P. Prestinenzi

Cyclosporine lowering with everolimus versus mycophenolate mofetil in heart transplant recipients: Long-term follow-up of the SHIRAKISS randomized, prospective study

BACKGROUND Cyclosporine nephrotoxicity negatively impacts long-term outcome after heart transplantation (HT). We previously reported 1-year results from a randomized study showing that cyclosporine-lowering strategies based on everolimus or mycophenolate mofetil (MMF) are equally effective for reducing progression of renal dysfunction. It is unknown whether this efficacy could be maintained over the long term. METHODS Thirty-four recipients 1 to 4 years after HT and with 25 to 60 ml/min of creatinine clearance (CrCl) were randomized to everolimus with a very low dose (C(0): 50 to 90 ng/ml, n = 17) or MMF with low dose of cyclosporine (C(0): 100 to 150 ng/ml, n = 17). Follow-up was prolonged up to 3 years, and calculated CrCl was the main efficacy measure. RESULTS Cyclosporine was maintained at 70% and 30% lower than baseline in the everolimus and MMF arms, respectively, throughout the 3-year study period. CrCl remained stable in the everolimus patients (+7% from baseline; p = 0.7), but improved in the MMF patients (+20% from baseline; p < 0.01), with a trend toward improved values compared with everolimus patients (46 ± 12 vs 56 ± 15 ml/min; p = 0.06). Subgroup analysis revealed that baseline proteinuria markedly influenced the renal function response to everolimus: whereas in patients with baseline proteinuria CrCl significantly worsened (-20%; p = 0.04), it improved in those without (+15%; p = 0.03). Safety was comparable between the two study arms. CONCLUSIONS Cyclosporine nephrotoxicity improved after a prolonged dose reduction in patients receiving MMF. The everolimus-based strategy provided a similar benefit only to patients without baseline proteinuria. While raising caution against the universal use of everolimus for kidney protection, our long-term results support the need for customized approaches in the management of drug toxicities in maintenance HT recipients.

Differential Effect of Everolimus on Progression of Early and Late Cardiac Allograft Vasculopathy in Current Clinical Practice

Randomized trials showed that mTOR inhibitors prevent early development of cardiac allograft vasculopathy (CAV). However, the action of these drugs on CAV late after transplant is controversial, and their effectiveness for CAV prevention in clinical practice is poorly explored. In this observational study we included 143 consecutive heart transplant recipients who underwent serial intravascular ultrasound (IVUS), receiving either everolimus or mycophenolate as adjunctive therapy to cyclosporine. Ninety‐one recipients comprised the early cohort, receiving IVUS at weeks 3–6 and year 1 after transplant, and 52 the late cohort, receiving IVUS at years 1 and 5 after transplant. Everolimus independently reduced the odds for early CAV (0.14 [0.01–0.77]; p = 0.02) but it did not appear to influence late CAV progression. High‐dose statins were found to be associated with reduced CAV progression both early and late after transplant (p ≤ 0.05). Metabolic abnormalities, such as high triglycerides, were associated with late, but not with early CAV progression. By highlighting a differential effect of everolimus and metabolic abnormalities on early and late changes of graft coronary morphology, this observational study supports the hypothesis that everolimus may be effective for CAV prevention but not for CAV treatment, and that risk factors intervene in a time‐dependent sequence during CAV development.

Interplay of coronary angiography and intravascular ultrasound in predicting long-term outcomes after heart transplantation

BACKGROUND Cardiac allograft vasculopathy (CAV) remains the major cause of late graft-related death after heart transplantation (HT). Identification of patients at risk of cardiovascular events has relevant implications in appropriately guiding resources and intensity of follow-up. In this context, the prognostic relevance of serial coronary imaging long-term after HT is unexplored. METHODS Recipients with intravascular ultrasound (IVUS) and coronary angiography performed 1 and 5 years after HT were monitored for subsequent 1 to 10 years to analyze the association of serial coronary imaging with cardiovascular death and major cardiovascular events (MACEs). RESULTS Included were 131 patients. The MACE incidence was 31.8 per 1,000 patient-years, and cardiovascular mortality was 17.4 per 1,000 patient-years. Progression of coronary lesions detected by angiography and changes in IVUS-defined parameters, including an increase in maximal intimal thickness (MIT) ≥0.35 mm and vascular remodeling, predicted MACE occurrence. However, only MIT change ≥0.35 mm also predicted cardiovascular mortality. Among patients with normal or stable angiography, an MIT change ≥0.35 mm identified those with a significantly higher MACE rate (80 vs 13 events/1,000 patient-years). Worsening metabolic parameters appeared associated with the increasing severity of CAV development. CONCLUSIONS Combined imaging analysis of progression of angiographic lesions and IVUS-detected MIT between 1 and 5 years post-HT allows discriminating patients at high, intermediate, and low risk for adverse long-term cardiovascular outcomes. The metabolic syndrome milieu is confirmed as a key risk factor for long-term CAV progression and adverse prognosis.