
No
Clinical Impact Rating
1
Review:
The authors used an innovative approach to provide a nutrition-based intervention for patients following heart or lung transplantation. Allocated intervention schemes included either Mediterranean or low-fat diet. Key findings address changes in nutrition-related adherence, and relevant bio-chemical measures. Nutrition-related adherence, as an indicator for change in behaviour, indicated improvement over time, and sustained in the Mediterranean subgroup during the 6-week post-intervention follow-up. Favourable changes in body weight, BMI and serum triglycerides for both diets were reported. Serum triglycerides levels declined in both groups as a result of changed nutritional habits over the intervention period. This was a randomized feasibility study limiting generalizability. In addition, generalizability was limited due to the sample size, comparison of two intervention groups with no control group, a non-comprehensively described intervention not allowing for repetition of the interventions based on that report, and no information given on routine care used in general practice. Sixty-four patients eligible for this study declined participation with no reasons given for why patients may have declined. However, it is important to note that almost all patients enrolled completed the study leading to an impressively low dropout rate. Given the overall impression of this study, the authors' findings have potential to have an impact on clinical practice in the future, however at the current state this study cannot (yet) be judged as practice changing. Instead, this study might be seen as a first initial step to guide further research in this area.
Aims:
To assess adherence to low-fat and Mediterranean diets among thoracic transplant recipients.
Interventions:
Participants were stratified according to organ type and transplant date, and then randomised to receive to either a Mediterranean diet or a low-fat diet.
Participants:
39 clinically stable heart and lung transplant recipients ≥ 6 months post-transplant, aged ≥16 years.
Outcomes:
The primary outcome was adherence, measured using a dietary assessment, adherence index and anthropometric and laboratory measurements.
Follow Up:
12 months
BACKGROUND:
Heart and lung transplant recipients are at a substantially increased risk of cardiovascular disease (CVD). Since both low-fat and Mediterranean diets can reduce CVD in immunocompetent people at high risk, we assessed adherence among thoracic transplant recipients allocated to one or other of these diets for 12 months.
METHODS:
Forty-one transplant recipients (20 heart; 21 lung) randomized to a Mediterranean or a low-fat diet for 12 months received diet-specific education at baseline. Adherence was primarily assessed by questionnaire: 14-point Mediterranean diet (score 0-14) and 9-point low-fat diet (score 0-16) respectively, high scores indicating greater adherence. Median scores at baseline, 6 months, 12 months, and 6-weeks post-intervention were compared by dietary group. We further assessed changes in weight, body mass index (BMI) and serum triglycerides from baseline to 12 months as an additional indicator of adherence.
RESULTS:
In those randomized to a Mediterranean diet, median scores increased from 4 (range 1-9) at baseline, to 10 (range 6-14) at 6-months and were maintained at 12 months, and also at 6-weeks post-intervention (median 10, range 6-14). Body weight, BMI and serum triglycerides decreased over the 12-month intervention period (mean weight - 1.8 kg, BMI -0.5 kg/m2, triglycerides - 0.17 mmol/L). In the low-fat diet group, median scores were 11 (range 9-14) at baseline; slightly increased to 12 (range 9-16) at 6 months, and maintained at 12 months and 6 weeks post-intervention (median 12, range 8-15). Mean changes in weight, BMI and triglycerides were - 0.2 kg, 0.0 kg/m2 and - 0.44 mmol/L, respectively.
CONCLUSIONS:
Thoracic transplant recipients adhered to Mediterranean and low-fat dietary interventions. The change from baseline eating habits was notable at 6 months; and this change was maintained at 12 months and 6 weeks post-intervention in both Mediterranean diet and low-fat diet groups. Dietary interventions based on comprehensive, well-supported education sessions targeted to both patients and their family members are crucial to success. Such nutritional strategies can help in the management of their substantial CVD risk.
TRIAL REGISTRATION:
The IRAS trial registry ( ISRCTN63500150 ). Date of registration 27 July 2016. Retrospectively registered.
This small, blinded pilot study represents the first experience of the use of AP301 in lung transplantation. AP301 is an activator of epithelial sodium channel-mediated Na+ uptake, which has demonstrated benefit in ARDS and animal models of lung transplantation. Lung transplant recipients with primary graft dysfunction were randomised to nebulised AP301 for 7 days (or until extubation) or placebo. Patients treated with AP301 were extubated earlier and demonstrated improved gas exchange compared to placebo (measured by the PaO2/FiO2 ratio). Long-term outcomes were equivalent. These results are very encouraging and pave the way for a larger trial to assess which patients may benefit most from this therapy.
Expert Review
Reviewer:
Professor John Dark, Institue of Cellular Medicine, Newcastle University, United Kingdom.
Conflicts of Interest:
No
Clinical Impact Rating
4
Review:
Primary graft dysfunction (PGD) after lung transplantation remains a major problem, with both short and long-term consequences. It reflects the vulnerability of the lung to injury in the donor. Treatment until now has been purely supportive, which makes the report of this small prospective clinical study of an intervention so important. The Vienna group randomised 20 patients with PGD to receive nebulised AP301, an activator of epithelial sodium channel–mediated Na uptake. This molecule has benefits in rat and porcine models of donor-acquired acute lung injury and is being studied in ARDS The results showed significant improvement in gas exchange, and a trend towards shorter intubation times. Lung compliance, in some respects a more sensitive marker of lung recovery after injury, because it reflects clearance of water from the whole lung, was also better in the treatment group. Whilst exciting, the paper is just a first step. The numbers were small and the really important clinical end-points not significantly different. However, this data will allow power calculations for definitive trials of this, and similar interventions. It is incumbent on Intensivists managing lung transplant recipients to work together in this exciting area.
Aims:
To investigate the clinical effects of inhaled AP301 on patients with primary graft dysfunction (PGD) > 1 according to the International Society of Heart and Lung Transplantation criteria after primary lung transplantation (LTx).
Interventions:
Participants were randomised to receive either inhaled AP301 or placebo administered by liquid neubulizer twice daily for 7 days or until exturberation.
Participants:
20 patients undergoing bilateral LTx with PGD > 1.
Outcomes:
The primary outcome measured was the individual mean of the partial pressure of arterial oxgen (PaO2)/fraction of inspired oxygen (FiO2) ratios between baseline and 72 hours. Secondary measured outcomes included the oxygenation index, and clinical paramaters such as ventilator time, duration of intensive care unit stay, hospital stay and graft survival.
Follow Up:
30 days
BACKGROUND:
Primary graft dysfunction (PGD) after lung transplantation (LTx) carries significant morbidity and mortality in the early post-operative period and is associated with the development of chronic lung allograft dysfunction. AP301, an activator of epithelial sodium channel-mediated Na+ uptake represents a new concept for prevention and treatment of pulmonary edema and has shown promising results in the pre-clinical setting. This pilot study investigated the clinical effect of inhaled AP301 on patients with development of PGD > 1 according to International Society of Heart and Lung Transplantation criteria after primary LTx in a high-volume center and was conducted as a randomized, placebo-controlled, single-center pilot-study including 20 patients. All consecutive patients fulfilling inclusion criteria were screened for PGD at arrival on the intensive care unit (ICU) after LTx. After randomization, inhaled AP301 or placebo was administered by nebulizer twice daily for 7 days or until extubation. Otherwise, patients were treated according to routine clinical protocol. Partial pressure of arterial oxygen (Pao2)/fraction of inspired oxygen (Fio2) values were obtained until extubation and assessed as a primary outcome parameter. Patients were monitored for 30 days within the study protocol.
RESULTS:
From July 2013 to August 2014, 20 patients were randomized 1:1 to AP301 (Group 1) or placebo (Group 2). Both groups were comparable with regard to sex (40% women/60% men vs 50% women/50% men), mean age (55 ± 13 vs 54 ± 6 years), comorbidities, and diagnosis leading to LTx. The Pao2/Fio2 ratio at the time of inclusion was comparable in both groups, with a mean 235.65 ± 90.78 vs 214.2 ± 95.84 (p = 0.405), and there was no significant difference in the extravascular lung water index (13.88 ± 5.28 vs 16 ± 6.29 ml/kg, p = 0.476). The primary end point was mean Pao2/Fio2 ratio values between baseline and Day 3. In the AP301 group, only 1 patient was ventilated at Day 4 and no patients were ventilated after Day 4. In the placebo group, 5 patients were ventilated on Day 4 and 2 patients on Days 5, 6, and 7. The mean increase in the Pao2/Fio2 ratio was significantly higher in Group 1 patients, and the mean between baseline and at 72 hours was 365.6 ± 90.4 in Group 1 vs 335.2 ± 42.3 in Group 2 (p = 0.049). The duration of intubation was shorter in Group 1 than in Group 2 patients (2 ± 0.82 vs 3.7 ± 1.95 days; p = 0.02). ICU stay was 7.5 ± 3.13 days in Group 1 vs 10.8 ± 8.65 days in group 2 (p = 0.57). Survival at 30 days was 100%. No severe adverse events were recorded.
CONCLUSIONS:
This study was designed as a proof-of-concept pilot study. Although it was not powered to achieve statistical significances, the study demonstrated relevant clinical effects of inhaled AP301 on patients with PGD after primary LTx. The improved gas exchange led to a significantly shorter duration of mechanical ventilation and a trend towards a shorter ICU stay. Further investigation of AP301 for treatment of PGD in larger studies is warranted.
TRIAL REGISTRATION:
The trial is registered at https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-000716-21/AT.
CET Conclusion