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  • The Appropriate Dose of Thymoglobulin Induction Therapy in Kidney Transplantation
    Clinical Transplantation. 2017;04:04

    Expert Review

    Reviewer: Professor Rita R. Alloway, Transplant Clinical Research, University of Cincinnati, College of Medicine, USA.
    Conflicts of interest: I am on the Sanofi/Genzyme speakers bureau and I served as a consultant on the Sanofi/Genzyme FDA submission.
    Clinical Impact Rating : ★☆☆☆☆ (1 of 5)
    This 90 patient randomized kidney transplant study by Nafar et al compared three different Thymoglobulin induction-dosing regimens of 4.5mg/kg over 3 days (Arm A), 4.5mg/kg as a single bolus, and 6mg/kg over 3 days (Arm C). The primary endpoint of incidence of rate and severity of biopsy proven acute rejection (BPAR) was low (2 per group) and not statistically different. Study results should be interpreted with caution due to 1) the sample size is inadequate to assess the endpoint, 2)16% and 10% of patients in Arm B and C respectively did not receive full randomized dose, and 3) the author acknowledged, the BPAR rate was limited by patients unwillingness to undergo biopsy. Recently Thymoglobulin was FDA approved for prophylaxis of acute rejection in patients receiving a kidney transplant at a dose of 1.5mg/kg administered daily for 4-7 days. This dose was based upon two historical randomized trials and extensive safety information. While this dose range is efficacious and safe, further refinements in Thymoglobulin dosing based upon 1) immunologic risk, 2) safety factors, 3) dosing factors (i.e. ideal body weight, actual body weight, dose maximum, etc.) and 4) concomitant immunosuppression, are desirable to individualize immunosuppression. While this study attempts to assess the impact of lower Thymoglobulin induction doses, these results are not generalizable. Appropriately, controlled and powered dose finding studies would be required.

    Abstract

    BACKGROUND Thymoglobulin is used effectively as an induction agent in kidney transplantation, but there is no consensus on the optimal dose. In order to delineate the safest effective dose an open-labeled randomized clinical trial was designed. METHODS In this study, 90 adult kidney transplant recipients (KTR) were randomized before transplantation in three groups to receive Thymoglobulin: Arm A (4.5 mg/kg in 3 days), Arm B (4.5 mg/kg single bolus dose), and Arm C (6 mg/kg in 3 days). Renal function, infections and rate of readmissions were evaluated during the first post transplantation year. RESULTS Ninety adult kidney recipients were enrolled (51% deceased donor) No significant statistical difference was found in acute rejection episodes or type of rejection between these groups, although patients in arm A showed more severe histopathologic changes according to Banff 2013 criteria, in renal biopsies(P = 0.03).At the first month after transplantation serum Cr was lower (P=0.001) and GFR was higher (P=0.04) in arm A, but there was no significant difference among the three groups at 3, 6 and 12 months post-transplant. CONCLUSION Although all regimens showed same efficacy regarding to the rate of rejection episodes, 3-day 4.5 mg/kg Thymoglobulin had significantly lower complications. This article is protected by copyright. All rights reserved. Copyright This article is protected by copyright. All rights reserved.
  • Anticipated regret and organ donor registration: A randomized controlled trial
    Health Psychology. 2016;35(11):1169-1177

    Study Details

    Aims: To investigate whether simply asking people to rate the extent to which they anticipate feeling regret for not registering as an organ donor after death increases subsequent verified organ donor registration.
    Interventions: The study involved 4 interventions with participants randomized to 1 of 4 arms, each receiving different questionnaires. The no-questionnaire control (NQC) arm received a survey measuring demographics and whether or not they were registered organ donors. The questionnaire control (QC) arm completed the NQC questions plus questions regarding affective attitudes and intention to register as an organ donor. The theory of planned behaviour (TPB) questionnaire arm received the QC questionnaire, plus additional items measuring TPB variables. The anticipated regret (AR) arm received the TPB questionn
    Participants: Adult, Scottish, members of the general public, not registered on the NHSBT before the application pack was sent, were eligible for the study.
    Outcomes: The primary outcome measures were number of nondonor participants who subsequently registered 6 months later, as verified by the United Kingdom national transplant register.

    CET Conclusion

    Reviewer: Centre for Evidence in Transplantation
    This RCT tested whether the emotional factor anticipated regret can be used for interventions aimed at increasing organ donor registration. A randomly selected sample of 14,509 members of the general public were randomised to one of four intervention arms using simple randomisation. The four intervention arms each received a different questionnaire and participants were blind to the experimental arm. The sample size calculation showed that 3,630 participants were needed, which was based on the results of a pilot study, taking into account the proportion of the population already registered as an organ donor and an expected low response rate to questionnaires. The intention to treat analysis of 9,208 participants, showed that 5.4% of participants registered as an organ donor after receiving the questionnaire. However participants in the anticipated regret intervention arm were less likely to register compared with the no-questionnaire control arm. The authors suggest that future research should take into account the possible effect of items in a questionnaire on the effectiveness of a proposed intervention.

    Expert Review

    Reviewer: Dr Anna Forsberg, Transplant Nursing at Lund University, Sweden.
    Conflicts of interest: No
    Clinical Impact Rating : ★★★☆☆ (3 of 5)
    This article focus on the emotional factor: anticipated regret (AR) in relation to organ donation. One assumption was that AR should motivate people to undertake an action to avoid harmful future consequences. Thus, manipulating exposure to anticipated regret should result in increased levels of organ donation. The main hypothesis was that simply asking people to think about and rate their anticipated regret should result in greater rates of verified organ donor registration. Findings reveal that there was a significant association between gender and compliance with the protocol. Participants who complied with the intervention seemed to register for donation to a higher degree. Women were more likely to register than men. The most prominent finding was that people were less likely to register when being manipulated with items regarding anticipated regret. However, in the specific AR-group, the registration rates to donate were significantly greater among those with high anticipated regret. The generalizability of the study is good at least among European countries, or countries with similar socio-economic conditions. The authors seem surprised by their findings. However, it is reasonable that peoples' minds are not easy to manipulate with two negatively loaded items. To suggest that a person might anticipate regret is also to trigger feelings of possible guilt and shame. A well-established consequence from these emotions is denial, not wanting to deal with the question of concern. Thus, this large scale epidemiological study seemed to press the "denial-button" by their intervention and subsequently the participants in the intervention group did not increase their organ donation registration. When trying to increase donation registration it is probably more useful to use positive aspects of organ donation as a motivator rather than discussing the possibility of anticipated regret.

    Abstract

    OBJECTIVE To test whether simply asking people to rate the extent to which they anticipate feeling regret for not registering as an organ donor after death increases subsequent verified organ donor registration. METHOD There were 14,509 members of the general public (both registered and nonregistered donors) randomly allocated to 1 of 4 arms, each receiving different questionnaires. The no-questionnaire control (NQC) arm received a survey measuring demographics and whether or not they were registered organ donors. The questionnaire control (QC) arm completed the NQC questions plus questions regarding affective attitudes and intention to register as an organ donor. The theory of planned behavior (TPB) questionnaire arm received the QC questionnaire, plus additional items measuring TPB variables. The anticipated regret (AR) arm received the TPB questionnaire, plus 2 additional items measuring anticipated regret. The main outcome measures were number of nondonor participants who subsequently registered 6 months later, as verified by the United Kingdom national transplant register. RESULTS Intention-to-treat (ITT) analysis in nonregistered donors (N = 9,139) revealed the NQC arm were more likely to register as an organ donor (6.39%) compared with the AR (4.51%) arm. CONCLUSIONS A brief anticipated regret intervention led to a decrease in registration. A potential reason is discussed in terms of questionnaire item content "priming" negative perceptions of organ donation. This is a methodological concern that needs to be addressed in studies that use similar interventions. Current controlled trials: www.controlled-trials.com number: ISRCTN922048897. (PsycINFO Database RecordCopyright (c) 2016 APA, all rights reserved).
  • Efficacy of a medication adherence enhancing intervention in transplantation: The MAESTRO-Tx trial
    Journal of Heart & Lung Transplantation. 2017;06:06

    Study Details

    Aims: To test the efficacy and sustainability of a 6-month post-transplant medication adherence enhancing intervention among adult heart, liver, and lung transplant recipients.
    Interventions: Participants were randomly assigned to either the intervention group or control group. Those in the intervention group received a theory-based multicomponent staged tailored medication adherence intervention using selected behavioural change techniques derived from the social-cognitive and trans-theoretical model, while the control group received usual care.
    Participants: 205 patients who had received their first single heart, liver or lung transplant at least one year prior to enrolment, aged ≥ 18 years and treated with tacrolimus twice-daily.
    Outcomes: The primary outcomes measured were medication adherence including correct dosing and timing adherence, and Basel Assessment of Adherence to Immunosuppressive medications (BAASIS) score. The seondary measured outcome was 5-year clinical event-free survival.

    CET Conclusion

    Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
    This interesting study investigated the effect of a multicomponent behavioural intervention in improving drug adherence in heart, liver and lung transplant recipients. Patients randomised to the intervention arm demonstrated significantly improved dosing and timing adherence compared to controls. This effect was maintained for 6 months. There was a trend towards improved clinical event-free survival, although this did not reach significance (82.5% vs. 72.5%). The study is well-designed, with a clearly described intervention, randomisation stratified by organ type, and blinding of outcome assessment. It should be noted, however, that 10.9% patients did not consent to the study, and a further 17% dropped out before intervention, which may mean that the sample receiving the intervention are not typical of the population as a whole. Future studies should assess similar interventions in the kidney transplant population, and further investigate the longevity of the effect.

    Expert Review

    Reviewer: Dr Patrizia Burra, Multivisceral Transplant Unit, Padova University Hospital, Padova, Italy.
    Conflicts of interest: No
    Clinical Impact Rating : ★★★★☆ (4 of 5)
    The key findings of this RCT are related to the efficacy of an adherence enhancing intervention in 205 transplant recipients. The Authors have found that the intervention group reported 16% higher adherence post-intervention compared to controls, which was 5 times higher. Moreover, in the intervention group, 5-year clinical event-free survival was 82.5% vs. 72.5% in the control group. The design of the study is well defined; the Authors have used a clear taxonomy in order to specify the assessed component of adherence, and to describe the interventions. The methodology is essential in this kind of study to allow the possibility of replicating the intervention. There are only few studies and RCTs that investigate the role of adherence enhancing interventions (and some of these have limitations due to a small sample size or a not well-defined framework). However, we are still missing the long-term assessment of adherence. The Authors have evaluated transplant recipients 6 months after interventions but as they stated, only a longer follow-up would improve the assessment of the intervention's efficacy. This may help to understand if some reinforcement measures need to be implemented after the intervention period.

    Abstract

    BACKGROUND Well-designed randomized controlled trials (RCTs) testing efficacy of post-transplant medication adherence enhancing interventions and clinical outcomes are scarce. METHODS This randomized controlled trial enrolled adult heart, liver, and lung transplant recipients who were >1 year post-transplant and on tacrolimus twice daily (convenience sample) (visit 1). After a 3-month run-in period, patients were randomly assigned 1:1 to intervention group (IG) or control group (CG) (visit 2), followed by a 6-month intervention (visits 2-4) and a 6-month adherence follow-up period (visit 5). All patients used electronic monitoring for 15 months for adherence measurement, generating a daily binary adherence score per patient. Post-intervention 5-year clinical event-free survival (mortality or retransplantation) was evaluated. The IG received staged multicomponent tailored behavioral interventions (visits 2-4) building on social cognitive theory and trans-theoretical model (e.g., electronic monitoring feedback, motivational interviewing). The CG received usual care and attended visits 1-5 only. Intention-to-treat analysis used generalized estimating equation modeling and Kaplan-Meier survival analysis. RESULTS Of 247 patients, 205 were randomly assigned (103 IG, 102 CG). At baseline, average daily proportions of patients with correct dosing (82.6% IG, 78.4% CG) and timing adherence (75.8% IG, 72.2% CG) were comparable. The IG had a 16% higher dosing adherence post-intervention (95.1% IG, 79.1% CG; p < 0.001), resulting in odds of adherence being 5 times higher in the IG than in the CG (odds ratio 5.17, 95% confidence interval 2.86-9.38). This effect was sustained at end of follow-up (similar results for timing adherence). In the IG, 5-year clinical event-free survival was 82.5% vs 72.5% in the CG (p = 0.18). CONCLUSION Our intervention was efficacious in improving adherence and sustainable. Further research should investigate clinical impact, cost-effectiveness, and scalability. Copyright © 2017 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.
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