Conversion From Immediate-Release Tacrolimus to Prolonged-Release Tacrolimus in Stable Heart Transplant Patients: A Retrospective Study Francisco González-Vílcheza,b,*, Juan F. Delgadoc, Jesús Palomod, Sonia Mirabete, Beatriz Díaz-Molinaf, Luis Almenarg, José M. Arizónh, Diego Rangel-Sousai, Félix Pérez-Villaj, Iris P. Garridok, Luis de la Fuentel, Manuel Gómez-Buenom, María L. Sanzn, and María G. Crespo-Leiroo a Registro Español de Transplante Cardiaco, Sección de Insuficiencia Cardiaca, Sociedad Española de Cardiología, Madrid, Spain; b Unidad de Transplante Cardiaco, Servicio de Cardiología, Hospital Universitario Marqués de Valdecilla, Santander, Spain; cHospital Universitario 12 de Octubre, CIBERCV, UCM, Madrid, Spain; dHospital Universitario Gregorio Marañón, Madrid, Spain; eHospital Santa Creu I Sant Pau, Barcelona, Spain; fHospital Universitario Central de Asturias, Oviedo, Spain; gHospital Universitario y Politécnico La Fe, Valencia, Spain; hHospital Universitario Reina Sofía, Córdoba, Spain; iHospital Universitario Virgen del Rocío, Seville, Spain; jHospital Clínic i Provincial, Barcelona, Spain; kHospital Universitario Virgen de la Arrixaca, Murcia, Spain; lHospital Universitario Clínico de Valladolid, CIBERCV, Valladolid, Spain; mHospital Universitario Puerta de Hierro, Majadahonda, Madrid, Spain; nHospital Universitario Miguel Servet, Zaragoza, Spain; and oUnidad de Insuficiencia Cardiaca Avanzada y Transplante Cardiaco, Servicio de Cardiologia, Instituto de Investigación Biomédica de A Corunea (INIBIC), Complexo Hospitalario Universitario de A Corunea (CHUAC), Sergas, Universidade da Corunea (UDC), CIBERCV, As Xubias, A Corunea, Spain ABSTRACT Background. Lifelong adherence with post-transplant immunosuppression is challenging, with nonadherence associated with greater acute rejection (AR) risk. Methods. This retrospective study evaluated conversion from immediate-release tacrolimus (IRT) to prolonged-release tacrolimus (PRT), between January 2008 and December 2012 in stable adult heart transplant recipients. Cumulative incidence rate (IR) of AR and infection pre- and postconversion, safety, tacrolimus dose and trough levels, concomitant immunosuppression, and PRT discontinuation were analyzed (intention-to-treat population). Results. Overall, 467 patients (mean age, 59.3 [SD, 13.3] years) converted to PRT at 5.1 (SD, 4.9) years post transplant and were followed for 3.4 (SD, 1.5) years. During the 6 months post conversion, 5 patients (1.1%; 95% CI, 0.35%e2.48%) had an AR episode and IR was 2.2/100 patient-years (95% CI, 0.91e5.26). Incidence of rejection preconversion varied by time from transplant to conversion. Infection IR was similar post- and preconversion (9.2/100 patient-years [95% CI, 7.4e11.3] vs 10.6/100 patient-years [95% CI, 8.8e12.3], respectively; P ¼ .20). Safety variables remained similar post conversion. The IR of mortality/graft loss was 2.3/100 patient-years (95% CI, 1.7e3.1). Declaration of Interest: Beatriz Díaz-Molina, Luis Almenar, José M. María G. Crespo-Leiro report grants from Astellas during the conduct Arizón, Diego Rangel-Sousa, Félix Pérez-Villa, Iris P. Garrido, Manuel of the study and cofinance from FEDER Funds. Gómez-Bueno, and María L. Sanz have no conflicts to disclose. Funding Sources: This study was sponsored by Astellas Pharma. Francisco Gonzalez-Vilchez reports other from Astellas during the Editorial assistance in the development of this manuscript was pro- conduct of the study and grants from Astellas outside the submitted vided by Cello Health MedErgy, funded by Astellas Pharma, Inc. work. Jesús Palomo reports personal fees from Astellas during the *Address correspondence to Dr Francisco González-Vílchez, conduct of the study. Sonia Mirabet reports other from Astellas during Servicio de Cardiología, Hospital Universitario Marqués de Val- the conduct of the study and nonfinancial support from Astellas and decilla, Avda. Valdecilla s/n, 39008 Santander, España. Tel: þ34 Novartis outside the submitted work. Luis de la Fuente reports other 699 446383; Fax: þ34 942 202761. E-mail: cargvf@gmail.com from Astellas during the conduct of the study. Juan F. Delgado and 0041-1345/19 ª 2019 The Authors. Published by Elsevier Inc. This is an open https://doi.org/10.1016/j.transproceed.2019.04.028 access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). 230 Park Avenue, New York, NY 10169 1994 Transplantation Proceedings, 51, 1994e2001 (2019) PROLONGED-RELEASED TACROLIMUS CONVERSION 1995 Conclusions. Conversion from IRT to PRT in heart transplant recipients in Spain was associated with no new safety concerns and appropriate immunosuppressive effectiveness. T ACROLIMUS is a well-established immunosuppressive agent for the prevention and treatment of allograft rejection. Two oral capsule formulations are currently between January 2008 and December 2012 were eligible to partici- pate in the study. Patients were followed up until June 2013; all study visits took place at the participating centers. All data were collected retrospectively from the centers’ registries in an electronic case report available. Prolonged-release tacrolimus (PRT), available in form. Data collection was performed by the investigator or the person Spain since 2007, is a once-daily formulation introduced as delegated to act on their behalf. The procedures used for assuring an alternative to twice-daily, immediate-release tacrolimus data quality were consistent with those reported for the Spanish (IRT). Previous studies have indicated that the area under Heart Transplantation Registry [24]. the concentrationetime curve of tacrolimus is approximately Tacrolimus daily dose and serum trough levels, concomitant 10% lower following conversion from IRT to PRT in kid- immunosuppression, concomitant medication, laboratory evalua- ney, liver, and heart recipients [1e3], and dose adjustments tion, and graft function were recorded at 6 months preconversion, may be required post conversion to achieve similar tacroli- at the time of conversion, and at 1, 6, 12, 24, 36, and 48 months post mus trough levels [4e6]. Simplifying transplant immuno- conversion. Occurrence of AR and infections was recorded from suppressive regimens is desirable, as patient adherence to a 2 years preconversion to the end of follow-up. Incidence and rea- sons for PRT discontinuation were recorded over the follow-up lifelong treatment remains challenging. This may be because period. of complex treatment regimens with multiple tablets and different frequencies of administration in addition to Variables and Endpoints adverse events (AEs). Nonadherence in transplant patients is especially important in the long term, where unsatisfac- No common strategy or specific protocol for rejection surveillance tory outcomes are observed [7e10]. Indeed, nonadherence is following PRT conversion was used across participating centers. increasingly recognized as an important and scarcely The primary endpoint was the cumulative incidence rate (IR) of AR at 6 months post conversion from IRT to PRT, defined as any reported cause of late acute rejection (AR), chronic rejec- episode of rejection determined by clinical suspicion, echocardio- tion, and graft loss [8,10e17]. Recent studies of converting gram, or biopsy that caused an intensification of immunosuppres- solid organ transplant recipients to PRT [18e21] suggest sive treatment. AR episodes separated by 15 days after the that once-daily dosing improves adherence vs twice-daily treatment of the preceding event were considered independent, in dosing [18e22]. line with recommendations from the Spanish Heart Transplant While many heart recipients in Spain have converted to Groups Consensus Conference [25]. PRT, the outcomes and safety of this conversion have not Secondary variables, including the incidence of biopsy-confirmed been evaluated. This retrospective observational study AR and infection, were compared before and after conversion from explored the conversion from IRT to PRT in the largest IRT to PRT. Infection was defined as any episode requiring intra- series of stable heart transplant patients to date, with the venous antibiotic therapy, hospital admission, or specific therapy for opportunistic infections (eg, tuberculosis). Safety analyses included primary aim to analyze AR episodes and infections, which the incidence of diabetes, and renal dysfunctioneas renal dysfunc- are associated with tacrolimus under- and over- tion has been associated with the use of calcineurin inhibitors [26] immunosuppression, respectively [23]. A secondary aim was and post-transplant diabetes mellitus has been reported in pa- to explore the dose and trough levels of tacrolimus, and tients receiving tacrolimus-based immunosuppression [27,28]. tolerability and safety after the conversion. Renal dysfunction was defined as a 25% increase in serum creati- nine at 2 consecutive determinations, in line with current consensus for the decrease in estimated glomerular filtration rate used to PATIENTS AND METHODS define chronic renal disease [29]. It was considered that an increase This multicenter, observational, retrospective study was carried out of <25% may be due to physiological variations in serum creatinine in 14 centers in Spain. The study was conducted according to the levels. At the end of the follow-up period, patient and graft survival, Declaration of Helsinki and was approved by the ethics committee and biopsy-confirmed AR, were also analyzed. of the University Hospital Marqués de Valdecilla (Santander, Spain). All current regulations for noninterventional studies, pa- Statistical Procedures tient and data protection, and the specific policy of each center or administrative region were applied. All patients provided written No formal sample size calculation was performed. Continuous informed consent for their data to be used. variables are summarized as mean (SD). Categorical variables are described as percentages. Differences in pre- and postconversion occurrence of AR and Patients and Procedures infection were assessed by comparing their respective IRs (number Adult patients (older than 18 years at the time of conversion) who of episodes per 100 patient-years on treatment) and by comparing had undergone heart transplant, received 6 months of continued the IR ratio using the preconversion period as reference. Because treatment with IRT (Prograf, Astellas Pharma Ltd, Chertsey, the incidence of rejection is influenced by the time elapsed since United Kingdom), and who underwent conversion to PRT transplant, differences between pre- and postconversion periods (Advagraf, Astellas Pharma Europe BV, Leiden, Netherlands) were analyzed in the whole study group and separately in 3 patient 1996 GONZÁLEZ-VÍLCHEZ, DELGADO, PALOMO ET AL Table 1. Patient Baseline and Preconversion Characteristics, tacrolimus trough level (preconversion) with IRT (8.93 [SD, Time of Conversion, and Donor Characteristics (N [ 467) 3.49] ng/mL) declined 1 month after conversion to PRT (7.86 Characteristic [SD, 2.86] ng/mL), and was 7.70 (SD, 2.91) ng/mL and 6.95 (SD, Age, mean (SD), y 59.3 (13.3) 2.53) ng/mL at months 6 and 48, respectively (Fig 1B). During Sex, male/female, % 68.5/31.5 the 48-month follow-up period, serum levels of PRT decreased Primary diagnosis of cardiopathy, % significantly vs preconversion levels (P < .01). Dilated 71.7 Ischemic 7.7 Concomitant Immunosuppression Others 20.6 Weight at baseline, mean (SD), kg 70.1 (14.5) Concomitant immunosuppression use is summarized in CMV serology positive, % 79.0 Table 2. The proportion of patients using mycophenolate Hypertension (n ¼ 454), % 60.4 mofetil and prednisone decreased between month 1 and Diabetes (n ¼ 454), % 29.1 month 48 post conversion. Use of mammalian target of Cerebrovascular accident, % 8.1 rapamycin inhibitors (largely everolimus and not sirolimus) Malignant neoplasm (n ¼ 32), % increased approximately 2-fold during follow-up. Cutaneous 56.3 Lymphoproliferative 12.5 Solid organ 34.4 Rejection and Infection History of heart failure, % 7.7 During the 6 months post conversion, 5 patients (1.1%; 95% Cardiac allograft vasculopathy, % 11.6 CI, 0.35%e2.48%) had an AR episode. The time-adjusted Cardiac rhythm (conversion visit) (n ¼ 463), % IR of AR 6 months after conversion was 2.19 (95% CI, Sinus rhythm 96.1 0.91e5.26) AR events per 100 patient-years, with a cumu- Atrial fibrillation 0.6 lative follow-up of 228.35 patient-years. Pacemaker 1.7 Other 1.5 In the 2 years before conversion (837.68 patient-years), there Time from transplant to conversion, mean (SD), y 5.1 (4.9) were 68 episodes of rejection in 48 patients. Thus, 10.3% of Conversion time post transplant, No. (%) patients had at least 1 rejection episode preconversion, with <2 y 119 (25.5) most (79.2%) of these patients experiencing 1 event. 2e4 y 82 (17.6) In the 2 years post conversion, with a cumulative follow-up 4 y 266 (57.0) of 891.56 patient-years, there were 18 rejection episodes. Donor age (n ¼ 466), mean (SD), y 34.7 (12.8) Fifteen patients (3.2%) presented with at least 1 rejection Donor sex, male/female (n ¼ 467), % 65.7/34.3 episode; 12 of these patients had 1 rejection episode, and 3 Abbrevation: CMV, cytomegalovirus. patients had 2 rejections. The 2-year preconversion rejection IR was 8.1 per 100 patient-years (95% CI, 6.4e10.3), and was 2.0 per 100 patient-years (95% CI, 1.3e3.2) in the 2-year subsets according to time from transplant to conversion (<2, 2e4, postconversion period (P < .0001) (Fig 2A). Therefore, the and 4 years). IR ratio of rejection (2 years post conversion:2 years pre- Significance level was established at P < .05, with no adjustment conversion) was 0.25 (95% CI, 0.14e0.42). This overall for multiplicity. The statistical package SPSS 17.0 (SPSS Inc., Chi- decrease was largely due to the decline in rejection IR among cago, Illinois) was used. patients converted <4 years post transplant, with no signifi- cant changes in those patients converted beyond 4 years post RESULTS transplant (Fig 2B). In the 2 years before conversion, 16 (23.5%), 50 (73.5%), and Overall, 467 heart recipients met eligibility criteria and were 15 (22.1%) rejection episodes were diagnosed based on clinical included in the study, and none were lost to follow-up; de- suspicion, biopsy, and echocardiogram, respectively (rejections mographic and clinical characteristics are summarized in could be diagnosed by more than 1 method). In the 2 years post Table 1. The mean time from transplant to conversion was 5.1 conversion, of the 18 rejection episodes, 16 (88.9%), 15 (SD, 4.9) years. Conversion from IRT to PRT was carried (83.3%), and 11 (61.1%) were diagnosed based on clinical out <2 years post transplant in 119 patients (25.5%), between suspicion, biopsy, and echocardiogram, respectively. Compared 2 and 4 years in 82 patients (17.6%), and 4 years after with the 2-year preconversion period, the 2-year postconversion transplant in 266 patients (57.0%). Patients were followed up period showed a trend toward a higher likelihood of a rejection after conversion for a mean of 3.4 (SD, 1.5) years. diagnosis being made by biopsy (73.5% vs 83.3%), a higher proportion of rejection episodes with hemodynamic compro- Tacrolimus Daily Dose and Serum Trough Levels mise (10.3% [n ¼ 7] vs 25.0% [n ¼ 4]), and a higher proportion The mean doses of IRT immediately preconversion and the of cytolytic therapy usage (4.4% [n ¼ 3] vs 11.1% [n ¼ 2]). initial dose of PRT at conversion were 3.84 (SD, 2.54) mg/d and Overall, there were 99 infection episodes in 82 patients in 3.97 (SD, 2.57) mg/d, respectively (P ¼ .27). Compared with the 2 years preconversion (infection rate 17.6%; IR, 10.6 preconversion values on IRT, mean PRT daily dose remained per 100 patient-years; 95% CI, 8.8e12.3) and 82 infections steady after 2 years had elapsed post conversion (Fig 1A). Mean in 67 patients in the 2-year postconversion period (IR, 9.2 PROLONGED-RELEASED TACROLIMUS CONVERSION 1997 A 7 6 Tacrolimus dose (mg/day) 5 4 3.9 3.8 3.9 3.9 4.0 3.8 3.6 3.6 3 2 1 0 Time (months) n= 467 467 281 425 419 387 323 247 B 14 Serum tacrolimus trough levels (ng/mL) 12 10 8 8.6 8.9 7.9 7.7 7.8 7.5 7.2 7.0 6 4 2 0 Fig 1. (A) Mean (SD) daily dose and (B) mean (SD) serum trough Time (months) levels of tacrolimus over the study period for all patients. Con- n= 460 465 281 424 415 383 321 246 version was at time point 0. per 100 patient-years; 95% CI, 7.4e11.3). The difference Safety Evaluation between the postconversion and preconversion IR was not Key safety findings among patients converted to PRT are statistically significant (IR ratio, 0.87; 95% CI, 0.64e1.17; summarized in Table 3. There were increases in leukocytes, P ¼ .17) (Fig 3). During the pre- and postconversion pe- hemoglobin, total cholesterol, low-density lipoprotein choles- riods, most infection episodes required hospitalization terol, body weight, systolic and diastolic blood pressure, and (82.8% vs 80.7%, respectively). the prevalence of nonsinus rhythm during follow-up. Cardiac 1998 GONZÁLEZ-VÍLCHEZ, DELGADO, PALOMO ET AL Table 2. Concomitant Immunosuppression Use in All Patients Defined According to Time From Conversion to Prolonged-Release Tacrolimus Immunosuppressive Agent, % Conversion Visit* 6 Mo (n ¼ 432) 12 Mo (n ¼ 434) 24 Mo (n ¼ 401) 36 Mo (n ¼ 341) 48 Mo (n ¼ 261) MMF 76.6 73.4 71.0 69.0 67.3 65.9 Mycophenolic acid 7.0 7.7 8.3 8.0 9.1 10.7 Prednisone 58.6 56.2 54.1 51.1 50.7 49.4 Azathioprine 5.4 5.1 5.1 5.0 5.3 4.6 Sirolimus 1.1 1.2 1.1 1.2 1.2 0.8 Everolimus 6.4 7.9 10.2 11.7 12.9 13.5 Information on immunosuppressive agent use in all patients was not available; therefore, denominators vary (n). Abbreviation: MMF, mycophenolate mofetil. *Because of missing data, n is: MMF, n ¼ 461; mycophenolic acid, n ¼ 444; prednisone, n ¼ 454; azathioprine, n ¼ 441; sirolimus, n ¼ 438; everolimus, n ¼ 437. and renal function, assessed by left ventricular ejection fraction transplant and conversion, the decrease in rejection IR was and serum creatinine levels, respectively, remained stable, and largely due to the decline in rejection IR among patients there was a decrease in glomerular filtration rate. The trends in converted <4 years post transplant, with no significant safety parameters were not considered clinically relevant. changes in those patients converted beyond 4 years post Between month 1 and month 24 post conversion, 6.5% of patients experienced renal dysfunction. The proportion of patients with diabetes in the preconversion period and 48 A months post conversion was similar (29.1% and 31.5%, 12 respectively). Incidence rate (per 100 patient-years) p<0.0001 PRT was discontinued in 33 patients (7.1%), who could 10 have more than 1 reason for discontinuation; in approxi- mately half of cases (n ¼ 15, 3.2% of the total study pop- 8 8.12 ulation), AEs were the reason for treatment discontinuation. Other reasons for discontinuation included 6 implementation of a calcineurin inhibitor-free regimen because of malignancy (8 patients, 1.7%), patients’ refusal 4 to take PRT (5 patients; 1.1%), inadequate tacrolimus serum trough levels (2 patients; 0.4%), renal failure (2 pa- 2 2.02 tients; 0.4%), AR (1 patient; 0.2%), and physician’s refusal to administer PRT (1 patient; 0.2%). 0 There were 34 deaths (7.3%) by the end of follow-up. Pre-conversion Post-conversion Causes of death were malignancy (10 patients; 2.1%), graft B vascular disease (6 patients; 1.3%), sudden death (6 patients; 2.8 p<0.001 p=0.002 p=0.665 1.3%), AR (4 patients; 0.9%), infection (1 patient; 0.2%), and “other” (7 patients; 1.5%). The IR of mortality/graft loss was 2.4 2.3 per 100 patient-years (95% CI, 1.7e3.1). 2.0 Incidence rate ratio DISCUSSION 1.6 To date, a small number of studies have explored the use of PRT immunosuppression in heart transplant recipients. As 1.2 these studies were small [5] or focused on pharmacokinetics 0.8 0.78 and drug dosage [1,4], data on the characteristics and results of tacrolimus conversion in cardiac recipients have not been 0.4 described. Our results from this large multicenter study 0.14 suggested that the rate of infection remained similar before 0.0 0.09 and after conversion from IRT to PRT. The incidence of <2 2–4 ≥4 AR was lower during the 48 months of follow-up post Time from transplant to conversion (years) conversion from IRT to PRT compared with the rates Fig 2. (A) Pre- and postconversion incidence rates of rejection within 2 years preconversion. However, the time since for all patients and (B) incidence rate ratio (post- to preconver- transplant was not accounted for in analyses of the overall sion) of rejection split by time from transplant to conversion cohort. Therefore, comparisons of rejection IR between from immediate- to prolonged-release tacrolimus (<2, 2e4, pre- and post conversion should be interpreted with caution. and 4 years). Bars represent the upper and lower limits of the Indeed, after stratifying our results by time between CI. IRT, immediate-release tacrolimus. PROLONGED-RELEASED TACROLIMUS CONVERSION 1999 14 during all study follow-up there was a higher proportion of p=0.17 rejection episodes with hemodynamic compromise, 12 although the cause for this is unclear. In our study, the PRT daily dose used at conversion was Incidence rate (per 100 patient-years) 10.6 only 0.13 mg higher than that used for IRT. Mean tacroli- 10 mus trough levels are approximately 10% lower immedi- 9.2 ately post conversion from IRT to PRT on a 1mg:1mg total 8 daily dose basis [1e3], and the reduction in trough levels may be greater in individual patients [2]. However, the 6 maintenance of target tacrolimus levels is manageable via trough level monitoring and dose adjustment [30]. Studies have shown that approximately 10% of kidney and liver 4 transplant patients converted from IRT to PRT on a 1mg:1mg total daily dose basis may require tacrolimus dose 2 adjustment [31,32]. In heart transplant patients, after con- version from IRT to PRT on day 8, Alloway et al reported 0 an increase of approximately 10% in tacrolimus dose by day Pre-conversion Post-conversion 35 to achieve tacrolimus trough levels within the range of 5 Fig 3. Pre- and postconversion incidence rates of infection for to 15 ng/mL [2]. Marzoa-Rivas et al report that a 25% in- all patients. Bars represent the upper and lower limits of the CI. crease in daily dose may be required to achieve the appro- IRT, immediate-release tacrolimus. priate trough levels immediately after conversion from IRT to PRT in heart transplant recipients [4]. Accordingly, in a transplant. As such, the reduction in rejection rates post recent study of heart transplant patients receiving de novo conversion may be due to greater time elapsed since PRT or IRT, a significantly higher daily dose of PRT was transplant than to a true positive effect of the conversion. required to provide similar trough levels to IRT [6]. In our Additionally, it is likely that the frequency of routine biopsy study, the trough level achieved with a mean IRT dose of surveillance was lower post- vs preconversion, and that 3.84 mg/d was higher than that achieved with a similar dose postconversion rejection episodes were diagnosed on the of PRT, which is consistent with other reports. However, the basis of clinical suspicion and were confirmed by biopsy levels determined during the 48 months of follow-up, with findings. Indeed, the frequency of diagnosis of rejection the steady dose reduction, were within target [30]. episodes based on clinical suspicion was substantially higher The tacrolimus trough levels achieved with PRT in our post conversion (88.9%) vs preconversion (23.5%). Inter- study were sufficient (with concomitant immunosuppressive estingly, compared with the 2-year preconversion period, agents) to avoid AR. We did not observe the previously Table 3. Safety Parameters in Patients Converted to Prolonged-Release Tacrolimus (N [ 467) Parameter Preconversion 6 Mo 12 Mo 24 Mo 36 Mo 48 Mo Leukocytes,  10 3 7.2 (2.3) 7.4 (2.1) 7.5 (2.2) 7.4 (2.4) 7.4 (2.2) 7.3 (2.1) Hemoglobin, g/dL 13.4 (1.8) 13.6 (1.7) 13.7 (1.7) 13.7 (1.7) 13.7 (1.8) 13.8 (1.7) Platelets,  103 211.5 (67.7) 209.2 (61.9) 211.0 (61.9) 205.7 (61.8) 207.2 (64.8) 208.4 (67.8) Fasting glycemia, mg/dL 106.4 (38.9) 107.4 (41.3) 107.7 (37.1) 106.61 (33.1) 106.5 (31.4) 107.1 (37.3) Insulin therapy, % 18.0 18.8 18.9 17.2 18.8 18.8 Serum creatinine, mg/dL 1.28 (0.61) 1.26 (0.62) 1.24 (0.62) 1.27 (0.61) 1.27 (0.52) 1.27 (0.56) GFR, mL/min/1.73 m2 71.9 (25.2) 66.4 (23.8) 67.5 (23.6) 73.3 (26.2) 65.9 (25.1) 65.7 (24.6) Total cholesterol, mg/dL 168.4 (35.2) 172.4 (34.6) 174.4 (35.5) 175.3 (35.9) 173.6 (35.7) 173.3 (34.2) HDL cholesterol, mg/dL 52.4 (15.6) 52.4 (15.6) 53.6 (15.2) 55.1 (15.9) 53.6 (15.5) 54.6 (17.2) LDL cholesterol, mg/dL 91.0 (28.5) 94.7 (28.5) 94.6 (26.8) 94.3 (28.9) 95.2 (26.3) 94.7 (25.8) Triglycerides, mg/dL 131.1 (82.2) 128.2 (82.2) 133.4 (95.1) 129.3 (69.3) 126.2 (64.2) 125.8 (63.6) AST, U/L 23.5 (15.7) 23.5 (15.7) 22.7 (16.9) 21.9 (13.8) 23.4 (18.2) 22.9 (16.6) ALT, U/L 23.1 (18.6) 23.1 (18.6) 21.3 (14.9) 21.2 (14.4) 22.2 (18.6) 22.7 (17.7) Weight, kg 74.7 (15.9) 74.7 (16.0) 75.6 (16.4) 76.3 (16.4) 76.2 (16.5) 76.3 (16.3) Systolic blood pressure, mm Hg 128.7 (16.7) 128.7 (16.7) 129.7 (16.5) 132.1 (16.4) 132.0 (18.4) 133.0 (17.4) Diastolic blood pressure, mm Hg 81.1 (10.7) 81.1 (10.7) 81.9 (10.6) 83.7 (11.9) 83.3 (11.8) 83.9 (11.9) Heart rate, bpm 88.8 (13.9) 88.8 (13.9) 88.0 (13.5) 87.9 (14.0) 88.6 (13.9) 88.2 (13.3) Nonsinus rhythm, % 3.9 3.9 5.5 5.0 6.2 7.7 Left ventricle ejection fraction, % 63.8 64.6 64.8 64.8 64.1 64.45 Data are mean (SD) unless otherwise stated. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; bpm, beats per minute; GFR, glomerular filtration rate; HDL, high-density lipo- protein; LDL, low-density lipoprotein. 2000 GONZÁLEZ-VÍLCHEZ, DELGADO, PALOMO ET AL reported substantial progressive reduction in serum tacro- retrospective nature of the study also makes it difficult to limus trough levels in patients receiving PRT de novo [5,6]. explain the trend toward a higher likelihood of a rejection Our results are more consistent with those of van Hooff diagnosis being made by biopsy and the increase in rejection et al, who found that tacrolimus trough concentrations were with hemodynamic compromise post vs preconversion to generally maintained at a stable level during 4 years of PRT, and patterns in cytolytic therapy usage. There was also follow-up in heart transplant patients who converted to a delay between study completion and manuscript prepa- PRT, while doses were slightly reduced [33]. In our study, ration; however, the data remain relevant. doses and serum trough levels maintained almost parallel curves during follow-up, which suggests good adherence to CONCLUSIONS PRT. Biochemical parameters indicate a comparable safety In summary, this study provides valuable information about profile between IRT and PRT in our study, which is tacrolimus dosing, trough levels, and clinical effectiveness consistent with other reports showing similar renal function, associated with the conversion of stable heart transplant blood cell counts, liver function tests [1,3,4,6,18,34], left recipients from IRT to PRT in clinical practice. The long- ventricular function [6], and glycemia [4] between the for- term experience reported here suggests that conversion mulations. Although there were changes in several param- from IRT to PRT in stable heart transplant recipients is eters, including blood cell counts, lipid levels, body weight, accompanied by appropriate immunosuppressive effective- and blood pressure, these trends were not considered to be ness, adequate tolerability, and no new safety concerns. clinically relevant. Regarding comorbidities and the safety Moreover, PRT offers a more convenient dosing regimen of conversion to PRT in our study, follow-up data did not that may have an impact on adherence, possibly influencing reveal substantial changes over time between the formula- effectiveness, since enhanced adherence may yield im- tions or compared with baseline. For instance, serum provements in long-term graft survival. glucose levels and the proportion of patients with insulin- dependent diabetes remained similar throughout the study. ACKNOWLEDGMENTS Conversion from IRT to PRT was generally well toler- This study was sponsored by Astellas Pharma. The authors thank Dr ated, as shown by the low dropout rate. There were 33 pa- Blanca Piedrafita, Medical Writer at Medical Statistics Consulting tients who discontinued PRT, with AEs the cause in (Valencia, Spain), for her assistance with the manuscript. Editorial approximately half of cases. The incidence of AEs with PRT assistance was also provided by Daniella T Draper, PhD, CMPP, from administration in a 4-year period is high, according to pre- Cello Health MedErgy (Europe), funded by Astellas Pharma, Inc. vious trials [33], but this aspect was not closely monitored in our study. Van Hooff et al found that the incidence of AEs DATA STATEMENT decreased over the 4-year follow-up, with infections, meta- Access to anonymized individual participant level data will bolic and nutrition disorders, and neoplasms being the most not be provided for this trial as it meets 1 or more of the commonly-reported events among heart transplant re- exceptions described on www.clinicalstudydatarequest.com cipients [33]. Of note, in this study, most infections (>80%) under “Sponsor Specific Details for Astellas.” required hospitalization. This may be related to the chal- lenge of tracking milder infections, for which patients may see their family physician or which may not be well docu- REFERENCES mented in outpatient notes. [1] Alloway R, Steinberg S, Khalil K, Gourishankar S, Miller J, There were some limitations to the study analyses. For Norman D, et al. 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