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, B: 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, B: CS>5 mg/d); SFM: steroid discontinuation after at least 1 year | Not analyzed | Not described | The incidence of hypertension increased with the increasing CS dosage. No difference were observed regarding incidence of diabetes and of bone fractures | Maintaining steroid therapy beyond the first year significantly increased their risk of becoming hypertensive over the following 2 years. Any effect on diabetes or liability to bone fracture must in general show a slower evolution; therefore, conclusions cannot be drawn | Medium quality |
| 69 | One-arm prospective trial | One arm: 40 patients, 82.5% males, mean age 56.5, 13 ± 3 years after HT. Steroid withdrawal and Cyc reduction attempted in the whole group with the introduction of MMF | Not analyzed. One patient died of miocardial infarction | Suspected rejections occurred in 8% of patients (one case for noncompliance) | Significant improvement of most cardiovascular risk factors, of blood pressure and of renal function. Quality of life decreased rapidly after steroid withdrawal. Dropouts occurred for 42% of patients. Of these, 36% were attributable to steroid withdrawal syndrome |
Better focusing on patients under CS for no longer than 2 years. In these patients, the cardiovascular risk will probably improve without the side effect of CS-withdrawal syndrome | 6/10 |
AZA, azathioprine; Cyc, cyclosporine; CSs, corticosteroids; MMF, mycophenolate mofetil; OKT3, muromonab-CD3; SFM, steroid-free maintenance group; SG, steroid group; TC, tacrolimus; TMG, thymoglobulin.
*
Delgado et al. report P-values not adequate to the frequencies indicated. Here are reported re-computed P-values from the chi-squares proposed in the original paper.