SAN FRANCISCO – Use of an everolimus-containing regimen with early stopping of cyclosporine after de novo heart transplantation improves renal function and reduces cardiac allograft vasculopathy, without compromising graft outcomes, new data suggest.
These was among key findings of the randomized, open-label SCHEDULE (Scandinavian Heart Transplant Everolimus De Novo Study with Early Calcineurin Inhibitor Avoidance) reported at the 2014 World Transplant Congress.
"Renal dysfunction and cardiac allograft vasculopathy are markers for increased morbidity and mortality after heart transplantation," lead author Dr. Vilborg Sigurdardottir commented when introducing the study.
Patients in the trial were randomized evenly to a three-drug regimen containing the calcineurin inhibitor cyclosporine (Sandimmune) or to a four-drug regimen also containing the mTOR inhibitor everolimus (Zortress) with discontinuation of cyclosporine at week 7-11. Everolimus is currently approved by the Food and Drug Administration to prevent graft rejection in kidney and liver transplant recipients and, under another brand name, to treat some cancers.
Measured glomerular filtration rate (GFR) at 12 months, the trial’s primary outcome, was 30% better in the everolimus group than in the cyclosporine group (79.8 vs. 61.5 mL/min per 1.73 m2; P less than .001), according to results presented at the congress and recently published (Am. J. Transplant. 2014;14:1828-38).
The urinary albumin-creatinine ratio was higher in the everolimus group, but none of the patients had nephrotic levels of proteinuria.
Rates of adverse events were similar, with the exception that the everolimus group had a lower rate of cytomegalovirus infection (5% vs. 30%) and a higher rate of pneumonia (12% vs. 3%), Dr. Sigurdardottir reported at the congress, which was sponsored by the American Society of Transplant Surgeons.
The incidence of biopsy-proven acute rejection of at least grade 2R was greater with everolimus (40% vs. 18%, P = .01). However, at 12 months, the groups did not differ with respect to left ventricular function as assessed by echocardiography and biomarkers, and, in a cardiac reserve substudy, with respect to cardiac output and pulmonary capillary wedge pressure.
The incidence of cardiac allograft vasculopathy, defined as a mean media-intima thickness of at least 0.5 mm on intravascular ultrasound (IVUS), was lower in the everolimus group (51% vs. 65%, P less than .01), and progression assessed as the change in percent atheroma volume was slower in that group.
"Everolimus initiation and early cyclosporine elimination in de novo heart transplant recipients showed a highly significant improvement of renal function in terms of measured GFR, a reduced incidence of cytomegalovirus [a confirmatory result of previous large-scale studies], similar numbers of adverse and serious adverse events, and an increased incidence of treated acute rejection, however, without hemodynamic compromise and with preserved cardiac function and preserved cardiac reserve," concluded Dr. Sigurdardottir, who is medical director of heart transplantation at the Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden. "We saw also favorable coronary remodeling and less graft vasculopathy, as previously shown."
Among patients whose donor hearts had such disease, the increase in media-intima thickness and percent atheroma volume was less with everolimus than with cyclosporine, Dr. Sigurdardottir said. "Interestingly, we saw here that the total atheroma volume decreased between baseline and 12 months in the everolimus group in the patients who had preexisting donor disease."
An attendee from Norway said, "I am a nephrologist, and if I were to get a new heart, I’d rather have a GFR of 61 and no rejection than a GFR of 73 with rejection. Have you looked at the development of donor-specific antibodies in the ones who had rejection, because I’d like to live for more than a year – I’d like to live 3 years or 5 years or 10 years."
"You are absolutely right. At the time of transplantation, we would be looking at the acute problems, and we often see the kidney dysfunction, so we want to do something about that. But of course these studies need to tell us how patients fare longer term," Dr. Sigurdardottir agreed. None of the patients were found to have donor-specific antibodies, but the trial protocol did not mandate routine measurement, she said.
An attendee from Los Angeles commented, "We tried to do CNI [calcineurin inhibitor] weaning in 2006 and had hemodynamically compromised rejection. Now, I congratulate you on being innovative and having quadruple therapy from the get-go and then taking off the CNI. But the issue of increased rejection is important because ISHLT [International Society for Heart and Lung Transplantation] data show that that does lead to poorer outcome. It is countered by your improvement in renal function, but also your IVUS result, I think, is very important as well."