Despite the enormous short-term benefit of calcineurin inhibitors (CNI) in solid-organ transplantation, the long-term adverse event profile of this therapeutic class prompted innumerous clinical trials investigating the feasibility, efficacy, and safety of CNI-free immunosuppressive regimens. The SCHEDULE trial is the first randomized multicenter trial to evaluate the efficacy and safety of an early CNI withdraw immunosuppressive regimen in de novo heart transplant recipients. The study randomized 115 heart transplant recipients to a CNI-free, everolimus-based immunosuppressive regimen (n = 56) or to a CNI-based regimen using cyclosporine (n = 59) and was powered to detect an 8 ± 10 mL/min difference in glomerular filtration rate (GFR) 12 months after transplantation. The incidence of treated acute rejection was higher in the everolimus group (42 vs 23%; P < 0.05), particularly after cyclosporine withdrawal at 7 to 11 weeks (38 vs 14%; P < 0.01). On the other hand, renal function (79.8 ± 17.7 mL/min per 1.73 m2 vs 61.5 ± 19.6 mL/min per 1.73 m2; P < 0.001) and the incidence of cardiac allograft vasculopathy (CAV) (50.0 ± 7.4% vs 64.6 ± 6.9%, P = 0.003) favored the everolimus group despite the lack of differences in cardiac function assessed by echocardiography. Although the incidence of pneumonia was higher (12.5% vs 3.4%), the incidence of CMV infection (5.4% vs 30.5%) was lower among patients receiving everolimus. Nine patients in the everolimus group resumed low-dose cyclosporine (6 adverse events and 3 repeat rejections) and 4 discontinued treatment due to adverse events.1
At 3 years of follow-up, a difference of 18.3 mL/min in measured GFR (77.4 ± 20.2 mL/min vs 59.2 17.4 mL/min; P < 0.001) favoring everolimus group was observed in the intention to treat population. The proportion of patients with CAV at month 36, defined as mean maximal intimal thickness of 0.5 mm or greater, was lower in the everolimus versus the CNI group (43.2% vs 53.8%; P = 0.104). Yet, higher incidence of biopsy-proven acute rejection grade ≥2R (10.2% vs 5.9%; P = 0.483) and of serious adverse events, mostly infections, (37.3% vs 19.6%; P = 0.078) were observed in the everolimus group during months 12 to 36. At 3 years, 84% of patients randomized to everolimus were still receiving everolimus, although 13 patients had resumed concomitant use of CNI. There were 10 deaths from transplant to 36 months: 3 in the everolimus group (graft failure, pleural hemorrhage, adenocarcinoma) and 7 in the cyclosporine group (cerebral accident, sepsis, cardiac arrest, unspecified malignancy, pulmonary cancer, sudden death, and graft failure).1,2
In this issue of Transplantation, the SCHEDULE investigators report another prespecified secondary endpoint of the trial: the 3-year analysis of sequential (week 2, weeks 7–11, year 1, and year 3) 24-hour ambulatory blood pressure monitoring in 83 patients. Overall, systolic blood pressure decreased from 2 weeks to 36 months (138 ± 15 mm Hg vs 132 ± 14 mm Hg; P = 0.003), whereas diastolic blood pressure did not change over time. The use of beta-blockers and angiotensinogen-converting enzyme inhibitors or angiotensin receptor blockers increased, whereas the proportion of patients on diuretics decreased during the follow-up. At 36 months, mean 24-hour systolic blood pressures were 131 ± 14 mm Hg in the everolimus and 134 ± 14 mm Hg in the cyclosporine group, with a statistically significant between-group difference in the reduction of 24-hour systolic blood pressure from week 2 to month 36 (−2.8 mm Hg; P = 0.02) in favor of everolimus. Patients receiving everolimus showed a mean 13 mm Hg reduction in 24-hour systolic blood pressure between week 2 and 36 months, whereas no changes were observed in the cyclosporine group (−13 ± 17 mm Hg vs 0 ± 17 mm Hg; P = 0.02). The proportion of patients with hypertension at 7 to 11 weeks and at 3 years, defined as a 24-hour average ambulatory blood pressure greater than 130/80 mm Hg, decreased in the everolimus group (78% to 52%) but did not change in the cyclosporine group (70% and 72%). There were no differences in the proportion of patients requiring antihypertensive treatment between the groups, and baseline blood pressure was the only parameter significantly associated with blood pressure after 36 months. There was no significant correlation between the change in the estimated GFR or urine albumin/creatinine ratio and the change in the 24-hour systolic blood pressure. Left ventricular mass or the proportion of patients with left ventricular hypertrophy did not differ between the treatment arms.3
Overall, the SCHEDULE trial shows that a CNI early withdrawal strategy is associated with improved renal function, lower incidence of CMV infection, and lower incidence of CAV measured by intravascular ultrasound, although the impact on clinically relevant coronary lesions is still unknown.4 On the other hand, higher incidences of acute rejection, serious adverse events, bacterial infections, and incremental treatment modification were observed during the 3-year follow-up, mirroring the efficacy and safety profile of several CNI-sparing immunosuppressive strategies conducted in kidney transplant recipients.5
Previous trials also showed inconclusive results regarding blood pressure in heart transplant recipients.6-8 The small decrease in mean systolic blood pressure with no differences in left ventricular hypertrophy, giving the pronounced renal function benefit, is disappointing and contrasts with previous data in heart8 and kidney transplant recipients.9 These data suggest that either longer follow-up is necessary to clearly demonstrate this effect or that other known risk factors play a major role in the development of hypertension and left ventricular hypertrophy after heart transplantation. Despite the prespecified definition of hypertension (24-h average ambulatory blood pressure > 130/80 mm Hg), there was no protocol defined algorithm for the treatment of hypertension, creating a condition for unintended bias, given the open label design of the trial. Furthermore, a more detailed analysis of pill burden is lacking, as no details are provided regarding the drug doses and combinations used to treat hypertension during the follow-up period. This analysis would certainly influence adherence to treatment.
The feasibility and efficacy/safety benefit ratio of this trial should take into account the stringent criteria for randomization and intervention at 7 to 11 weeks, the contrasting incidence of intermediate biomarkers (acute rejection vs renal function for example), changes in immunosuppression, and the small and decreasing sample size that ultimately limits the analysis of hard outcomes such as patient survival, which is ultimately the goal of this strategy. The lack of association between acute rejection and inferior long-term survival10 and between changes in renal function and blood pressure11 are 2 examples. Therefore, based on these data, it is not possible to speculate whether the observed everolimus treatment effect, including the small reduction in blood pressure, will be associated with superior patient survival. Finally, it remains to be determined the impact of a CNI-free immunosuppressive regimen on the development of donor-specific HLA antibodies and antibody-mediated rejection phenotypes after heart transplantation.12 After all, the search for a CNI-free immunosuppressive regimen continues.
1. Andreassen AK, Andersson B, Gustafsson F, et al. Everolimus initiation and early calcineurin inhibitor withdrawal in heart transplant recipients: a randomized trial. Am J Transplant. 2014;14:1828–1838.
2. Andreassen AK, Andersson B, Gustafsson F, et al. Everolimus initiation with early calcineurin inhibitor withdrawal in de novo heart transplant recipients: three-year results from the randomized SCHEDULE study. Am J Transplant. 2016;16:1238–1247.
3. Andreassen AK, Broch K, Eiskjær K. SCHEDULE (SCandinavian Heart transplant everolimus De-novo stUdy with earLy calcineurin inhibitors avoidancE) investigators. Blood pressure in De novo heart transplant recipients treated with Everolimus compared with a cyclosporine-based regimen: results from the randomized SCHEDULE trial [published online September 11, 2018]. Transplantation. doi:10.1097/TP.0000000000002445
4. Zuckermann A, Osorio-Jamillio E, Aliabadi-Zuckermann AZ. mTOR inhibition and clinical transplantation: heart. Transplantation. 2018;102(2S Suppl 1):S27–S29.
5. Budde K, Lehner F, Sommerer C, et al. Five-year outcomes in kidney transplant patients converted from cyclosporine to everolimus: the randomized ZEUS study. Am J Transplant. 2015;15:119–128.
6. Rothenburger M, Teerling E, Bruch C, et al. Calcineurin inhibitor-free immunosuppression using everolimus (Certican) in maintenance heart transplant recipients: 6 months' follow-up. J Heart Lung Transplant. 2007;26:250–257.
7. Engelen MA, Welp HA, Gunia S, et al. Prospective study of everolimus with calcineurin inhibitor-free immunosuppression after heart transplantation: results at four years. Ann Thorac Surg. 2014;97:888–893.
8. Imamura T, Kinugawa K, Nitta D, et al. Everolimus attenuates myocardial hypertrophy and improves diastolic function in heart transplant recipients. Int Heart J. 2016;57:204–210.
9. Paoletti E, Marsano L, Bellino D, et al. Effect of everolimus on left ventricular hypertrophy of de novo kidney transplant recipients: a 1 year, randomized, controlled trial. Transplantation. 2012;93:503–508.
10. Hertz MI. The registry of the International Society for Heart and Lung Transplantation—introduction to the 2012 annual reports: new leadership, same vision. J Heart Lung Transplant. 2012;31:1045–1051.
11. Wang X, Garrett MR. Nephron number, hypertension, and CKD: physiological and genetic insight from humans and animal models. Physiol Genomics. 2017;49:180–192.
12. Manfredini V, Leone O, Agostini V, et al. Antibody-mediated rejection in heart transplantation: new developments and old uncertainties. Curr Opin Organ Transplant. 2017;22:207–214.