- Email: [email protected]
Once-daily prolonged-release tacrolimus versus twice-daily tacrolimus in liver transplantation
SCIENCE AND PRACTICE Journal of the American Pharmacists Association 59 (2019) 816e823
Contents lists available at ScienceDirect
Journal of the American Pharmacists Association journal homepage: www.japha.org
RESEARCH
Once-daily prolonged-release tacrolimus versus twice-daily tacrolimus in liver transplantation Bingsong Huang, Jun Liu, Jun Li, Paul M. Schroder, Maogen Chen, Ronghai Deng*, Suxiong Deng* a r t i c l e i n f o
a b s t r a c t
Article history: Received 25 February 2019 Accepted 2 August 2019 Available online 11 September 2019
Objective: For patients who have received a kidney transplant, studies have shown that oncedaily prolonged-release tacrolimus (TAC) has similar efficacy and safety to standard twicedaily dosing. The purpose of this study was to perform a meta-analysis to compare the effectiveness and safety of daily TAC (TAC qd) versus standard twice-daily TAC (TAC bid) administration in liver transplantation (LT). Design: Meta-analysis. Setting and participants: We systematically searched the PubMed/MEDLINE, Web of Science, and Cochrane Library databases for studies comparing outcomes of LT patients who received TAC qd versus TAC bid. Outcome measures: Results were reported as odds ratios (ORs) with 95% CIs. Results: Six studies, which included 5179 LT recipients (TAC qd ¼ 951; TAC bid ¼ 4228) were included in the analysis. The TAC qd group had a low 1-year graft loss rate (OR 0.70 [95% CI 0.54e0.91], P ¼ 0.008) and lower rate of biopsy-proven acute rejection (BPAR) at 90 days (OR 0.46 [95% CI 0.24e0.89], P ¼ 0.02) compared with the TAC bid group. There was no significant difference in 1-year mortality or the incidence of adverse events after LT between the 2 groups. Conclusions: Current evidence suggests that TAC qd is safe and effective for LT patients during the first year after transplantation. Longer-term follow-up studies are necessary to determine if TAC qd is safe and effective beyond the first year after LT. © 2019 Published by Elsevier Inc. on behalf of the American Pharmacists Association.
Background After organ transplantation, patients must follow a complex immunosuppression regimen with a large number of medications and frequent dosing intervals. Noncompliance with posttransplant immunosuppressive medications is an important cause of graft dysfunction and graft loss.1,2 A systematic review of the literature found that simpler, less-frequent dosing
Disclosure: The authors declare no relevant conflicts of interest or financial relationships. Funding: This work was in part supported by the National Natural Science Foundation of China (81770410 and 81401324), and the Scientific Program for Young teacher of Sun Yat-sen University (16ykpy05). Bingsong Huang, Jun Liu, and Jun Li contributed equally to this work and considered as co-first authors. * Correspondence: Ronghai Deng, MD, PhD, and Suxiong Deng, MD, PhD, Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan 2nd Road, Guangzhou 510080, China. E-mail addresses: [email protected] (R. Deng) and 1726695578@qq. com (S. Deng).
regimens resulted in better compliance.3 Tacrolimus (TAC) is a widely used immunosuppressant in organ transplantation, and the twice-a-day formulation (TAC bid; PROGRAFdAstellas Pharma US) has well-documented efficacy and safety profiles in patients who have received allogeneic kidney, liver, and heart transplantation.3 To minimize noncompliance in organ transplantation, a simpler dosing regimen, prolonged-release TAC (TAC qd; AdvagrafdAstellas Pharma Europe Ltd) was developed and licensed in Europe in 2007.4 The European Medicines Agency proposed that a once-daily dosing formulation of TAC with an immediate-release action might provide potential benefits for patients.5,6 A recent cost-effectiveness study showed that, compared with TAC bid, TAC qd would decrease cost to patients.7 In addition to improved medication compliance,8,9 some studies have shown that TAC qd has pharmacokinetic (PK), efficacy, and safety profiles comparable with TAC bid in kidney transplantation patients.10 In contrast, other randomized controlled trials (RCTs) of TAC qd in kidney transplantation have reported higher rates of rejection in patients receiving TAC qd.11 A recent retrospective study with a large number of liver transplanttion (LT) patients found that those
https://doi.org/10.1016/j.japh.2019.08.002 1544-3191/© 2019 Published by Elsevier Inc. on behalf of the American Pharmacists Association.
SCIENCE AND PRACTICE TAC versus TAC bid in liver transplantation
Key Points Background: Tacrolimus prolonged release is a new and simpler dosing immunosuppressant in organ transplanation. Findings: Tacrolimus prolonged release dosing is safe and effective in liver transplant.
receiving TAC qd had a higher rate of postoperative infections than those receiving TAC bid.4 There have also been reports that liver transplant recipients taking TAC qd have higher rates of TAC-related adverse events (AEs), such as infections, renal failure and impairment, headaches, and abnormal liver function tests.5,12,13 Because of these conflicting reports, Ho et al.14 conducted a systematic review of the 2 TAC dosing regimens in kidney transplant patients and concluded that the 2 regimens have similar efficacy and rates of complications at 12 months. To our knowledge, no systematic review has been performed examining the 2 TAC dosing regimens in LT patients. Thus, the purpose of the study was to perform a meta-analysis to compare the efficacy and safety of these 2 regimens in LT recipients. Methods Data sources and search methods We searched the PubMed/MEDLINE, Web of Science, and Cochrane Library databases using the terms “tacrolimus” OR “FK506” AND “liver transplant.” The search included all studies published up to March 2018. Only those reporting clinical results and outcomes of interest were reviewed for potential inclusion. Inclusion and exclusion criteria Criteria for inclusion in the meta-analysis were that (1) TAC was the primary immunosuppressant used in patients who received LT and (2) the outcomes of patients who received TAC qd versus TAC bid had been compared. Exclusion criteria were (1) lack of a control group (the study had only included patients who received TAC qd); (2) that the study purpose had been to examine conversion from TAC bid to TAC qd; (3) that the study purpose had been to evaluate the PK of TAC; and (4) studies in which patients who had received multiorgan transplants. Data extraction and quality assessment Outcomes of the meta-analysis were 1-year patient mortality and 1-year graft loss rates, and the rate of biopsy-proven acute rejection (BPAR) at 90 days. Postoperative complications were also compared and included the rate of postoperative renal disorders, the rate of new-onset diabetes after transplantation (NODAT), and infection rates.
The methodological quality of observational studies was assessed using the Newcastle-Ottawa Scale15 (Supplemental Table 1). “Selection,” “comparability,” and “outcome” are the 3 categories included in the Newcastle-Ottawa Scale for the assessment of cohort studies. Statistical analysis Odds ratios (ORs) and 95% CIs were used to evaluate event rates. Study heterogeneity was evaluated using the chi-square and I2 statistical tests; values of P < 0.05 or I2 > 50% were considered to indicate significant heterogeneity, and a random effects model of analysis was used. When significant heterogeneity was not present, a fixed effects model was used. Publication bias was assessed by funnel plot, and asymmetry may indicate the presence of bias. A value of P < 0.05 was considered to indicate a statistically significant difference between the 2 groups. Statistical analyses were performed with Review Manager (RevMan, version 5.3.5; The Nordic Cochrane Centre). Results Search results and study characteristics The Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram of the literature search results is shown in Figure 1. A total of 8910 articles were identified in the literature search, 2290 duplicates were removed, and 6439 were excluded after screening titles. The full texts of the remaining 181 articles were reviewed. Of these, 6 met the inclusion/exclusion criteria and were included in the meta-analysis. The 6 studies included 956 LT recipients who received TAC qd, and 4223 who received TAC bid. Study characteristics are summarized in Table 1. In addition, the Adjunct Regimen and Model for End-stage Liver Disease (MELD) score (the average score for patients) of each included study are shown in Table 1. MELD score was used to evaluate a patient’s clinical suitability for LT. MELD score was calculated as: 9.57 loge(creatinine) þ 3.78 Loge(total bilirubin) þ 11.2 *loge(international normalized ratio) þ 6.43).16 Funnel plot analysis indicated that there was no obvious publication bias present among the included studies (Supplemental Figure 1Ae1F). One-year mortality Five studies17-20 reported 1-year mortality or survival rates (935 patients were treated with TAC qd and 4214 LT with TAC bid). No significant heterogeneity was identified among the studies (c2 ¼ 1.73, P ¼ 0.79, I2 ¼ 0%). The combined 1-year mortality rate was 7.59% for the TAC qd group and 8.90% for the TAC bid group. The OR for 1-year mortality of the TAC qd group compared with the TAC bid group was 0.89 (95% CI 0.67e1.18, P ¼ 0.43), indicating there was no difference in 1-year mortality between the groups (Figure 2). Graft loss rate Four studies17,18,20,21 reported data of graft loss at 1 year (875 patients were treated with TAC qd and 4186 with TAC bid). No heterogeneity was detected among the studies (c2 ¼ 2.26, P ¼ 0.52, I2 ¼ 0%). Patients treated with TAC qd had 817
SCIENCE AND PRACTICE
Identification
B. Huang et al. / Journal of the American Pharmacists Association 59 (2019) 816e823
Potentially relevant studies identified by primary search (n=8910)
Included
Eligibility
Screening
Duplicates removed (n=2290)
Studies retrieved for more detailed evaluation (n=6620)
Potentially appropriate studies to be included in the analysis (n=181)
Studies excluded after title review (n=6439) 4588 not relevant to tacrolimus research 1409 involved patients without LT(not relevant to transplantation research) 266 basic science articles on tacrolimus 109 focused on conversion from TAC BID to TAC QD 33 reviews or commentaries 22 focused on clinical reports 12 pediatric research
Studies excluded after abstract and full-text review (n=175) 75 had no control group 34 pharmacokinetics research 25 involved multi-organ transplant 23 focused on conversion from TAC BID to TAC QD 10 no data available 8 not relevant to tacrolimus research
Studies included (n=6) 4 observational and 2 randomized controlled studies
Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram showing literature search results.
significantly better 1-year graft survival (OR 0.70 [95% CI 0.54e0.91], P ¼ 0.008) than those treated with TAC bid (Figure 3). BPAR Five studies17-20,22 included data of BPAR (368 patients were treated with TAC qd and 333 with TAC bid). The combined BPAR rate (no time interval limited) was 27.9% (range: 13.3%e36.3%) for the TAC qd group, and 31.8% (26.9%e50.0%) for the TAC bid group. No significant heterogeneity was observed among the studies (c2 ¼ 6.29, P ¼ 0.18, I2 ¼ 36%); OR 0.76 (95% CI 0.47e1.22, P ¼ 0.26), indicating no difference in BPAR between the groups (Figure 4). Three studies reported the BPAR rate at 90 days after transplant (124 patients were treated with TAC qd and 88 with TAC bid). No significant heterogeneity was found (c2 ¼ 1.38, P ¼ 0.50, I2 ¼ 0%). Analysis indicated that the TAC qd group had a significantly lower 90-day BPAR rate than the TAC bid group (0.46 [95% CI 0.24e0.89], P ¼ 0.02) (Figure 5).
study reported renal conditions in a different way, such as renal insufficiency, renal impairment, development of chronic kidney disease, renal failure, or acute kidney injury. Thus, we classified all these events as 1 category, renal disorders. No heterogeneity was detected among the studies (c2 ¼ 3.33, P ¼ 0.34, I2 ¼ 10%). The rate of renal disorders was similar between the groups (OR 1.37 [95% CI 0.98e1.91], P ¼ 0.07) (Figure 6). NODAT Three studies17-19 reported the incidence of NODAT (359 patients received TAC qd and 329 TAC bid). No heterogeneity was detected (c2 ¼ 0.56, P ¼ 0.76, I2 ¼ 0%). The rate of NODAT was similar between the groups (OR 0.88 [95% CI 0.60e1.29], P ¼ 0.53) (Figure 7). Infections Four studies17,19,20,22 reported infection rates after transplantation (361 patients received TAC qd and 322 TAC bid). No heterogeneity was detected (c2 ¼ 5.69, P ¼ 0.13, I2 ¼ 47%). The infection rates were similar between the 2 groups (OR 0.81 [95% CI 0.41e1.62], P ¼ 0.55) (Figure 8).
Postoperative complications Discussion Renal disorders Four studies17-20 reported AEs related to impaired renal function (407 patients received TAC qd and 375 TAC bid). Each
818
In this systematic review and meta-analysis, we compared the outcomes of patients who received TAC qd with those who
SCIENCE AND PRACTICE
19.0 ± 6.9 20.3 ± 8.4 5 50.0 ± 13.9 52.1 ± 11.4 2005e2015 CS, MMF 28 60
2008e2012 3839
Okumura et al.20 (2017)
Adam et al.4 (2015)
European Liver Transplant Registry (ELTR) Japan
528
CS, MMF
2006e2010 2010e2012 CS, MMF, mAb CS, MMF, AZA mAb 14 46 16 48 Marubashi et al.22 (2012) Dannhorn et al.20 (2014)
Fischer et al.18 (2011):
Abbreviations: AZA, azathioprine; CS, corticosteroid; mAb, basiliximab; MELD, Model for End-Stage Liver Disease; MMF, mycophenolate mofetil; NS, nonsignificant difference; trial;A, Jadad score. * P < 0.05.
5 52.1
5 5
52.4 (27e68) 45.5 ± 14.9 49 (38e56)
49.4 (24e65) 55.3 ± 7.9 58 (50e61)* 49.6 2003e2004 CS, MM, AZA 62 67
52.7 52.8 2004e2006 CS, MMF 234
5A
:
, random controlled, double-blind
29
21.8 ± 10.4 15 (10e18.5) 27.8
NS
NS
TAC qd TAC qd
237
Europe, Brazil, Canada, etc. Europe, Canada, Australia Japan United Kingdom Trune cka et al.17 (2010):
Recipient age References
Table 1 Characteristics of included trials
Institute
Sample size
TAC bid
Adjunct regimen
Study periods
TAC qd
TAC bid
5A
NOS star level
MELD score
TAC bid
20.1 ± 6.7 13 (9e19)
TAC versus TAC bid in liver transplantation
received TAC bid after LT. Six studies with 5179 patients were included in the meta-analysis. The graft loss rate and BPAR rate at 90 days after transplantation were significantly lower in the TAC qd group, whereas other end points including 1year mortality, and the rates of infection, NODAT, and renal disorders were not different between the groups. To our knowledge, this is the first comprehensive analysis on this topic and therefore provides important insight into the clinical use of TAC qd in LT patients. Improvement in LT outcomes is largely because of the development of effective immunosuppressants.21 TAC is the primary drug used for immunosuppression in LT patients, but nonadherence and high variability of exposure impedes the recovery of recipients after transplantation. A once-a-day formulation of TAC (TAC qd; Advagraf) has been approved for clinical use in many countries since 2007. Many studies of TAC qd after LT have confirmed that it is safe and effective with a low rate of acute rejection episodes and excellent short-term graft and patient survival,13,23,24 as well as in long-term follow-up.25,26 Studies have also suggested that TAC can safely be converted from the twice-daily to once-daily administration, with an increase in patient compliance.6,27-31 However, studies comparing the initiation of TAC dosing at TAC qd with traditional TAC bid dosing in LT are lacking. A randomized, double-blind study showed that TAC qd was well tolerated with similar patient survival, graft survival, and AEs compared with TAC bid.17 Recently, a large retrospective analysis from the European Liver Transplant Registry showed significant improvements in long-term graft and patient survivals (3-year follow-up) in patients treated with TAC qd versus TAC bid.4 Furthermore, it is known that a low variability in TAC exposure is important for graft and patient survival. Studies of the conversion from TAC bid to TAC qd have shown that TAC qd reduces intrapatient and interpatient variability and has a more coherent PK profile.32,33 Studies in healthy volunteers34,35 showed that TAC qd had similar exposure and trough levels as TAC bid, but with a reduced peak level. All 6 studies included in this meta-analysis provided a TAC PK analysis. Ficher et al.18 and Okumura et al.19 reported that TAC mean whole-blood trough levels were lower in the TAC qd group than in TAC bid the first day after LT and were similar for both formulations at other time points. Dannhorn et al.20 measured TAC levels at days 5, 10, 14, and 30, and at 1 year, after LT, and showed no differences at any time point between the 2 formulations. Marubashi et al.22 reported that TAC trough levels were similar between TAC qd and TAC bid, except on postoperative days 7 and 90 when trough levels were lower in the TAC qd group. Thus, to achieve similar TAC exposure, the initial dose of TAC qd needs to be higher. The reasons for differences in absorption between the 2 TAC formulations during the early posttransplant period are not yet fully understood. TAC is characterized by a narrow therapeutic window and highly variable PK profile, which necessitate therapeutic drug monitoring to individualize the dosing regimen and prevent rejection and toxicity.36 Nephrotoxicity remains a major limitation of TAC and other calcineurin inhibitors.37 Renal dysfunction after LT is a major problem,38-40 and renal insufficiency is strongly associated with an increased risk of
819
SCIENCE AND PRACTICE B. Huang et al. / Journal of the American Pharmacists Association 59 (2019) 816e823
Figure 2. Patient mortality at 1 year.
Figure 3. Graft loss at 1 year.
Figure 4. Biopsy-proven acute rejection (BPAR) rates.
Figure 5. Biopsy-proven acute rejection (BPAR) rates at 90 days.
820
SCIENCE AND PRACTICE TAC versus TAC bid in liver transplantation
Figure 6. Renal disorders postoperatively.
death 1 year or more after LT.41 In studies of conversion from TAC bid to TAC qd, some researchers have reported improvements in renal function after conversion to TAC qd in renal transplant recipients.42,43 However, a multicenter study in which kidney transplant patients were switched from TAC bid to TAC qd showed no changes in renal function.12 In an observational, multicenter study of TAC qd, renal function was well maintained and consistent with conventional TAC dosing in LT recipients.4 Zaltzman et al.34 reported that, compared with TAC bid, TAC qd has a reduced Cmax and only a single peak. Thus, renal perfusion is greater with TAC qd.34 However, Dannhorn et al.20 reported that acute kidney injury after LT was more frequent in patients receiving TAC qd than TAC bid (45% and 23%, respectively), although this difference did not reach statistical significance.20 Our analysis indicated no difference in renal dysfunction between the 2 dosing regimens. NODAT, previously referred to as posttransplantation diabetes, is a frequent complication in solid organ transplant recipients. Development of NODAT after LT has been associated with increased risk of mortality and posttransplant infections and has negative effects on graft function.44 The incidence of NODAT has been reported to range from 5% to 50%, and TAC is an independent risk factor for NODAT.45-48 In addition, some systematic reviews have suggested that NODAT occurs more frequently with TAC than with cyclosporine. A study that included both liver and kidney transplant recipients reported no difference in the NODAT rate between the TAC qd and TAC bid.49 In our analysis, NODAT rates were similar between the 2 formulations, which is consistent with that reported in kidney transplantation.14 A retrospective study observed that a lower serum level of TAC was better at preventing infections.50 According to the TAC PK profiles reported by the studies included in this metaanalysis, there were no significant differences between TAC levels of the 2 formulations at all time points. The infection
rates were also similar between the 2 formulations in our analysis. A study of kidney transplant patients showed similar rates of viral infections, but a lower rate of bacterial infections in the TAC qd group.14 As with any retrospective meta-analysis, there are some limitations that need to be considered when interpreting the results. First, most studies included were retrospective, observational studies. All but 2 of the studies had small numbers of patients, which might have precluded an accurate assessment of heterogeneity. It is well known that donor factors such as preoperative medical conditions, age, cold and warm ischemia times, and donation type have a great impact on the postoperative outcomes of LT recipients. Particularly, donation after cardiac death is associated with worse longterm outcomes, with an increase in biliary complications, ischemic cholangiopathy, graft loss, and mortality compared with donation after brain death.51 Half of the included studies in this meta-analysis did not provide donor information, which may represent a confounding variable that could influence the mortality rate. Another limitation to this study is that the follow-up time was short (1 year), and thus might not be representative of long-term outcomes. All 6 studies reported PK analysis results; however, only 1 study reported numeric results, while the other studies reported results in graphic form without exact numeric results. Finally, some studies had no baseline data available, such as MELD score, which again could be a confounding variable that would influence the outcomes. This meta-analysis showed that TAC qd was associated with a lower 1-year graft loss rate and a lower BPAR rate at 90 days postoperatively in LT recipients compared with TAC bid. Because the PK profile of TAC qd is similar to that of TAC bid, the incidence of AEs is comparable between the 2 formulations. These results suggest that TAC qd is safe and effective for LT patients for at least for the first year after
Figure 7. New-onset diabetes after transplantation (NODAT).
821
SCIENCE AND PRACTICE B. Huang et al. / Journal of the American Pharmacists Association 59 (2019) 816e823
Figure 8. Infections postoperatively.
transplantation. However, further RCTs with larger sample sizes and long-term follow-up are needed to provide more robust evidence to determine guidelines for the use of TAC qd in LT recipients. References 1. Berlakovich GA, Langer F, Freundorfer E, et al. General compliance after liver transplantation for alcoholic cirrhosis. Transpl Int. 2000;13(2): 129e135. 2. Stuber ML, Shemesh E, Seacord D, Washington 3rd J, Hellemann G, McDiarmid S. Evaluating non-adherence to immunosuppressant medications in pediatric liver transplant recipients. Pediatr Transplant. 2008;12(3):284e288. 3. Claxton AJ, Cramer J, Pierce C. A systematic review of the associations between dose regimens and medication compliance. Clin Ther. 2001;23(8):1296e1310. 4. Adam R, Karam V, Delvart V, et al. Improved survival in liver transplant recipients receiving prolonged-release tacrolimus in the European Liver Transplant Registry. Am J Transplant. 2015;15(5):1267e1282. 5. Barraclough KA, Isbel NM, Johnson DW, Campbell SB, Staatz CE. Onceversus twice-daily tacrolimus: are the formulations truly equivalent? Drugs. 2011;71(12):1561e1577. 6. Florman S, Alloway R, Kalayoglu M, et al. Once-daily tacrolimus extended release formulation: experience at 2 years postconversion from a Prograf-based regimen in stable liver transplant recipients. Transplantation. 2007;83(12):1639e1642. 7. Muduma G, Odeyemi I, Pollock RF. Evaluating the cost-effectiveness of prolonged-release tacrolimus relative to immediate-release tacrolimus in liver transplant patients based on data from routine clinical practice. Drugs Real World Outcomes. 2016;3(1):61e68. 8. Beckebaum S, Iacob S, Sweid D, et al. Efficacy, safety, and immunosuppressant adherence in stable liver transplant patients converted from a twice-daily tacrolimus-based regimen to once-daily tacrolimus extended-release formulation. Transpl Int. 2011;24(7):666e675. 9. de Mare-Bredemeijer EL, Metselaar HJ. Optimization of the use of calcineurin inhibitors in liver transplantation. Best Pract Res Clin Gastroenterol. 2012;26(1):85e95. 10. Silva Jr HT, Yang HC, Abouljoud M, et al. One-year results with extendedrelease tacrolimus/MMF, tacrolimus/MMF and cyclosporine/MMF in de novo kidney transplant recipients. Am J Transplant. 2007;7(3):595e608. €mer BK, Charpentier B, B€ 11. Kra ackman L, et al. Tacrolimus Prolonged Release Renal Study Group. Tacrolimus once daily (ADVAGRAF) versus twice daily (PROGRAF) in de novo renal transplantation: a randomized phase III study. Am J Transplant. 2010;10(12):2632e2643. 12. Guirado L, Cantarell C, Franco A, et al. GREAT Study Group. Efficacy and safety of conversion from twice-daily to once-daily tacrolimus in a large cohort of stable kidney transplant recipients. Am J Transplant. 2011;11(9):1965e1971. 13. Uemoto S, Abe R, Horike H, So M. Safety and efficacy of once-daily modified-release tacrolimus in liver transplant recipients: a multicenter postmarketing surveillance in Japan. Transplant Proc. 2014;46(3): 749e753. 14. Ho ET, Wong G, Craig JC, Chapman JR. Once-daily extended-release versus twice-daily standard-release tacrolimus in kidney transplant recipients: a systematic review. Transplantation. 2013;95(9):1120e1128. 15. Adam R, Karam V, Delvart V, et al. All contributing centers (www.eltr.org); European Liver and Intestine Transplant Association (ELITA). Evolution of indications and results of liver transplantation in Europe. A report from the European Liver Transplant Registry (ELTR). J Hepatol. 2012;57(3):675e688.
822
16. Marubashi S, Wada H, Kobayashi S, et al. Once-daily prolonged-release tacrolimus in de novo liver transplantation: a single center cohort study. Hepatogastroenterology. 2012;59(116):1184e1188. 17. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25(9):603e605. 18. Kamath PS, Kim WR, Advanced Liver Disease Study Group. The model for end-stage liver disease (MELD). Hepatology. 2007;45(3):797e805. 19. Trune cka P, Boillot O, Seehofer D, et al. Tacrolimus Prolonged Release Liver Study Group. Once-daily prolonged-release tacrolimus (ADVAGRAF) versus twice-daily tacrolimus (PROGRAF) in liver transplantation. Am J Transplant. 2010;10(10):2313e2323. 20. Fischer L, Trune cka P, Gridelli B, et al. Pharmacokinetics for once-daily versus twice-daily tacrolimus formulations in de novo liver transplantation: a randomized, open-label trial. Liver Transpl. 2011;17(2):167e177. 21. Okumura Y, Noda T, Eguchi H, et al. Short- and long-term outcomes of de novo liver transplant patients treated with once-daily prolonged-release tacrolimus. Transplant Direct. 2017;3(9):e207. 22. Dannhorn E, Cheung M, Rodrigues S, et al. De novo use of generic tacrolimus in liver transplantation - a single center experience with oneyr follow-up. Clin Transplant. 2014;28(12):1349e1357. L, et al. A prospective, multicenter study of 23. Charco R, Caralt M, Llado once-daily extended-release tacrolimus in de novo liver transplant recipients. Transplant Proc. 2011;43(3):718e723. 24. Ortiz de Urbina J, Valdivieso A, Matarranz A, et al. Advagraf de novo in liver transplantation: a single-center experience. Transplant Proc. 2011;43(3):724e725. 25. Gastaca M, Valdivieso A, Bustamante J, et al. Favorable longterm outcomes of liver transplant recipients treated de novo with once-daily tacrolimus: results of a single-center cohort. Liver Transpl. 2016;22(10): 1391e1400. 26. van Hooff JP, Alloway RR, Trune cka P, Mourad M. Four-year experience with tacrolimus once-daily prolonged release in patients from phase II conversion and de novo kidney, liver, and heart studies. Clin Transplant. 2011;25(1):E1eE12. €ckman L, Persson CA. An observational study evaluating tacrolimus 27. Ba dose, exposure, and medication adherence after conversion from twiceto once-daily tacrolimus in liver and kidney transplant recipients. Ann Transplant. 2014;19:138e144. 28. Wu YJ, Lin YH, Yong CC, et al. Safe one-to-one dosage conversion from twice-daily to once-daily tacrolimus in long-term stable recipients after liver transplantation. Ann Transplant. 2016;21:30e34. 29. Kim SH, Lee SD, Kim YK, Park SJ. Outcomes of early conversion from Prograf to generic tacrolimus in adult living donor liver transplant recipients. Transplant Proc. 2015;47(6):1915e1916. 30. Thorat A, Chou HS, Lee CF, et al. Effects of converting tacrolimus formulation from twice-daily to once-daily in liver transplantation recipients. BioMed Res Int. 2014;2014:265658. 31. Kim SH, Lee SD, Kim YK, Park SJ. Conversion of twice-daily to once-daily tacrolimus is safe in stable adult living donor liver transplant recipients. Hepatobiliary Pancreat Dis Int. 2015;14(4):374e379. 32. Florman S, Alloway R, Kalayoglu M, et al. Conversion of stable liver transplant recipients from a twice-daily Prograf-based regimen to a once-daily modified release tacrolimus-based regimen. Transplant Proc. 2005;37(2):1211e1213. ko-Resmer J, Boillot O, Wolf P, Thorburn D. Renal function, efficacy 33. San and safety postconversion from twice- to once-daily tacrolimus in stable liver recipients: an open-label multicenter study. Transpl Int. 2012;25(3): 283e293. 34. Zaltzman JS, Lai V, Schulz MZ, Moon KH, Cherney DZ. A randomized cross-over comparison of short-term exposure of once-daily extended release tacrolimus and twice-daily tacrolimus on renal function in healthy volunteers. Transpl Int. 2014;27(12):1294e1302.
SCIENCE AND PRACTICE TAC versus TAC bid in liver transplantation
35. Park K, Kim YS, Kwon KI, Park MS, Lee YJ, Kim KH. A randomized, openlabel, two-period, crossover bioavailability study of two oral formulations of tacrolimus in healthy Korean adults. Clin Ther. 2007;29(1): 154e162. 36. Beckebaum S, Cicinnati VR, Radtke A, Kabar I. Calcineurin inhibitors in liver transplantation - still champions or threatened by serious competitors? Liver Int. 2013;33(5):656e665. 37. Ojo AO, Held PJ, Port FK, et al. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med. 2003;349(10):931e940. 38. Bahirwani R, Reddy KR. Outcomes after liver transplantation: chronic kidney disease. Liver Transpl. 2009;15(suppl 2):S70eS74. 39. Karie-Guigues S, Janus N, Saliba F, et al. Long-term renal function in liver transplant recipients and impact of immunosuppressive regimens (calcineurin inhibitors alone or in combination with mycophenolate mofetil): the TRY study. Liver Transpl. 2009;15(9):1083e1091. 40. Allen AM, Kim WR, Therneau TM, Larson JJ, Heimbach JK, Rule AD. Chronic kidney disease and associated mortality after liver transplantation–a time-dependent analysis using measured glomerular filtration rate. J Hepatol. 2014;61(2):286e292. 41. Watt KD, Pedersen RA, Kremers WK, Heimbach JK, Charlton MR. Evolution of causes and risk factors for mortality post-liver transplant: results of the NIDDK long-term follow-up study. Am J Transplant. 2010;10(6): 1420e1427. 42. Kolonko A, Chudek J, Wiecek A. Improved kidney graft function after conversion from twice daily tacrolimus to a once daily prolonged-release formulation. Transplant Proc. 2011;43(8):2950e2953. 43. Tinti F, Meçule A, Poli L, et al. Improvement of graft function after conversion to once daily tacrolimus of stable kidney transplant patients. Transplant Proc. 2010;42(10):4047e4048. 44. Baid S, Cosimi AB, Farrell ML, et al. Posttransplant diabetes mellitus in liver transplant recipients: risk factors, temporal relationship with hepatitis C virus allograft hepatitis, and impact on mortality. Transplantation. 2001;72(6):1066e1072. 45. Kuo HT, Sampaio MS, Ye X, Reddy P, Martin P, Bunnapradist S. Risk factors for new-onset diabetes mellitus in adult liver transplant recipients, an analysis of the Organ Procurement and Transplant Network/ United Network for Organ Sharing database. Transplantation. 2010;89(9): 1134e1140. 46. Davidson J, Wilkinson A, Dantal J, et al, International Expert Panel. Newonset diabetes after transplantation: 2003 International consensus
47.
48. 49.
50.
51.
guidelines. Proceedings of an international expert panel meeting. Barcelona, Spain, 19 February 2003. Transplantation. 2003;75(10 Suppl): SS3eSS24. Heisel O, Heisel R, Balshaw R, Keown P. New onset diabetes mellitus in patients receiving calcineurin inhibitors: a systematic review and metaanalysis. Am J Transplant. 2004;4(4):583e595. Bodziak KA, Hricik DE. New-onset diabetes mellitus after solid organ transplantation. Transpl Int. 2009;22(5):519e530. First MR, Dhadda S, Croy R, Holman J, Fitzsimmons WE. New-onset diabetes after transplantation (NODAT): an evaluation of definitions in clinical trials. Transplantation. 2013;96(1):58e64. Nacif LS, David AI, Pinheiro RS, et al. An analysis of tacrolimus-related complications in the first 30 days after liver transplantation. Clinics (Sao Paulo). 2014;69(11):745e749. O'Neill S, Roebuck A, Khoo E, Wigmore SJ, Harrison EM. A meta-analysis and meta-regression of outcomes including biliary complications in donation after cardiac death liver transplantation. Transpl Int. 2014;27(11):1159e1174.
Bingsong Huang, MD, PhD, intern, Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Neurosurgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China Jun Li, MD, PhD, Associate Chief Physician, Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China Jun Liu, MD, Associate Chief Physician, Department of Respiratory, the First People’s Hospital affiliated to Guangzhou Medical University, Guangzhou, China Paul M. Schroder, MD, PhD, Attending Physician, Department of Surgery, Duke University Medical Center, Durham, NC Maogen Chen, MD, PhD, Associate Chief Physician, Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China Ronghai Deng, MD, PhD, Associate Chief Physician, Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China Suxiong Deng, MD, PhD, Chief Physician, Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
823
SCIENCE AND PRACTICE B. Huang et al. / Journal of the American Pharmacists Association 59 (2019) 816e823
Appendix
Supplemental Figure 1. Funnel plot for results. (A) Patient mortality at 1 year. (B) Graft loss at 1 year. (C) Biopsy-proven acute rejection (BPAR) rates. (D) Renal disorders postoperatively. (E) New-onset diabetes after transplantation (NODAT) postoperatively. (F) Infections postoperatively.
823.e1
SCIENCE AND PRACTICE TAC versus TAC bid in liver transplantation
Supplemental Table 1 The Newcastle-Ottawa Quality Assessment Scale Note: A study can be awarded a maximum of 1 star for each numbered item within the Selection and Exposure categories. A maximum of 2 stars can be given for comparability. Selection 1) Is the case definition adequate? a) yes, with independent validation
b) yes, e.g., record linkage or based on self-reports c) no description 2) Representativeness of the cases a) consecutive or obviously representative series of cases
b) potential for selection biases or not stated 3) Selection of controls a) community controls
b) hospital controls c) no description 4) Definition of controls a) no history of disease (endpoint)
b) no description of source Comparability 1) Comparability of cases and controls on the basis of the design or analysis a) study controls for _______________ (Select the most important factor.)
b) study controls for any additional factor (These criteria could be modified to indicate specific control for a second important factor.)
Exposure 1) Ascertainment of exposure a) secure record (e.g., surgical records)
b) structured interview where blind to case/control status
c) interview not blinded to case/control status
d) written self-report or medical record only e) no description 2) Same method of ascertainment for cases and controls a) yes
b) no 3) Nonresponse rate a) same rate for both groups
b) nonrespondents described c) rate different and no designation
823.e2
Contents lists available at ScienceDirect
Journal of the American Pharmacists Association journal homepage: www.japha.org
RESEARCH
Once-daily prolonged-release tacrolimus versus twice-daily tacrolimus in liver transplantation Bingsong Huang, Jun Liu, Jun Li, Paul M. Schroder, Maogen Chen, Ronghai Deng*, Suxiong Deng* a r t i c l e i n f o
a b s t r a c t
Article history: Received 25 February 2019 Accepted 2 August 2019 Available online 11 September 2019
Objective: For patients who have received a kidney transplant, studies have shown that oncedaily prolonged-release tacrolimus (TAC) has similar efficacy and safety to standard twicedaily dosing. The purpose of this study was to perform a meta-analysis to compare the effectiveness and safety of daily TAC (TAC qd) versus standard twice-daily TAC (TAC bid) administration in liver transplantation (LT). Design: Meta-analysis. Setting and participants: We systematically searched the PubMed/MEDLINE, Web of Science, and Cochrane Library databases for studies comparing outcomes of LT patients who received TAC qd versus TAC bid. Outcome measures: Results were reported as odds ratios (ORs) with 95% CIs. Results: Six studies, which included 5179 LT recipients (TAC qd ¼ 951; TAC bid ¼ 4228) were included in the analysis. The TAC qd group had a low 1-year graft loss rate (OR 0.70 [95% CI 0.54e0.91], P ¼ 0.008) and lower rate of biopsy-proven acute rejection (BPAR) at 90 days (OR 0.46 [95% CI 0.24e0.89], P ¼ 0.02) compared with the TAC bid group. There was no significant difference in 1-year mortality or the incidence of adverse events after LT between the 2 groups. Conclusions: Current evidence suggests that TAC qd is safe and effective for LT patients during the first year after transplantation. Longer-term follow-up studies are necessary to determine if TAC qd is safe and effective beyond the first year after LT. © 2019 Published by Elsevier Inc. on behalf of the American Pharmacists Association.
Background After organ transplantation, patients must follow a complex immunosuppression regimen with a large number of medications and frequent dosing intervals. Noncompliance with posttransplant immunosuppressive medications is an important cause of graft dysfunction and graft loss.1,2 A systematic review of the literature found that simpler, less-frequent dosing
Disclosure: The authors declare no relevant conflicts of interest or financial relationships. Funding: This work was in part supported by the National Natural Science Foundation of China (81770410 and 81401324), and the Scientific Program for Young teacher of Sun Yat-sen University (16ykpy05). Bingsong Huang, Jun Liu, and Jun Li contributed equally to this work and considered as co-first authors. * Correspondence: Ronghai Deng, MD, PhD, and Suxiong Deng, MD, PhD, Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan 2nd Road, Guangzhou 510080, China. E-mail addresses: [email protected] (R. Deng) and 1726695578@qq. com (S. Deng).
regimens resulted in better compliance.3 Tacrolimus (TAC) is a widely used immunosuppressant in organ transplantation, and the twice-a-day formulation (TAC bid; PROGRAFdAstellas Pharma US) has well-documented efficacy and safety profiles in patients who have received allogeneic kidney, liver, and heart transplantation.3 To minimize noncompliance in organ transplantation, a simpler dosing regimen, prolonged-release TAC (TAC qd; AdvagrafdAstellas Pharma Europe Ltd) was developed and licensed in Europe in 2007.4 The European Medicines Agency proposed that a once-daily dosing formulation of TAC with an immediate-release action might provide potential benefits for patients.5,6 A recent cost-effectiveness study showed that, compared with TAC bid, TAC qd would decrease cost to patients.7 In addition to improved medication compliance,8,9 some studies have shown that TAC qd has pharmacokinetic (PK), efficacy, and safety profiles comparable with TAC bid in kidney transplantation patients.10 In contrast, other randomized controlled trials (RCTs) of TAC qd in kidney transplantation have reported higher rates of rejection in patients receiving TAC qd.11 A recent retrospective study with a large number of liver transplanttion (LT) patients found that those
https://doi.org/10.1016/j.japh.2019.08.002 1544-3191/© 2019 Published by Elsevier Inc. on behalf of the American Pharmacists Association.
SCIENCE AND PRACTICE TAC versus TAC bid in liver transplantation
Key Points Background: Tacrolimus prolonged release is a new and simpler dosing immunosuppressant in organ transplanation. Findings: Tacrolimus prolonged release dosing is safe and effective in liver transplant.
receiving TAC qd had a higher rate of postoperative infections than those receiving TAC bid.4 There have also been reports that liver transplant recipients taking TAC qd have higher rates of TAC-related adverse events (AEs), such as infections, renal failure and impairment, headaches, and abnormal liver function tests.5,12,13 Because of these conflicting reports, Ho et al.14 conducted a systematic review of the 2 TAC dosing regimens in kidney transplant patients and concluded that the 2 regimens have similar efficacy and rates of complications at 12 months. To our knowledge, no systematic review has been performed examining the 2 TAC dosing regimens in LT patients. Thus, the purpose of the study was to perform a meta-analysis to compare the efficacy and safety of these 2 regimens in LT recipients. Methods Data sources and search methods We searched the PubMed/MEDLINE, Web of Science, and Cochrane Library databases using the terms “tacrolimus” OR “FK506” AND “liver transplant.” The search included all studies published up to March 2018. Only those reporting clinical results and outcomes of interest were reviewed for potential inclusion. Inclusion and exclusion criteria Criteria for inclusion in the meta-analysis were that (1) TAC was the primary immunosuppressant used in patients who received LT and (2) the outcomes of patients who received TAC qd versus TAC bid had been compared. Exclusion criteria were (1) lack of a control group (the study had only included patients who received TAC qd); (2) that the study purpose had been to examine conversion from TAC bid to TAC qd; (3) that the study purpose had been to evaluate the PK of TAC; and (4) studies in which patients who had received multiorgan transplants. Data extraction and quality assessment Outcomes of the meta-analysis were 1-year patient mortality and 1-year graft loss rates, and the rate of biopsy-proven acute rejection (BPAR) at 90 days. Postoperative complications were also compared and included the rate of postoperative renal disorders, the rate of new-onset diabetes after transplantation (NODAT), and infection rates.
The methodological quality of observational studies was assessed using the Newcastle-Ottawa Scale15 (Supplemental Table 1). “Selection,” “comparability,” and “outcome” are the 3 categories included in the Newcastle-Ottawa Scale for the assessment of cohort studies. Statistical analysis Odds ratios (ORs) and 95% CIs were used to evaluate event rates. Study heterogeneity was evaluated using the chi-square and I2 statistical tests; values of P < 0.05 or I2 > 50% were considered to indicate significant heterogeneity, and a random effects model of analysis was used. When significant heterogeneity was not present, a fixed effects model was used. Publication bias was assessed by funnel plot, and asymmetry may indicate the presence of bias. A value of P < 0.05 was considered to indicate a statistically significant difference between the 2 groups. Statistical analyses were performed with Review Manager (RevMan, version 5.3.5; The Nordic Cochrane Centre). Results Search results and study characteristics The Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram of the literature search results is shown in Figure 1. A total of 8910 articles were identified in the literature search, 2290 duplicates were removed, and 6439 were excluded after screening titles. The full texts of the remaining 181 articles were reviewed. Of these, 6 met the inclusion/exclusion criteria and were included in the meta-analysis. The 6 studies included 956 LT recipients who received TAC qd, and 4223 who received TAC bid. Study characteristics are summarized in Table 1. In addition, the Adjunct Regimen and Model for End-stage Liver Disease (MELD) score (the average score for patients) of each included study are shown in Table 1. MELD score was used to evaluate a patient’s clinical suitability for LT. MELD score was calculated as: 9.57 loge(creatinine) þ 3.78 Loge(total bilirubin) þ 11.2 *loge(international normalized ratio) þ 6.43).16 Funnel plot analysis indicated that there was no obvious publication bias present among the included studies (Supplemental Figure 1Ae1F). One-year mortality Five studies17-20 reported 1-year mortality or survival rates (935 patients were treated with TAC qd and 4214 LT with TAC bid). No significant heterogeneity was identified among the studies (c2 ¼ 1.73, P ¼ 0.79, I2 ¼ 0%). The combined 1-year mortality rate was 7.59% for the TAC qd group and 8.90% for the TAC bid group. The OR for 1-year mortality of the TAC qd group compared with the TAC bid group was 0.89 (95% CI 0.67e1.18, P ¼ 0.43), indicating there was no difference in 1-year mortality between the groups (Figure 2). Graft loss rate Four studies17,18,20,21 reported data of graft loss at 1 year (875 patients were treated with TAC qd and 4186 with TAC bid). No heterogeneity was detected among the studies (c2 ¼ 2.26, P ¼ 0.52, I2 ¼ 0%). Patients treated with TAC qd had 817
SCIENCE AND PRACTICE
Identification
B. Huang et al. / Journal of the American Pharmacists Association 59 (2019) 816e823
Potentially relevant studies identified by primary search (n=8910)
Included
Eligibility
Screening
Duplicates removed (n=2290)
Studies retrieved for more detailed evaluation (n=6620)
Potentially appropriate studies to be included in the analysis (n=181)
Studies excluded after title review (n=6439) 4588 not relevant to tacrolimus research 1409 involved patients without LT(not relevant to transplantation research) 266 basic science articles on tacrolimus 109 focused on conversion from TAC BID to TAC QD 33 reviews or commentaries 22 focused on clinical reports 12 pediatric research
Studies excluded after abstract and full-text review (n=175) 75 had no control group 34 pharmacokinetics research 25 involved multi-organ transplant 23 focused on conversion from TAC BID to TAC QD 10 no data available 8 not relevant to tacrolimus research
Studies included (n=6) 4 observational and 2 randomized controlled studies
Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram showing literature search results.
significantly better 1-year graft survival (OR 0.70 [95% CI 0.54e0.91], P ¼ 0.008) than those treated with TAC bid (Figure 3). BPAR Five studies17-20,22 included data of BPAR (368 patients were treated with TAC qd and 333 with TAC bid). The combined BPAR rate (no time interval limited) was 27.9% (range: 13.3%e36.3%) for the TAC qd group, and 31.8% (26.9%e50.0%) for the TAC bid group. No significant heterogeneity was observed among the studies (c2 ¼ 6.29, P ¼ 0.18, I2 ¼ 36%); OR 0.76 (95% CI 0.47e1.22, P ¼ 0.26), indicating no difference in BPAR between the groups (Figure 4). Three studies reported the BPAR rate at 90 days after transplant (124 patients were treated with TAC qd and 88 with TAC bid). No significant heterogeneity was found (c2 ¼ 1.38, P ¼ 0.50, I2 ¼ 0%). Analysis indicated that the TAC qd group had a significantly lower 90-day BPAR rate than the TAC bid group (0.46 [95% CI 0.24e0.89], P ¼ 0.02) (Figure 5).
study reported renal conditions in a different way, such as renal insufficiency, renal impairment, development of chronic kidney disease, renal failure, or acute kidney injury. Thus, we classified all these events as 1 category, renal disorders. No heterogeneity was detected among the studies (c2 ¼ 3.33, P ¼ 0.34, I2 ¼ 10%). The rate of renal disorders was similar between the groups (OR 1.37 [95% CI 0.98e1.91], P ¼ 0.07) (Figure 6). NODAT Three studies17-19 reported the incidence of NODAT (359 patients received TAC qd and 329 TAC bid). No heterogeneity was detected (c2 ¼ 0.56, P ¼ 0.76, I2 ¼ 0%). The rate of NODAT was similar between the groups (OR 0.88 [95% CI 0.60e1.29], P ¼ 0.53) (Figure 7). Infections Four studies17,19,20,22 reported infection rates after transplantation (361 patients received TAC qd and 322 TAC bid). No heterogeneity was detected (c2 ¼ 5.69, P ¼ 0.13, I2 ¼ 47%). The infection rates were similar between the 2 groups (OR 0.81 [95% CI 0.41e1.62], P ¼ 0.55) (Figure 8).
Postoperative complications Discussion Renal disorders Four studies17-20 reported AEs related to impaired renal function (407 patients received TAC qd and 375 TAC bid). Each
818
In this systematic review and meta-analysis, we compared the outcomes of patients who received TAC qd with those who
SCIENCE AND PRACTICE
19.0 ± 6.9 20.3 ± 8.4 5 50.0 ± 13.9 52.1 ± 11.4 2005e2015 CS, MMF 28 60
2008e2012 3839
Okumura et al.20 (2017)
Adam et al.4 (2015)
European Liver Transplant Registry (ELTR) Japan
528
CS, MMF
2006e2010 2010e2012 CS, MMF, mAb CS, MMF, AZA mAb 14 46 16 48 Marubashi et al.22 (2012) Dannhorn et al.20 (2014)
Fischer et al.18 (2011):
Abbreviations: AZA, azathioprine; CS, corticosteroid; mAb, basiliximab; MELD, Model for End-Stage Liver Disease; MMF, mycophenolate mofetil; NS, nonsignificant difference; trial;A, Jadad score. * P < 0.05.
5 52.1
5 5
52.4 (27e68) 45.5 ± 14.9 49 (38e56)
49.4 (24e65) 55.3 ± 7.9 58 (50e61)* 49.6 2003e2004 CS, MM, AZA 62 67
52.7 52.8 2004e2006 CS, MMF 234
5A
:
, random controlled, double-blind
29
21.8 ± 10.4 15 (10e18.5) 27.8
NS
NS
TAC qd TAC qd
237
Europe, Brazil, Canada, etc. Europe, Canada, Australia Japan United Kingdom Trune cka et al.17 (2010):
Recipient age References
Table 1 Characteristics of included trials
Institute
Sample size
TAC bid
Adjunct regimen
Study periods
TAC qd
TAC bid
5A
NOS star level
MELD score
TAC bid
20.1 ± 6.7 13 (9e19)
TAC versus TAC bid in liver transplantation
received TAC bid after LT. Six studies with 5179 patients were included in the meta-analysis. The graft loss rate and BPAR rate at 90 days after transplantation were significantly lower in the TAC qd group, whereas other end points including 1year mortality, and the rates of infection, NODAT, and renal disorders were not different between the groups. To our knowledge, this is the first comprehensive analysis on this topic and therefore provides important insight into the clinical use of TAC qd in LT patients. Improvement in LT outcomes is largely because of the development of effective immunosuppressants.21 TAC is the primary drug used for immunosuppression in LT patients, but nonadherence and high variability of exposure impedes the recovery of recipients after transplantation. A once-a-day formulation of TAC (TAC qd; Advagraf) has been approved for clinical use in many countries since 2007. Many studies of TAC qd after LT have confirmed that it is safe and effective with a low rate of acute rejection episodes and excellent short-term graft and patient survival,13,23,24 as well as in long-term follow-up.25,26 Studies have also suggested that TAC can safely be converted from the twice-daily to once-daily administration, with an increase in patient compliance.6,27-31 However, studies comparing the initiation of TAC dosing at TAC qd with traditional TAC bid dosing in LT are lacking. A randomized, double-blind study showed that TAC qd was well tolerated with similar patient survival, graft survival, and AEs compared with TAC bid.17 Recently, a large retrospective analysis from the European Liver Transplant Registry showed significant improvements in long-term graft and patient survivals (3-year follow-up) in patients treated with TAC qd versus TAC bid.4 Furthermore, it is known that a low variability in TAC exposure is important for graft and patient survival. Studies of the conversion from TAC bid to TAC qd have shown that TAC qd reduces intrapatient and interpatient variability and has a more coherent PK profile.32,33 Studies in healthy volunteers34,35 showed that TAC qd had similar exposure and trough levels as TAC bid, but with a reduced peak level. All 6 studies included in this meta-analysis provided a TAC PK analysis. Ficher et al.18 and Okumura et al.19 reported that TAC mean whole-blood trough levels were lower in the TAC qd group than in TAC bid the first day after LT and were similar for both formulations at other time points. Dannhorn et al.20 measured TAC levels at days 5, 10, 14, and 30, and at 1 year, after LT, and showed no differences at any time point between the 2 formulations. Marubashi et al.22 reported that TAC trough levels were similar between TAC qd and TAC bid, except on postoperative days 7 and 90 when trough levels were lower in the TAC qd group. Thus, to achieve similar TAC exposure, the initial dose of TAC qd needs to be higher. The reasons for differences in absorption between the 2 TAC formulations during the early posttransplant period are not yet fully understood. TAC is characterized by a narrow therapeutic window and highly variable PK profile, which necessitate therapeutic drug monitoring to individualize the dosing regimen and prevent rejection and toxicity.36 Nephrotoxicity remains a major limitation of TAC and other calcineurin inhibitors.37 Renal dysfunction after LT is a major problem,38-40 and renal insufficiency is strongly associated with an increased risk of
819
SCIENCE AND PRACTICE B. Huang et al. / Journal of the American Pharmacists Association 59 (2019) 816e823
Figure 2. Patient mortality at 1 year.
Figure 3. Graft loss at 1 year.
Figure 4. Biopsy-proven acute rejection (BPAR) rates.
Figure 5. Biopsy-proven acute rejection (BPAR) rates at 90 days.
820
SCIENCE AND PRACTICE TAC versus TAC bid in liver transplantation
Figure 6. Renal disorders postoperatively.
death 1 year or more after LT.41 In studies of conversion from TAC bid to TAC qd, some researchers have reported improvements in renal function after conversion to TAC qd in renal transplant recipients.42,43 However, a multicenter study in which kidney transplant patients were switched from TAC bid to TAC qd showed no changes in renal function.12 In an observational, multicenter study of TAC qd, renal function was well maintained and consistent with conventional TAC dosing in LT recipients.4 Zaltzman et al.34 reported that, compared with TAC bid, TAC qd has a reduced Cmax and only a single peak. Thus, renal perfusion is greater with TAC qd.34 However, Dannhorn et al.20 reported that acute kidney injury after LT was more frequent in patients receiving TAC qd than TAC bid (45% and 23%, respectively), although this difference did not reach statistical significance.20 Our analysis indicated no difference in renal dysfunction between the 2 dosing regimens. NODAT, previously referred to as posttransplantation diabetes, is a frequent complication in solid organ transplant recipients. Development of NODAT after LT has been associated with increased risk of mortality and posttransplant infections and has negative effects on graft function.44 The incidence of NODAT has been reported to range from 5% to 50%, and TAC is an independent risk factor for NODAT.45-48 In addition, some systematic reviews have suggested that NODAT occurs more frequently with TAC than with cyclosporine. A study that included both liver and kidney transplant recipients reported no difference in the NODAT rate between the TAC qd and TAC bid.49 In our analysis, NODAT rates were similar between the 2 formulations, which is consistent with that reported in kidney transplantation.14 A retrospective study observed that a lower serum level of TAC was better at preventing infections.50 According to the TAC PK profiles reported by the studies included in this metaanalysis, there were no significant differences between TAC levels of the 2 formulations at all time points. The infection
rates were also similar between the 2 formulations in our analysis. A study of kidney transplant patients showed similar rates of viral infections, but a lower rate of bacterial infections in the TAC qd group.14 As with any retrospective meta-analysis, there are some limitations that need to be considered when interpreting the results. First, most studies included were retrospective, observational studies. All but 2 of the studies had small numbers of patients, which might have precluded an accurate assessment of heterogeneity. It is well known that donor factors such as preoperative medical conditions, age, cold and warm ischemia times, and donation type have a great impact on the postoperative outcomes of LT recipients. Particularly, donation after cardiac death is associated with worse longterm outcomes, with an increase in biliary complications, ischemic cholangiopathy, graft loss, and mortality compared with donation after brain death.51 Half of the included studies in this meta-analysis did not provide donor information, which may represent a confounding variable that could influence the mortality rate. Another limitation to this study is that the follow-up time was short (1 year), and thus might not be representative of long-term outcomes. All 6 studies reported PK analysis results; however, only 1 study reported numeric results, while the other studies reported results in graphic form without exact numeric results. Finally, some studies had no baseline data available, such as MELD score, which again could be a confounding variable that would influence the outcomes. This meta-analysis showed that TAC qd was associated with a lower 1-year graft loss rate and a lower BPAR rate at 90 days postoperatively in LT recipients compared with TAC bid. Because the PK profile of TAC qd is similar to that of TAC bid, the incidence of AEs is comparable between the 2 formulations. These results suggest that TAC qd is safe and effective for LT patients for at least for the first year after
Figure 7. New-onset diabetes after transplantation (NODAT).
821
SCIENCE AND PRACTICE B. Huang et al. / Journal of the American Pharmacists Association 59 (2019) 816e823
Figure 8. Infections postoperatively.
transplantation. However, further RCTs with larger sample sizes and long-term follow-up are needed to provide more robust evidence to determine guidelines for the use of TAC qd in LT recipients. References 1. Berlakovich GA, Langer F, Freundorfer E, et al. General compliance after liver transplantation for alcoholic cirrhosis. Transpl Int. 2000;13(2): 129e135. 2. Stuber ML, Shemesh E, Seacord D, Washington 3rd J, Hellemann G, McDiarmid S. Evaluating non-adherence to immunosuppressant medications in pediatric liver transplant recipients. Pediatr Transplant. 2008;12(3):284e288. 3. Claxton AJ, Cramer J, Pierce C. A systematic review of the associations between dose regimens and medication compliance. Clin Ther. 2001;23(8):1296e1310. 4. Adam R, Karam V, Delvart V, et al. Improved survival in liver transplant recipients receiving prolonged-release tacrolimus in the European Liver Transplant Registry. Am J Transplant. 2015;15(5):1267e1282. 5. Barraclough KA, Isbel NM, Johnson DW, Campbell SB, Staatz CE. Onceversus twice-daily tacrolimus: are the formulations truly equivalent? Drugs. 2011;71(12):1561e1577. 6. Florman S, Alloway R, Kalayoglu M, et al. Once-daily tacrolimus extended release formulation: experience at 2 years postconversion from a Prograf-based regimen in stable liver transplant recipients. Transplantation. 2007;83(12):1639e1642. 7. Muduma G, Odeyemi I, Pollock RF. Evaluating the cost-effectiveness of prolonged-release tacrolimus relative to immediate-release tacrolimus in liver transplant patients based on data from routine clinical practice. Drugs Real World Outcomes. 2016;3(1):61e68. 8. Beckebaum S, Iacob S, Sweid D, et al. Efficacy, safety, and immunosuppressant adherence in stable liver transplant patients converted from a twice-daily tacrolimus-based regimen to once-daily tacrolimus extended-release formulation. Transpl Int. 2011;24(7):666e675. 9. de Mare-Bredemeijer EL, Metselaar HJ. Optimization of the use of calcineurin inhibitors in liver transplantation. Best Pract Res Clin Gastroenterol. 2012;26(1):85e95. 10. Silva Jr HT, Yang HC, Abouljoud M, et al. One-year results with extendedrelease tacrolimus/MMF, tacrolimus/MMF and cyclosporine/MMF in de novo kidney transplant recipients. Am J Transplant. 2007;7(3):595e608. €mer BK, Charpentier B, B€ 11. Kra ackman L, et al. Tacrolimus Prolonged Release Renal Study Group. Tacrolimus once daily (ADVAGRAF) versus twice daily (PROGRAF) in de novo renal transplantation: a randomized phase III study. Am J Transplant. 2010;10(12):2632e2643. 12. Guirado L, Cantarell C, Franco A, et al. GREAT Study Group. Efficacy and safety of conversion from twice-daily to once-daily tacrolimus in a large cohort of stable kidney transplant recipients. Am J Transplant. 2011;11(9):1965e1971. 13. Uemoto S, Abe R, Horike H, So M. Safety and efficacy of once-daily modified-release tacrolimus in liver transplant recipients: a multicenter postmarketing surveillance in Japan. Transplant Proc. 2014;46(3): 749e753. 14. Ho ET, Wong G, Craig JC, Chapman JR. Once-daily extended-release versus twice-daily standard-release tacrolimus in kidney transplant recipients: a systematic review. Transplantation. 2013;95(9):1120e1128. 15. Adam R, Karam V, Delvart V, et al. All contributing centers (www.eltr.org); European Liver and Intestine Transplant Association (ELITA). Evolution of indications and results of liver transplantation in Europe. A report from the European Liver Transplant Registry (ELTR). J Hepatol. 2012;57(3):675e688.
822
16. Marubashi S, Wada H, Kobayashi S, et al. Once-daily prolonged-release tacrolimus in de novo liver transplantation: a single center cohort study. Hepatogastroenterology. 2012;59(116):1184e1188. 17. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25(9):603e605. 18. Kamath PS, Kim WR, Advanced Liver Disease Study Group. The model for end-stage liver disease (MELD). Hepatology. 2007;45(3):797e805. 19. Trune cka P, Boillot O, Seehofer D, et al. Tacrolimus Prolonged Release Liver Study Group. Once-daily prolonged-release tacrolimus (ADVAGRAF) versus twice-daily tacrolimus (PROGRAF) in liver transplantation. Am J Transplant. 2010;10(10):2313e2323. 20. Fischer L, Trune cka P, Gridelli B, et al. Pharmacokinetics for once-daily versus twice-daily tacrolimus formulations in de novo liver transplantation: a randomized, open-label trial. Liver Transpl. 2011;17(2):167e177. 21. Okumura Y, Noda T, Eguchi H, et al. Short- and long-term outcomes of de novo liver transplant patients treated with once-daily prolonged-release tacrolimus. Transplant Direct. 2017;3(9):e207. 22. Dannhorn E, Cheung M, Rodrigues S, et al. De novo use of generic tacrolimus in liver transplantation - a single center experience with oneyr follow-up. Clin Transplant. 2014;28(12):1349e1357. L, et al. A prospective, multicenter study of 23. Charco R, Caralt M, Llado once-daily extended-release tacrolimus in de novo liver transplant recipients. Transplant Proc. 2011;43(3):718e723. 24. Ortiz de Urbina J, Valdivieso A, Matarranz A, et al. Advagraf de novo in liver transplantation: a single-center experience. Transplant Proc. 2011;43(3):724e725. 25. Gastaca M, Valdivieso A, Bustamante J, et al. Favorable longterm outcomes of liver transplant recipients treated de novo with once-daily tacrolimus: results of a single-center cohort. Liver Transpl. 2016;22(10): 1391e1400. 26. van Hooff JP, Alloway RR, Trune cka P, Mourad M. Four-year experience with tacrolimus once-daily prolonged release in patients from phase II conversion and de novo kidney, liver, and heart studies. Clin Transplant. 2011;25(1):E1eE12. €ckman L, Persson CA. An observational study evaluating tacrolimus 27. Ba dose, exposure, and medication adherence after conversion from twiceto once-daily tacrolimus in liver and kidney transplant recipients. Ann Transplant. 2014;19:138e144. 28. Wu YJ, Lin YH, Yong CC, et al. Safe one-to-one dosage conversion from twice-daily to once-daily tacrolimus in long-term stable recipients after liver transplantation. Ann Transplant. 2016;21:30e34. 29. Kim SH, Lee SD, Kim YK, Park SJ. Outcomes of early conversion from Prograf to generic tacrolimus in adult living donor liver transplant recipients. Transplant Proc. 2015;47(6):1915e1916. 30. Thorat A, Chou HS, Lee CF, et al. Effects of converting tacrolimus formulation from twice-daily to once-daily in liver transplantation recipients. BioMed Res Int. 2014;2014:265658. 31. Kim SH, Lee SD, Kim YK, Park SJ. Conversion of twice-daily to once-daily tacrolimus is safe in stable adult living donor liver transplant recipients. Hepatobiliary Pancreat Dis Int. 2015;14(4):374e379. 32. Florman S, Alloway R, Kalayoglu M, et al. Conversion of stable liver transplant recipients from a twice-daily Prograf-based regimen to a once-daily modified release tacrolimus-based regimen. Transplant Proc. 2005;37(2):1211e1213. ko-Resmer J, Boillot O, Wolf P, Thorburn D. Renal function, efficacy 33. San and safety postconversion from twice- to once-daily tacrolimus in stable liver recipients: an open-label multicenter study. Transpl Int. 2012;25(3): 283e293. 34. Zaltzman JS, Lai V, Schulz MZ, Moon KH, Cherney DZ. A randomized cross-over comparison of short-term exposure of once-daily extended release tacrolimus and twice-daily tacrolimus on renal function in healthy volunteers. Transpl Int. 2014;27(12):1294e1302.
SCIENCE AND PRACTICE TAC versus TAC bid in liver transplantation
35. Park K, Kim YS, Kwon KI, Park MS, Lee YJ, Kim KH. A randomized, openlabel, two-period, crossover bioavailability study of two oral formulations of tacrolimus in healthy Korean adults. Clin Ther. 2007;29(1): 154e162. 36. Beckebaum S, Cicinnati VR, Radtke A, Kabar I. Calcineurin inhibitors in liver transplantation - still champions or threatened by serious competitors? Liver Int. 2013;33(5):656e665. 37. Ojo AO, Held PJ, Port FK, et al. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med. 2003;349(10):931e940. 38. Bahirwani R, Reddy KR. Outcomes after liver transplantation: chronic kidney disease. Liver Transpl. 2009;15(suppl 2):S70eS74. 39. Karie-Guigues S, Janus N, Saliba F, et al. Long-term renal function in liver transplant recipients and impact of immunosuppressive regimens (calcineurin inhibitors alone or in combination with mycophenolate mofetil): the TRY study. Liver Transpl. 2009;15(9):1083e1091. 40. Allen AM, Kim WR, Therneau TM, Larson JJ, Heimbach JK, Rule AD. Chronic kidney disease and associated mortality after liver transplantation–a time-dependent analysis using measured glomerular filtration rate. J Hepatol. 2014;61(2):286e292. 41. Watt KD, Pedersen RA, Kremers WK, Heimbach JK, Charlton MR. Evolution of causes and risk factors for mortality post-liver transplant: results of the NIDDK long-term follow-up study. Am J Transplant. 2010;10(6): 1420e1427. 42. Kolonko A, Chudek J, Wiecek A. Improved kidney graft function after conversion from twice daily tacrolimus to a once daily prolonged-release formulation. Transplant Proc. 2011;43(8):2950e2953. 43. Tinti F, Meçule A, Poli L, et al. Improvement of graft function after conversion to once daily tacrolimus of stable kidney transplant patients. Transplant Proc. 2010;42(10):4047e4048. 44. Baid S, Cosimi AB, Farrell ML, et al. Posttransplant diabetes mellitus in liver transplant recipients: risk factors, temporal relationship with hepatitis C virus allograft hepatitis, and impact on mortality. Transplantation. 2001;72(6):1066e1072. 45. Kuo HT, Sampaio MS, Ye X, Reddy P, Martin P, Bunnapradist S. Risk factors for new-onset diabetes mellitus in adult liver transplant recipients, an analysis of the Organ Procurement and Transplant Network/ United Network for Organ Sharing database. Transplantation. 2010;89(9): 1134e1140. 46. Davidson J, Wilkinson A, Dantal J, et al, International Expert Panel. Newonset diabetes after transplantation: 2003 International consensus
47.
48. 49.
50.
51.
guidelines. Proceedings of an international expert panel meeting. Barcelona, Spain, 19 February 2003. Transplantation. 2003;75(10 Suppl): SS3eSS24. Heisel O, Heisel R, Balshaw R, Keown P. New onset diabetes mellitus in patients receiving calcineurin inhibitors: a systematic review and metaanalysis. Am J Transplant. 2004;4(4):583e595. Bodziak KA, Hricik DE. New-onset diabetes mellitus after solid organ transplantation. Transpl Int. 2009;22(5):519e530. First MR, Dhadda S, Croy R, Holman J, Fitzsimmons WE. New-onset diabetes after transplantation (NODAT): an evaluation of definitions in clinical trials. Transplantation. 2013;96(1):58e64. Nacif LS, David AI, Pinheiro RS, et al. An analysis of tacrolimus-related complications in the first 30 days after liver transplantation. Clinics (Sao Paulo). 2014;69(11):745e749. O'Neill S, Roebuck A, Khoo E, Wigmore SJ, Harrison EM. A meta-analysis and meta-regression of outcomes including biliary complications in donation after cardiac death liver transplantation. Transpl Int. 2014;27(11):1159e1174.
Bingsong Huang, MD, PhD, intern, Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Neurosurgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China Jun Li, MD, PhD, Associate Chief Physician, Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China Jun Liu, MD, Associate Chief Physician, Department of Respiratory, the First People’s Hospital affiliated to Guangzhou Medical University, Guangzhou, China Paul M. Schroder, MD, PhD, Attending Physician, Department of Surgery, Duke University Medical Center, Durham, NC Maogen Chen, MD, PhD, Associate Chief Physician, Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China Ronghai Deng, MD, PhD, Associate Chief Physician, Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China Suxiong Deng, MD, PhD, Chief Physician, Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
823
SCIENCE AND PRACTICE B. Huang et al. / Journal of the American Pharmacists Association 59 (2019) 816e823
Appendix
Supplemental Figure 1. Funnel plot for results. (A) Patient mortality at 1 year. (B) Graft loss at 1 year. (C) Biopsy-proven acute rejection (BPAR) rates. (D) Renal disorders postoperatively. (E) New-onset diabetes after transplantation (NODAT) postoperatively. (F) Infections postoperatively.
823.e1
SCIENCE AND PRACTICE TAC versus TAC bid in liver transplantation
Supplemental Table 1 The Newcastle-Ottawa Quality Assessment Scale Note: A study can be awarded a maximum of 1 star for each numbered item within the Selection and Exposure categories. A maximum of 2 stars can be given for comparability. Selection 1) Is the case definition adequate? a) yes, with independent validation
b) yes, e.g., record linkage or based on self-reports c) no description 2) Representativeness of the cases a) consecutive or obviously representative series of cases
b) potential for selection biases or not stated 3) Selection of controls a) community controls
b) hospital controls c) no description 4) Definition of controls a) no history of disease (endpoint)
b) no description of source Comparability 1) Comparability of cases and controls on the basis of the design or analysis a) study controls for _______________ (Select the most important factor.)
b) study controls for any additional factor (These criteria could be modified to indicate specific control for a second important factor.)
Exposure 1) Ascertainment of exposure a) secure record (e.g., surgical records)
b) structured interview where blind to case/control status
c) interview not blinded to case/control status
d) written self-report or medical record only e) no description 2) Same method of ascertainment for cases and controls a) yes
b) no 3) Nonresponse rate a) same rate for both groups
b) nonrespondents described c) rate different and no designation
823.e2