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29 December 2021: Meta-Analysis

Efficacy and Safety of Tacrolimus-Based Maintenance Regimens in De Novo Kidney Transplant Recipients: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials

T A Manjunatha 1ABCDEF* , Rebecca Chng 1ABCDEF , Wai-Ping Yau 2ADE

DOI: 10.12659/AOT.933588

Ann Transplant 2021; 26:e933588

Table 3 Rejection outcomes: acute rejection and biopsy-proven acute rejection among all included studies in which 1 or more of the treatment arms used Advagraf or Prograf.

StudyDefinition of rejectionPopulationTime pointTreatment armsNRejection typeMetricRejection, nRejection, %
Albano 2013A kidney biopsy was performed before initiation of antirejection therapy if clinical and/or laboratory signs indicated rejection and was evaluated by a local histopathologist following Banff 1997 criteriaFAS6 monthsTAC BID+MPA+CS309BPARFrequency4213.6
FAS6 monthsTAC QD_0.20+MPA+CS302BPARFrequency3110.3
FAS6 monthsTAC QD_0.30+MPA+CS304BPARFrequency4916.1
FAS6 monthsTAC QD_0.20+MPA+CS (+BAS)283BPARFrequency3612.7
Arns 2017ITT6 monthsTAC BID (TacHexal)+MPA+CS35BPARFrequency25.7
ITT6 monthsTAC BID (Prograf)+MPA+CS38BPARFrequency37.9
Arriola 2018 (CA)ITT12 monthsTAC BID+MPA+SRL+CS55ARFrequency12.7
ITT12 monthsTAC QD+MPA+EVR+CS52ARFrequency11.5
ITT72 monthsTAC BID+MPA+SRL+CS55ARFrequency16.6
ITT72 monthsTAC QD+MPA+EVR+CS52ARFrequency15.3
Asher 2014ITT12 monthsSRL QD+MPA+CS19BPARFrequency526.3
ITT12 monthsTAC BID+MPA+CS19BPARFrequency210.5
Bakr 2018All episodes of rejection were verified by biopsy and graded using the Banff 2011 working classificationITT12 monthsTAC BID+MPA+CS66BPARFrequency1116.7
ITT12 monthsTAC QD+MPA+CS33BPARFrequency515.2
Chen 2008AR was suspected when >30% increase in serum Cr was noted. Graft biopsy was performed in every patient with suspected ARITT12 monthsCsA BID+SRL QD+CS20BPAR Banff IAFrequency15.0
ITT12 monthsTAC BID+SRL QD+CS21BPAR Banff IAFrequency14.8
Cockfield 2019TCMR including borderline changes using Banff 2007 criteriaITT24 monthsTAC QD_Low+ ACEi/ARB71TCMRFrequency1419.8
ITT24 monthsTAC QD_Low+OAH69TCMRFrequency2739.6
ITT24 monthsTAC QD_Std+ACEi/ARB71TCMRFrequency1724.2
ITT24 monthsTAC QD_Std+OAH70TCMRFrequency1216.5
ITT6 monthsTAC QD_Low+ACEi/ARB71TCMRFrequency2332.1
ITT6 monthsTAC QD_Low+OAH69TCMRFrequency3956.2
ITT6 monthsTAC QD_Std+ACEi/ARB71TCMRFrequency2129.6
ITT6 monthsTAC QD_Std+OAH70TCMRFrequency2434.0
De Graav 2017Total BPAR, scored as part of routine clinical care by a renal pathologist per the Banff 2015 classification. Incidence of the first rejection episodeITT12 monthsMPA+CS20BPARFrequency1155.0
ITT12 monthsTAC BID+MPA+CS20BPARFrequency210.0
Demirbas 2009Excluding patients with borderline BPAR valuesGermany (ITT)12 monthsSRL QD+MPA+CS296BPARFrequency54.2
Germany (ITT)12 monthsTAC BID+MPA+CS296BPARFrequency21.0
Germany (ITT)12 monthsCsA BID_Std+MPA+CS296BPARFrequency26.6
Germany (ITT)12 monthsCsA BID_Low+MPA+CS296BPARFrequency27.2
Overall (ITT)12 monthsSRL QD+MPA+CS1589BPARFrequency37.2
Overall (ITT)12 monthsTAC BID+MPA+CS1589BPARFrequency12.3
Overall (ITT)12 monthsCsA BID_Std+MPA+CS1589BPARFrequency25.8
Overall (ITT)12 monthsCsA BID_Low+MPA+CS1589BPARFrequency24.0
Spain (ITT)12 monthsSRL QD+MPA+CS269BPARFrequency23.7
Spain (ITT)12 monthsTAC BID+MPA+CS269BPARFrequency8.4
Spain (ITT)12 monthsCsA BID_Std+MPA+CS269BPARFrequency20.1
Spain (ITT)12 monthsCsA BID_Low+MPA+CS269BPARFrequency16.5
Turkey (ITT)12 monthsSRL QD+MPA+CS246BPARFrequency19.4
Turkey (ITT)12 monthsTAC BID+MPA+CS246BPARFrequency6.7
Turkey (ITT)12 monthsCsA BID_Std+MPA+CS246BPARFrequency15.1
Turkey (ITT)12 monthsCsA BID_Low+MPA+CS246BPARFrequency19.8
Ferguson 2011Biopsy-proven and either clinically suspected for protocol-defined reasons or clinically suspected for other reasons and treatedITT12 monthsMPA+CS33BPARFrequency515.2
ITT12 monthsSRL QD+CS26BPARFrequency13.8
ITT12 monthsTAC BID+MPA+CS30BPARFrequency13.3
ITT6 monthsMPA+CS33BPARFrequency412.1
ITT6 monthsSRL QD+CS26BPARFrequency13.8
ITT6 monthsTAC BID+MPA+CS30BPARFrequency13.3
Frei 2010 (SP)BPAR excluding borderline episodes. Biopsies were assessed by local pathologists using the modified Banff criteria. Protocol recommended a biopsy in cases of clinically suspected acute allograft rejection, in the absence of medical contraindication, but there was no further specific guidance. KM estimatesITT12 monthsCsA BID_Std+MPA+CSBPARFrequency26
ITT12 monthsCsA BID_Low+MPA+CSBPARFrequency24
ITT12 monthsTAC BID_Low+MPA+CSBPARFrequency12
ITT12 monthsSRL QD_Low+MPA+CSBPARFrequency37
ITT6 monthsCsA BID_Std+MPA+CSBPARFrequency24
ITT6 monthsCsA BID_Low+MPA+CSBPARFrequency22
ITT6 monthsTAC BID_Low+MPA+CSBPARFrequency11
ITT6 monthsSRL QD_Low+MPA+CSBPARFrequency35
Gaston 2009Diagnosis of BPAR was confirmed histologically using the Banff 1997 classificationITT12 monthsCNI_Low+MPA_Controlled+CS243BPARFrequency156.2
ITT12 monthsCNI_Std+MPA_Controlled+CS237BPARFrequency239.7
ITT12 monthsCNI_Std+MPA_Fixed+CS240BPARFrequency239.6
Hamdy 2008Event biopsy carrie out in case of nephrotic range proteinuria or episodes of renal dysfunction (25% increase in Cr from baseline) for which histopathologic examination was performed according to Banff 1997ITT>24 monthsSRL QD+MPA+CS67BPARFrequency00
ITT>24 monthsTAC BID+SRL QD+CS65BPARFrequency00
Harland 2019Including transplant recipients lost to follow-up; BPAR defined as biopsy-proven acute (T or B cell) rejection, Banff grade ≥1 by local reviewFAS36 monthsTAC BID+BLES+CS44BPARFrequency1534.1
FAS36 monthsTAC BID+MPA+CS48BPARFrequency1735.4
FAS36 monthsBLES+MPA+CS46BPARFrequency2758.7
FAS6 monthsTAC BID+BLES+CS44BPARFrequency49.1
FAS6 monthsTAC BID+MPA+CS48BPARFrequency714.6
FAS6 monthsBLES+MPA+CS46BPARFrequency1941.3
Huh 2017Excluding borderlines values. Pathologist gathered pathology reports from participating centers and re-assessed the results using the Banff 1997 classification to confirm the diagnosis of BPARITT12 monthsTAC QD+MPA+CS75BPARFrequency1013.3
ITT12 monthsTAC QD+SRL QD+CS76BPARFrequency45.3
Kramer 2010aHistologically confirmed episode for which a Banff score of I (mild), II (moderate), or III (severe) was recorded. Banff criteria published in 1993 and 1995FAS12 monthsTAC BID153BPARFrequency4227.5
FAS12 monthsTAC BID+MPA151BPARFrequency4831.8
FAS12 monthsTAC BID+MPA+CS147BPARFrequency128.2
FAS0–6 monthsTAC BID153BPARFrequency4026.1
FAS0–6 monthsTAC BID+MPA151BPARFrequency4630.5
FAS0–6 monthsTAC BID+MPA+CS147BPARFrequency128.2
Kramer 2010bARs confirmed by local biopsy classified as BPARITT12 monthsTAC BID+MPA+CS336BPAR localFrequency5014.9
ITT12 monthsTAC QD+MPA+CS331BPAR localFrequency5917.8
PP12 monthsTAC BID+MPA+CS291BPAR localFrequency4916.8
PP12 monthsTAC QD+MPA+CS280BPAR localFrequency5921.1
Kramer 2012 (SP)Histologically confirmed episode for which a Banff score of I (mild), II (moderate), or III (severe) was recorded. Banff criteria published in 1993 and 1995ITT6–36 monthsTAC BID143BPARFrequency32.1
ITT6–36 monthsTAC BID+MPA139BPARFrequency32.2
ITT6–36 monthsTAC BID+MPA+CS139BPARFrequency42.9
Langer 2012ITT12 monthsTAC BID_1.5–3 ng/mL +EVR BID+CS107BPARFrequency2018.7
ITT12 monthsTAC BID_4–7 ng/mL+EVR BID+CS117BPARFrequency97.7
Liu 2015BPAR was classified according to the 1997–2007 update classification criteria by the local pathologistITT24 monthsCsA BID+MPA+CS36BPARFrequency25.6
ITT24 monthsTAC BID+MPA+CS36BPARFrequency38.3
Tsuchiya 2013BPAR excluding borderline cases, rejection or other pathologic findings were diagnosed according to the Banff 2007 criteriaITT12 monthsTAC BID+MPA+CS52BPARFrequency917.3
ITT12 monthsTAC QD+MPA+CS50BPARFrequency510.0
The terms BPAR and biopsy-confirmed acute rejection were used interchangeably. ACEi/ARB – angiotensin-converting enzyme inhibitor/angiotensin II receptor 1 blocker; AR – acute rejection; BID – twice daily; BLES – bleselumab; BPAR – biopsy-proven acute rejection; CA – conference abstract; CNI – calcineurin inhibitor; Cr – creatinine; CS – corticosteroid; CsA – cyclosporin A; EVR – everolimus; FAS – full analysis set; ITT – intention-to-treat; MPA – mycophenolic acid; OAH – other antihypertensive; PP – per-protocol; QD – once daily; SP – secondary publication; SRL – sirolimus; Std – standard dose; TAC – tacrolimus; TCMR – T cell-mediated rejection.

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Annals of Transplantation eISSN: 2329-0358
Annals of Transplantation eISSN: 2329-0358