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Steroid‐free and steroid withdrawal protocols in heart transplantation: the review of literature

2014; Springer Science+Business Media; Volume: 27; Issue: 6 Linguagem: Inglês

10.1111/tri.12309

1432-2277

Massimo Baraldo, Giorgia Gregoraci, Ugolino Livi,

Mechanical Circulatory Support Devices

Transplant InternationalVolume 27, Issue 6 p. 515-529 ReviewOpen Access Steroid-free and steroid withdrawal protocols in heart transplantation: the review of literature Massimo Baraldo, Corresponding Author Massimo Baraldo Department of Experimental and Clinical Medicine, Medical School, University of Udine, Udine, Italy SOC Institute of Clinical Pharmacology, University-Hospital Santa Maria della Misericordia, Udine, Italy Correspondence Massimo Baraldo MD Associate Professor of Pharmacology, SOC Institute of Clinical Pharmacology, University-Hospital Santa Maria della Misericordia, 25, 33100 Udine, Italy. Tel.: 0049 0432 559833; fax: 0049 0432 559291; e-mail: massimo.baraldo@uniud.itSearch for more papers by this authorGiorgia Gregoraci, Giorgia Gregoraci Department of Medical and Biological Sciences, Section of Statistics, University of Udine, Udine, Italy Department of Medical and Biological Sciences, Institute of Hygiene and Clinical Epidemiology, University of Udine, Udine, ItalySearch for more papers by this authorUgolino Livi, Ugolino Livi Department of Experimental and Clinical Medicine, Medical School, University of Udine, Udine, Italy Cardiothoracic Department, University-Hospital Santa Maria della Misericordia, Udine, ItalySearch for more papers by this author Massimo Baraldo, Corresponding Author Massimo Baraldo Department of Experimental and Clinical Medicine, Medical School, University of Udine, Udine, Italy SOC Institute of Clinical Pharmacology, University-Hospital Santa Maria della Misericordia, Udine, Italy Correspondence Massimo Baraldo MD Associate Professor of Pharmacology, SOC Institute of Clinical Pharmacology, University-Hospital Santa Maria della Misericordia, 25, 33100 Udine, Italy. Tel.: 0049 0432 559833; fax: 0049 0432 559291; e-mail: massimo.baraldo@uniud.itSearch for more papers by this authorGiorgia Gregoraci, Giorgia Gregoraci Department of Medical and Biological Sciences, Section of Statistics, University of Udine, Udine, Italy Department of Medical and Biological Sciences, Institute of Hygiene and Clinical Epidemiology, University of Udine, Udine, ItalySearch for more papers by this authorUgolino Livi, Ugolino Livi Department of Experimental and Clinical Medicine, Medical School, University of Udine, Udine, Italy Cardiothoracic Department, University-Hospital Santa Maria della Misericordia, Udine, ItalySearch for more papers by this author First published: 11 March 2014 https://doi.org/10.1111/tri.12309Citations: 25 Conflicts of interestThe authors of this manuscript have no conflict of interests to disclose. AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Summary Corticosteroids (CSs) are still the mainstay of induction, rescue, and maintenance in heart transplantation (HTx). However, their use is associated with significant and well-documented side effects usually related to the dose administered and the duration of therapy. Moreover, CSs interfere with the recipient's quality of life and with the active process of graft tolerance. Physicians have been exploring ways to avoid or reduce CSs in association with other immunosuppressive drugs, minimizing side effects and costs. The regimens are classified as steroid-free or steroid withdrawal protocols. The studies analyzed in this review come to similar conclusions as benefits and adverse consequences: steroid-free protocols should be advisable and mandatory in pediatric patients, insulin-dependent diabetes mellitus (IDDM), presence of infection, familial metabolic disorders/obesity, severe osteoporosis, and in the elderly. On the other hand, steroid withdrawal can be successfully achieved in 50–80%, with late better than early withdrawal, no increase in rejection-related mortality, no adverse impact on survival, and probably a better quality of live. Safety and efficacy can certainly be improved by an individualized approach to the transplant recipient. Introduction Every year, about 4000 heart transplantations (HTx) are performed worldwide according to the ISHLT registry. Median survival is steadily improved from 8.5 years (1982–1992) to 10.9 years (1993–2002), and it is further improved since 2003 1. Acute rejection is now a fairly uncommon cause of death, being responsible for no more than 11% of deaths, whereas graft failure of different origin is the leading cause of death in the first 30 days after transplant and later. Even if the exact etiology of late graft failure is unknown, deaths are mainly due to cardiac allograft vasculopathy (CAV), an immunomediated process possibly worsened by other comorbidities as hypertension, diabetes mellitus, and hyperlipidemia. These deaths can at least in part be attributed to the effects of immunosuppressive therapies 1. Calcineurin inhibitors (CNIs), mycophenolic acid (MPA), mammalian target of rapamycin inhibitors (mTOR), and corticosteroids therapy continue to be the dominant immunosuppressive choice after HTx 1. CSs are a standard part of every phase of immunosuppression (induction, maintenance, rejection treatment). Their use is associated with significant and well-documented side effects usually related to the dose administered and the treatment duration 2, 3. The most frequent and distressing side effects of steroid association in transplant recipients are metabolic 4-8, skeletal 9-12, and vascular disorders 13, often combined with a higher susceptibility to infections 14. The optimal immunosuppressive therapy is the combination of different drugs to enhance their immunosuppressive potential and decrease their toxic effects by lowering the single dosage of each, also allowing the reduction or suppression of steroids. Thus, physicians have been exploring ways to avoid or eliminate the need for long-term steroid treatment, thereby minimizing side effects and costs. These regimens classified as steroid-free or steroid withdrawal protocols (early within the first 3–6 months after HTx or late between 6–12 months and beyond post-transplant) have been applied in several solid organ transplantations. In the early 1980s, the European transplant community tried to withdraw from standard immunosuppression or avoid completely the use of CSs in organ transplantation, but the results were varied and might be not applicable to the actual therapies 15, 16. Instead, in a more recent analysis, Lerut 17 evaluated studies using more innovative drugs and concluded that results were satisfying in almost all types of solid organ transplants if steroid avoidance had been accomplished. Moreover, the same author reported that in clinical practice of liver transplantation, there was a tendency toward steroids minimization with their avoidance more favorable than their withdrawal 18. CS minimization protocols and sparing have been applied even in kidney transplantation 19, 20, and a meta-analysis of Knight SR et al. 21 revealed an increase in the risk of acute rejection (AR) with steroid avoidance or withdrawal protocol (RR 1.56, CI 1.31–1.87, P < 0.0001), but with no measurable effect on graft or patient survival, reporting at the same time significant benefits in cardiovascular risk profile. Steroid withdrawal in pancreas and islet transplantation, even if the success has been validated by several transplant centers, cannot currently be recommended because lacking in prospective randomized studies to verify the risk/benefit ratio 22, 23. The first to describe results with steroid-free immunosuppression in HTx was Yacoub et al. 24 in 1985, whereas the first experience with steroid withdrawal was reported by Pritzker et al. 25. Moreover, this therapeutic approach was proven to be feasible also in pediatric HTx 26, 27. Experience with the minimization of CSs in heart transplantation is relatively poor and more heterogeneous when compared with other solid organs, and results are difficult to interpret. In fact, the clinical use of different CSs minimization protocols and different co-treatments in various clinical settings might make clinical outcomes difficult to compare. Thus, the purpose of this paper was to focus only on CSs-free and CSs-withdrawal protocols in HTx patients to evaluate the results achieved on survival, rejection and infection rate, or other drug side effects. The role of steroids in heart transplantation CSs immunosuppressive action is multifactorial depending on the target cell type considered and their activation state: (i) synthesis of lipocortins which prevent arachidonic acid release from membrane-bound stores; (ii) blockade of selected elements of the signal transduction pathways that operate as a consequence of T-cell activation; (iii) inhibition of leukocyte adhesion molecule expression; and (iv) suppression of cytokine production and action 28. To influence cellular function, CSs must enter the cell and bind to and activate intracellular receptors, named glucocorticoid receptors (GRs), type-I and type-II 29. Type-II GRs, widely distributed in the immune system, affect all immune cells at an intermediate level in mature T and B cells and at very low level in neutrophils 30. GRs density in peripheral T cells is a critical determinant of sensitivity, and despite the presence of functional GRs, clinical CSs resistance can arise 31. It has been demonstrated that chronically CSs drug therapy may alter immune cell differentiation which may be of relevance in the induction of peripheral tolerance to allergenic stimuli 32-35. The main CSs used to prevent and treat allograft rejection are prednisolone and prednisone. From a pharmacokinetic point of view, synthetic CSs present increased bioavailability, poor linkage to CS-binding globulin (CBG) and have much longer half-life than endogenous CSs (cortisol, corticosterone) 36, 37. CSs administration to humans results in rapid but transient lymphopenia (especially T cells) 38 and in a significant reduction in eosinophil and basophil numbers, whereas vice versa neutrophil exhibits a marked increase 39. In clinical setting, beside the well-known effect on acute rejection, CSs could impact also on coronary allograft vasculopathy (CAV), present in 90% of patients within 10 years and considered one of the major cause of late death following HTx 40-43. Etiology of CAV is mostly immunologic, but nonimmune pathways contribute to its development. Inflammatory cells and humoral injuries are present in evolving lesions 44; cytokines and chemokines are known to mediate local and systemic immune responses and to recruit and activate inflammatory cells. Thus, CS minimization might accelerate the course of CAV being the disease for great part immunomediated. However, Ratkovec et al. 45 demonstrated that CSs minimization does not adversely affect the prevalence or progression of CAV during the first 2 years after HTx. Moreover, while cyclosporine and tacrolimus are not effective in preventing CAV 46, mychophenolate mofetil, sirolimus, and everolimus seem to impact on the appearance and progression of CAV, allowing a consistent reduction in CSs 47-49. As it has been demonstrated that cumulative CSs dose in HTx recipients has been associated with hyperlipidemia and possibly with more diabetes and hypertension, CSs withdrawal or avoidance would decrease the incidence and progression of CAV 50. Methods This review is focusing on strategies to avoid CSs after HTx as a means to improve short- and long-term outcome. To analyze the impact of different CSs protocols, we searched the PubMed database up to June 2013 using the following keywords: heart transplantation, corticosteroids, steroid-free, complete steroid avoidance, steroid withdrawal, steroid minimization, and steroid side effects. Inclusion criteria specified any prospective or retrospective trial or observational study in adult and pediatric HTx recipients. This research was considering only studies that compared steroid groups (SG) versus steroid-free groups (SFG). Studies with steroid avoidance [steroid free = SF], with early steroid withdrawal (within the first 6 months) [early withdrawal in steroid, free maintenance immunosuppression = ew-SFM], and late steroid withdrawal (between 6 and 12 months and beyond post-HTx) [late withdrawal in steroid-free maintenance immunosuppression = lw-SFM] regimens, including pediatric experiences, were then analyzed separately. Quality assessment was performed according to the Cochrane Collaboration Criteria for the evaluation of RCTs 51 and according to the GRACE principles for the evaluation of observational studies 52. For the evaluation of RCTs, only internal validity criteria were computed for the final 10-points score (for each item, a yes/no/unclear evaluation was made; then, 1 point was assigned for each positive mark). For the evaluation of observational studies, an overall assessment was performed in accordance with GRACE principles, ranking studies as low, medium, or high quality. Considering the different quality levels, the variety in patients' characteristics, the fact that most studies had only one arm and that evaluation of the outcomes was different among studies, a meta-analysis was not attempted. Patients were divided in steroid group (SG) and steroid-free (maintenance) group (SFG). To compare the results of the studies, the following parameters were selected: graft and patient survival, rejection and infection rate, or other complications. Results of comparison among different drug therapy approaches and relative quality assessment results are reported in Tables 1-4. Finally, authors' conclusions were compared. Table 1. Steroid-free regimen in adult heart transplantation recipients. References Study design Participants and intervention Survival Rejection Infections and other ADRs Authors' conclusions Quality assessment 53 Prospective RCT N = 60. SG: 29 pts, mean age 42 years, M:F = 23:6; SFG: 31 pts, mean age 40 years, M:F = 25:5 SG: Cyc + AZA + CSs SFG: Cyc + AZA SG: 2-year survival = 92%, SFG: 2-year survival = 93%. No patient died for transplant-related adverse events in both the groups Higher overall incidence of rejection and at 1, 3, 6 and 12 months in the SFG (overall: 2.3 in SFG vs. 1.1 in SG, P < 0.002) Overall incidence of infections: 1.6 in SG vs. 1.3 in SFG (P > 0.05). Similar occurrence of other ADRs, apart from obesity, being more common among SG pts (14/29 in SG vs. 9/31 in SFG) The two protocols of therapy produce actuarial survival and morbidity rates comparable 3/10 54 Prospective RCT N = 112 SG: 59 pts; SFG: 53 pts. Reported as well matched at randomization. SG: Cyc + AZA + CSs SFG: Cyc + AZA Analyses were conducted "as treated". SG survival rates: 86% and 78% at 2 years and 5 years, respectively; SFG survival rates: 85% and 82% at 2 years and 5 years, respectively (P > 0.05) Analyses were conducted "as treated". Higher incidence of rejection at 3 months in the SFG (2.3 episodes/100 patients vs. 1.5/100 patients in the SG, P = 0.01). No differences in rejection rates thereafter Analyses were conducted "as treated". Similar total infection rates but increased antihypertensive drug use and cholesterol levels in SG. Steroid-related morbidity and coronary artery disease were comparable between the two groups The rate of steroid-related morbidity (diabetes, bone complications, cataracts, and obesity) was low in both the groups and did not differ significantly 3/10 55 Retrospective, observational Only SFG. N = 112, M:F = 92:20, median age 50 (1–68 years). All patients: Cyc + AZA 95% and 94% at 1 year and 2 years, respectively Acute rejection was common (nearly 100%). Overall rejection rate: 1.7 ± 1.0 episodes per patient. Rejection-free survival rates: 20%, 10%, 7%, and 5% at 1, 6, 12, and 48 months. 21% of patients required steroid addition for persistent or repeated rejection Infection rate was 0.1 ± 0.4 episode/patient. Freedom from infection survival rate was 85% at 2 years. Increasing trend in hypertension occurrence up to 57%. Lipid metabolism normal during follow-up High incidence of acute rejection. Excellent medium-term survival and low incidence of both infection and chronic rejection High quality 56 Prospective, open-label RCT N = 32, 1:1 randomization. SG: mean age 49 years, M:F = 14:18. SFG: mean age 51 years, M:F = 13:19. SG: TC + MMF + Prednisone. SFG: TC + MMF + TMG. All patients received intra-operative TMG One death per group (no further information) Acute cellular rejections occurred in 69% of SG vs. 50% of SFG (P = 0.29). Mean number of acute cellular rejection episodes not significantly different between the two groups (1.07 in SG vs. 0.81 in SFG) No difference in opportunistic infections incidence. Reduction in bone loss and augmented cardiac strength in the SFG. Four cases of skin cancers in the SFG group. No major bleedings, no lymphoproliferative disorders With use of TMG, CSs avoidance seems to be safe with significant improvement in muscular strength and lower lost in bone density 4/10 AZA, azathioprine; CSs, corticosteroids; Cyc, cyclosporine; OKT3, muromonab-CD3; SFG, steroid-free group; SG, steroid group; MMF, mycophenolate mofetil; TC, tacrolimus; TMG, thymoglobulin. Table 2. Early withdrawal of steroid therapy in adult heart transplantation recipients. References Study design Participants and intervention Survival Rejection Infections and other ADRs Authors' conclusions Quality assessment 25 Observational prospective SG: 32 patients, mean age 53 years, M:F = 30:0; SFM: 36 (29 on final analyses) patients, mean age 49 years, M:F = 20:9. Therapeutic groups were defined by indication. SG: Cyc + AZA + prednisone; SFM: as SG + prophylactic OKT3 and steroid withdrawal within 3 months Survival in SG group: 94%, 94% and 81% at 1, 2, and 3 years; in SFM group: 100%, 100%, and 100% at 1, 2, and 3 years (P = 0.171 at 1 and 2 years, P = 0.049 at 3 years). Rejection episodes' rates similar in both the groups (SG: 53% vs. SFM: 48%, P = 0.910), while rejection-free survival higher in SFM group (27 ± 17 days in SG vs. 205 ± 214 days in SFM, P = 0.020) Significantly higher total cholesterol (P = 0.003) and LDL (P = 0.013) levels in SG at 1-year follow-up, but not at 2 years. Prevalence of hypertension similar in both the groups (P = 0.242) and weight gain/BMI increase slightly higher in SG (P = 0.170 and 0.108, respectively). Infectious complications similar in both the groups (P = 0.091) Steroid-free maintenance immunotherapy is feasible and was attained in a high percentage of targeted patients (81%) with additionally lower lipid values, less hypertension, less weight gain, and similar infection rates High quality 58 Retrospective SG: 263 patients, mean age 49.4 years, M:F = 2018:45; SFM: 111 patients, mean age 48.4 years, M:F = 104:7. Steroid withdrawal was attempted in the whole group. Analyses were then conducted "as treated". SG: Cyc or AZA + OKT3 + methylprednisolone/prednisone; SFM: as SG plus steroid withdrawal within 3 months Analyses were conducted as treated. Ten-year survival was markedly better in SFM group (P < 0.0001). Independent predictors of mortality were as follows: total number of post-transplantation infections (P < 0.001), older age (P = 0.001), failed early corticosteroid withdrawal (P = 0.006), female gender (P = 0.016). Also allograft survival was better in SFM group Rejection rates were lower in SFM group both during the first year (P not shown) and after the first year (0.07 episodes per pt/y in SFM vs. 0.15 episodes/pt/y in SG, P = 0.0002). Female recipients had more rejection episodes (P = 0.054) Treated infections were more common in patients in which early corticosteroid weaning failed (P not shown). Severe allograft coronary artery diseases were lower in SFM group (P = 0.10) Analyses not appropriate to evaluate outcome. Authors' statement: successful early corticosteroid withdrawal identifies a subgroup of "immunologically privileged" patients with a very low risk for long-term mortality and, when reached, is not associated with an increased prevalence of late rejection or clinically significant coronary artery disease High quality 59 Retrospective SG: 46 patients, mean age 53.5 years, M:F = 41:5; SFM: 93 patients, mean age 52.9 years, M:F = 71:22. Comparison of two different therapeutic approaches instituted at the hospital at different times (SG: 1988–1990, SFM: 1990 onward). SG: Cyc + AZA + prednisone; SFM: as SG plus steroid withdrawal within 6 months Overall survival in SFM group trended to be higher than in SG (P = 0.06). No differences regarding causes of death except for infections, more common in SG (P = 0.06) Better freedom from rejection in SG (P < 0.01) Overall freedom from infection similar in both the groups with a trend for higher incidence in SG (P = 0.10). Better overall freedom from malignancy in SFM group (P < 0.01), mainly because of fewer skin cancers (P = 0.03). Similar occurrence of other conditions (renal dysfunction, obesity, diabetes, coronary artery disease) Steroid withdrawal is a possible and safe approach showing prolonged survival and lower/later occurrence of malignancies High quality AZA, azathioprine; Cyc, cyclosporine; CSs, corticosteroids; MMF, mycophenolate mofetil; OKT3, muromonab-CD3; SFM, steroid-free maintenance group; SG, steroid group; TC, tacrolimus; TMG, thymoglobulin. Table 3. Late-withdrawal of steroid therapy in adult heart transplantation recipients. References Study design Participants and intervention Survival Rejection Infections and other ADRs Authors' conclusions Quality assessment 60 Retrospective SG: 27 patients, mean age 51 years, 89% of males. SFM: 37 patients, mean age 45 years, 81% males. Steroid withdrawal was attempted in the whole group. Analyses were then conducted "as treated". SG: Cyc + AZA + prednisone; SFM: as SG plus steroid withdrawal within 1 year Not analyzed Rejection rates similar in both the groups, with a nonsignificant lower trend in the SFM group at 12- and 24-month follow-up Incidence of infections similar in both the groups with a trend toward lower rates among SFM patients from 6 months on (P = ns). After transplantation, there was a significant weight gain in both the groups compared with baseline, but no direct comparison between the 2 groups was performed There is a trend toward reduction of rejection incidence after 12 months with no increase in the number of infection episodes High quality 61* Observational prospective study SG: 21 patients, mean age 44.5 years, 86% males; SFM group: 23 patients, mean age 45.6 years, 91% males. Analyses were probably conducted as treated. Many patients were excluded from analysis. SG: Cyc + AZA + prednisone; SFM: as SG plus steroid withdrawal within 1 year Not analyzed End point analysis was performed at 1 year post-transplantation. Rejection rates were similar in both the groups (SG: 18% vs. SFM: 23%, P = 0.825) Similar proportion of overweight (P = 0.384), hypertension (P = 0.490), diabetes (P = 0.187) and severe infections (P = 0.592) in SG compared with SFM The use of corticosteroids for more than 1 year is not likely to provide clinical benefit in orthotopic heart transplantation Medium quality 62 Retrospective Fifty-six patients discharged on triple-drug immunosuppression and on whom steroid withdrawal was attempted after 6 months. 12% (5/43) of patients were steroid-free at 1 year, and this proportion grew up to 75% (28/37) at 2 years. No data on demographic characteristics were shown. All patients: Cyc + AZA or MMF + Prednisone and steroid withdrawal attempted at 6 months Analyses were conducted on the whole sample. 1-, 2-, 3-, 4-, and 5-year survival rates were 98%, 93%, 93%, 88% (one moment missing, not clear which) On the whole sample, freedom from a first rejection episode was 71% at 1 month, 61% at 6 months, 61% at 12 months, 59% at 24 months, and 53% at 36 months On the whole sample, freedom from infection was 85%, 79%, 77% 72% and 67% at 1, 6, 24 and 36 months, respectively Despite the small number of patients in the series, the rate of infection, rejection, and transplant vasculopathy seemed not to be increased using a protocol that stressed steroid withdrawal High quality 63 Retrospective SG: 65 patients, mean age 47 years, M:F = 48:17. SFM: 72 patients, mean age 48.4 years, M:F = 60:12. Steroid withdrawal was attempted in the whole group. SG: Cyc + AZA + prednisone; SFM: as SG plus steroid withdrawal within 1 year. Analyses were conducted on patients still alive at 1 year after transplantation, and groups were defined "as treated" At 5 years, estimated survival was 93% in SFM group vs. 77% in SG (P = 0.0001). Independent predictors of better survival were being a white patient in both SMF and SG groups, while group per se had no significant impact on survival Rejection rates were lower in SFM group (1.3 episode/pt in SFM vs. 2.3 episodes/pt in SG, P < 0.0001) However, no difference in severity was observed (P = 0.158 for year 1 and P = 0.930 for subsequent years) Not analyzed In the context of tailoring immunosuppressive treatment, the results of this study support the approach of attempting to wean steroids in white recipients of heart transplantation. High quality 64 Observational prospective study SG: 16 patients, mean age 54 years, 71% males. SFM group: 25 patients, mean age 52 years, 58% males. Steroid withdrawal was attempted in the whole group. Analyses were then conducted "as treated". SG: MMF + TC+ Corticosteroids SFM: as SG plus steroid withdrawal within 1 year matched Not analyzed Outcomes were assessed after 1 year following steroids' discontinuation. SFM group had significantly lower rejection rates compared with SG (0.22 vs. 0.82 episodes/pt/year, P = 0.04) Serious late infections were significantly more frequent in SG compared with SFM group (0.60 vs. 0 infections/pt/year, P < 0.001). No significant differences with respect to blood pressure, hyperglycemia, body mass index, cholesterol and LDL levels were observed between the two groups, but almost all patients were also receiving statins Unlike metabolic benefits of steroid withdrawal with Cyc, heart transplant recipients treated with TC and MMF demonstrated no incremental metabolic benefits, but instead experienced benefits of decreased serious late infections High quality 65 Observational prospective study with retrospective controls SG: 1260 patients retrospectively reviewed, mean age 48.8 years, 82.7% males. SFM: 420 patients followed prospectively, mean age 48 years, 82.9% males. Most patients (>90%) received Cyc-based immunosuppression. Steroid withdrawal was attempted in the SFM group at 6 months after transplantation. No further details are provided Seven-year survival rates were significantly higher in SFM group (76% in SFM vs. 66.9% in SG, P = 0.0008) The rate of patients requiring treatment for rejection at 5 years was similar in the two groups (35% in SFM vs. 30.6% in SG, P = 0.148) SFM group experienced lower high cholesterol cases (total cholesterol >300 mg/dL: 5.3% in SFM vs. 8.4 in SG, P = 0.007) and a trend toward lower high pressure cases (SBP >150 mmHg: 22.1% in SFM vs. 25.9 in SG, P = 0.063). No significant differences were found regarding any other secondary end point (hypertension treatment rates, osteonecrosis, osteoporosis, cataracts) Good long-term outcomes and no worsening of allograft function after steroid withdrawal in low-risk cardiac transplant recipients on Cyc-based immunosuppression Medium quality 66 Retrospective SG: 82 patients transplanted between 1999 and 2001, mean age 51 years, 78% males. SFM: 83 patients transplanted between 2002 and 2004, mean age 53 years, 66% males. Comparison of two different therapeutic approaches instituted at the hospital in different times (SG: 1999–2001, SFM: 2002–2004). SG: Cyc or TAC + MMF or AZA + Prednisone. SFM: as SG plus steroid withdrawal starting at 1 year No difference in estimated survival rates between the two groups (P = 0.53) No statistically significant differences in the rates of significant rejections at 1 year (40% in SG vs. 49% in SFM, P = 0.24) nor at 2 years (7.4% in SG vs. 9.2% in SFM, P = 0.70) Data on lipids and HgA1c not comparable between the two groups because of different dyslipidemia treatment regimen or not routine testing of HgA1c until 2001 With an aggressive steroid-weaning strategy, it seems to be possible to have almost all patients steroid-free by 1 year post-transplant High quality 67 Retrospective Comparison of 4 groups of patients >50 years, 82% males, as treated. SG: continuation of steroids for 5 years after HT (A: CS 5 mg/d); SFM: steroid discontinuation after at least 1 years (C: with subsequent CS reintroduction, D: complete steroid withdrawal) No differences in the estimated survival rates between the four groups (P = 0.34) Not analyzed Not described Late steroid withdrawal was not associated with an increased mortality. Patients from whom CSs are withdrawn must be monitored to detect the need for reintroduction Medium quality 68 Retrospective Comparison of 3 groups of patients >50 years, 82% males, as treated. SGs: continuation of steroids for 5 years after HT (A: CS 5 mg/d); SFM: steroid discontinuation after at least 1 year Not