The introduction of cyclosporine as a maintenance immunosuppressive agent for heart transplantation in the early 1980s transformed the outlook for heart transplant recipients and initiated a decade of rapid global growth in heart transplant activity. Between 1982 and 1992, the number of heart transplants reported to the International Society for Heart and Lung Transplantation increased exponentially from <200 to >4000 heart transplants per year.1 Growth in transplant activity has been more gradual since then, but in the last few years, heart transplant numbers have exceeded 5000 per year.1 Although cyclosporine has been replaced by tacrolimus as the calcineurin inhibitor (CNI) of choice in most heart transplant programs, the vast majority of heart transplant recipients are maintained on 1 or other CNI.1
Median survival after heart transplantation is now 11 years and close to 14 years if early deaths due to primary graft failure are excluded.1 The major benefit of CNIs has been to reduce the morbidity and mortality associated with acute cellular rejection, which has its greatest impact during the first 12 months posttransplant.1 Nonetheless, most heart transplant recipients remain on long-term CNIs. As a consequence, almost 1 in 4 develop severe renal impairment within the first 10 years of transplant, with 5%–10% requiring permanent renal replacement therapy.1 In addition, CNIs have adverse effects on a number of cardiovascular risk factors—hypertension and hyperlipidemia in the case of cyclosporine and diabetes mellitus in the case of tacrolimus.2 Partly for this reason, the impact of CNIs on the development of coronary allograft vasculopathy, a major cause of death beyond the first year posttransplant, remains uncertain. More broadly, in combination with prednisolone and anti-metabolites, they contribute to the increased risk of infection and malignancy after transplantation.
Largely because of the morbidity associated with chronic CNI nephrotoxicity, there has been an increasing interest in the development of immunosuppressive protocols that facilitate CNI minimization or withdrawal. The emergence of mammalian target of rapamycin (mTOR) inhibitors as alternative class of immunosuppressive agents provided hope that the goal of CNI minimization or withdrawal was achievable. In addition, the favorable impact of mTOR inhibitors on the development of posttransplant coronary artery vasculopathy and malignancy,3 thought to be related to the potent antiproliferative properties of these drugs, has made them an attractive option for long-term immunosuppressive maintenance after heart transplantation.
Unfortunately, mTOR inhibitors, like all other immunosuppressive drugs, have side effects and toxicities that limit their effectiveness. Problems with surgical wound healing have discouraged the early de novo administration of mTOR inhibitors and a range of side effects including refractory leg edema, painful mouth ulcers, and gastrointestinal symptoms have contributed to relatively high rates of discontinuation of these drugs.4 Less common but more serious and potentially life-threatening toxicities, such as pneumonitis, have further dampened enthusiasm for the use of mTOR inhibitors.5 Possibly as a reflection of these concerns, the proportion of heart transplant recipients receiving an mTOR inhibitor at 1-year posttransplant has halved from 16% in 2004 to 8% in 2017.1
Studies of conversion to mTOR inhibitors combined with minimization or withdrawal of CNI after heart transplantation have generally shown stabilization of renal function at the cost of increased acute rejection in the CNI minimization/withdrawal groups with similar rates of overall survival.3,6 The benefits of this immunosuppressive strategy may be time dependent—the shorter the time between transplant and conversion to mTOR, the greater the benefit in terms of preservation of renal function and the greater the risk of acute rejection. However, the overall benefit/risk ratio of early conversion to mTOR inhibitor combined with minimization/withdrawal of CNI in terms of long-term patient survival and quality of life remains uncertain. To address this issue, studies looking at the long-term outcomes of this immunosuppressive strategy are needed.
In this issue of the Journal, Gustafsson et al7 report 5–7-year follow-up of the Scandinavian heart transplant everolimus de novo study with early calcineurin inhibitors aviodance (SCHEDULE) Trial. In this Scandanavian multicenter trial, the authors randomized 115 heart transplant recipients to 1 of 2 immunosuppressive protocols: de novo everolimus combined with reduced-dose cyclosporine followed by cyclosporine withdrawal 7–11 weeks posttransplant or standard-dose cyclosporine. Both groups received mycophenolate and steroids. Twelve-month and 3-year outcomes have already been reported.8,9 At 12 months, preservation of renal function was better in the everolimus group, but acute rejection was higher with no difference in patient survival or graft function at 12 months.8 By 3 years, there was evidence of reduced development of coronary allograft vasculopathy in addition to improved renal function and lower blood pressure in the everolimus-treated recipients.9,10 The results of the 5–7-year analysis published in this issue show that the benefits observed at 3 years are still evident at the most recent follow-up and that heart size and function are similar between the 2 treatment strategies. Although not powered to detect an effect on major morbidity or mortality, it is noteworthy that major adverse clinical events including death were less common in the everolimus group.
Although these results are encouraging, they should be interpreted with caution. Patients with proteinuria (albumin/creatinine ratio >300 mg/mmol) were excluded. Conversion from CNI to mTOR after kidney transplantation has been associated with increased development of Class II donor-specific antibodies11; however, monitoring for development of de novo donor-specific antibodies post-transplant was not undertaken during the SCHEDULE Trial. There were substantial crossovers after the 12-month follow-up so that by the 5–7-year follow-up, almost 40% of the cyclosporine withdrawal group had recommenced a CNI and 10% of the cyclosporine group had been converted to everolimus and withdrawn from CNI. The results of the SCHEDULE Trial suggest that de novo everolimus, combined with early withdrawal of CNI, provides safe and effective immunosuppression for many but not all heart transplant recipients. The challenge for the future is to distinguish those who will benefit from mTOR-based, CNI-free regimens from those who will not. As acknowledged by the authors, further studies of the effect of mTOR-based, CNI-free regimens on morbidity and mortality after heart transplantation are needed.
1. Khush KK, Cherikh WS, Chambers DC, et al; International Society for Heart and Lung Transplantation. The international thoracic organ transplant registry of the International Society for Heart and Lung Transplantation: thirty-fifth adult heart transplantation report-2018; focus theme: multiorgan transplantation. J Heart Lung Transplant. 2018; 37101155–1168
2. Chakkera HA, Sharif A, Kaplan B. Negative cardiovascular consequences of small molecule immunosuppressants. Clin Pharmacol Ther. 2017; 1022269–276
3. Zuckermann A, Osorio-Jaramillo E, Aliabadi-Zuckermann AZ. mTOR inhibition and clinical transplantation: heart. Transplantation. 2018; 102(2S Suppl 1):S27–S29
4. Fine NM, Kushwaha SS. Recent advances in mammalian target of rapamycin inhibitor use in heart and lung transplantation. Transplantation. 2016; 100122558–2568
5. Otton J, Hayward CS, Keogh AM, et al. Everolimus-associated pneumonitis in 3 heart transplant recipients. J Heart Lung Transplant. 2009; 281104–106
6. Jennings DL, Lange N, Shullo M, et al. Outcomes associated with mammalian target of rapamycin (mTOR) inhibitors in heart transplant recipients: a meta-analysis. Int J Cardiol. 2018; 265:71–76
7. Gustafsson F, Andreassen AK, Andersson B, et al. Everolimus initiation with early calcineurin inhibitor withdrawal in de novo heart transplant recipients: long-term follow-up from the randomized SCHEDULE study. Transplantation. [Epub ahead of print. March 12, 2019]. doi: 10.1097/TP.0000000000002702
8. Andreassen AK, Andersson B, Gustafsson F, et al; SCHEDULE Investigators. Everolimus initiation and early calcineurin inhibitor withdrawal in heart transplant recipients: a randomized trial. Am J Transplant. 2014; 1481828–1838
9. Andreassen AK, Andersson B, Gustafsson F, et al; SCHEDULE Investigators. 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; 1641238–1247
10. Andreassen AK, Broch K, Eiskjær H, et al. Blood pressure in de novo heart transplant recipients treated with everolimus compared with a cyclosporine-based regimen: results from the randomized SCHEDULE Trial. Transplantation. 2018; 1034781–788
11. Croze LE, Tetaz R, Roustit M, et al. Conversion to mammalian target of rapamycin inhibitors increases risk of de novo donor-specific antibodies. Transpl Int. 2014; 278775–783