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This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 29th Annual Meeting and Scientific Sessions of the International Society for Heart and Lung Transplantation

Paris, France / April 22-25, 2009

Four groups of patients are known to be at especially high risk for poor outcomes following heart transplantation: women, people of African ancestry, patients with heart failure supported by a ventricular assist device (VAD) and patients with allosensitization, defined as a panel-reactive antibody (PRA) score of <u>></u>10%. Such patients are often critically ill and are at elevated risk for infections when they are treated with corticosteroid-containing immunosuppressive regimens, which leads to the need to study steroid-free approaches.

An analysis of data from the TICTAC (Tacrolimus in Combination, Tacrolimus Alone Compared) trial indicated that the use of calcineurin inhibitor (CNI) monotherapy for maintenance immunosuppression in high-risk patients is associated with excellent results and allows rapid steroid weaning, reported Dr. David Baran, Director of Heart Failure/Transplant Research, Newark Beth Israel Medical Center, New Jersey, and colleagues. The TICTAC trial was a prospective, randomized, controlled, open-label trial in which 150 adult heart transplant recipients received tacrolimus, corticosteroids and mycophenolate mofetil (MMF) for two weeks, and were then randomized to maintenance with either tacrolimus and MMF or tacrolimus alone, which began after the patients were weaned off steroids at six to eight weeks. The patients did not receive induction therapy. They were followed for one year on study, with some followed for as long as five years.

Outcomes in High-risk Patients

The investigators analyzed outcomes for patients in the aforementioned high-risk groups, looking at mean International Society for Heart and Lung Transplantation (ISHLT) biopsy score at six and 12 months, freedom from ISHLT grade 2R/3R rejection at one year and one- and three-year survival. The analysis included high-risk patients randomized to tacrolimus monotherapy or tacrolimus/MMF.

In an analysis of 28 female patients, the mean 12-month biopsy score was 0.57 ± 0.40 compared with 0.67 ± 0.39 for male patients; neither this difference nor the six-month difference between biopsy scores of males and females were statistically significant. Similarly, there were no differences at either time point in ISHLT biopsy scores for African-Americans vs. non-African-Americans (0.69 ± 0.44/0.65 ± 0.41 vs. 0.67 ± 0.42/0.65 ± 0.39, respectively).

There were also no significant differences at either six or 12 months among 38 patients on VADs pre-transplant and 112 patients who were not on a VAD, and results between the 45 patients with a PRA score <u>></u>10% and a PRA score <10% were also statistically similar. The authors also found that the five-year mortality curves for each risk factor group were also statistically similar, suggesting that neither corticosteroid weaning nor tacrolimus monotherapy presented any undetected long-term hazard.

The authors concluded that their data support the strategy of rapid steroid weaning early after transplantation. “The prospective, randomized trial data presented here suggest that the risk of allograft rejection is low with a minimized immunosuppression regimen and the five-year mortality plots demonstrated the long-term safety of this novel approach,” they reported.

“If we have to give out one message, it is this: cut the steroids,” said Dr. Baran. “In the field, people have this conundrum: if you have to stop the azathioprine or the MMF, what do you do? You do not need to add anything at all. I do not know whether this would hold up with cyclosporine, but I suspect most people would be loath to do that because of the decrease in potency.”

Renal Dysfunction: CNIs or Pre-existing Pathology?

Dr. Sean Pinney, Director, Advanced Heart Failure and Cardiac Transplant Program, Mount Sinai Medical Center, New York City, presented a retrospective review of clinical data from 18 heart transplant patients with chronic kidney disease (CKD) referred for renal consultation at his centre from January 2005 through January 2009. In all, 83% of the patients were men, 44% were Caucasian, 33% of African heritage and 17% of Latin American background. At the time of transplant, the mean patient age was 55.2 ± 10. Nearly one-third of the patients (29%) had diabetes as a pre-transplant comorbidity, 89% were hypertensive and 72% had ischemic cardiomyopathy as a pre-transplant diagnosis. Other diagnoses included myocarditis in two, hypertrophic cardiomyopathy/restrictive cardiomyopathy in two and sarcoidosis in one. CNIs used were tacrolimus (70.6%), cyclosporine alone (17.6%) or cyclosporine/sirolimus (11.8%).

Biopsy results showed that of the 18 patients, only one (5.5%) had renal pathology that could directly be attributed to CNI toxicity, which the authors defined as the presence of interstitial fibrosis or nodular arteriolar hyalinization. Histology studies of samples from the 18 patients showed that nine had nephrosclerosis with diabetic changes, four had nephrosclerosis with focal segmental glomerular sclerosis, four had nephrosclerosis alone and one had no signs of nephrosclerosis.

Dr. Pinney reported that comorbidities with known deleterious effects on renal vasculature, including both type two diabetes mellitus and hypertension, are prevalent after orthotopic heart transplantation. “Our results do not identify direct CNI toxicity as a frequent cause of CKD,” he told delegates.

CAPRI Study

The findings of the Mount Sinai group were supported at the ISHLT conference by the 14-centre CAPRI study, a Spanish trial that examined risk factors associated with moderate-to-severe renal disease in heart transplant patients. The study involved 1062 adult outpatients with a first heart transplant who presented for follow-up from November 2007 through March 2008. The investigators studied renal function parameters, including glomerular filtration rate (GFR), with moderate to severe renal dysfunction defined as a GFR <60 mL/min/1.73 m². They found that about 27% of patients had diabetes and 64% had hypertension, both risk factors for renal dysfunction. At the time of assessment, 68% of patients were receiving steroids, 53.9% cyclosporine, 33.2% tacrolimus, 66.5% MMF, 11.7% azathioprine, 5.9% sirolimus and 14.2% everolimus.

CAPRI co-investigator Dr. Juan F. Delgado, Hospital 12 de octubre, Madrid, Spain, and Chair, Heart Failure and Heart Transplant Association, Spanish Society of Cardiology, reported that among 924 patients on a CNI at the time of follow-up, significant predictors for renal disease included female gender (P=0.001), pre-transplant creatinine (P<0.001), age at transplant (P<0.001), creatinine 30 days’ post-transplant (P<0.001) and time since transplant (P<0.001). There was a trend toward lower risk for patients put on tacrolimus vs. cyclosporine at the time of follow-up, although this was not statistically significant.

Changes in Left Ventricular Function

There is evidence to suggest that adverse events such as hypertension, left ventricular hypertrophy (LVH) and chronic renal insufficiency seen with cyclosporine use may be mitigated by a switch to tacrolimus. In a study published in a supplement to the Journal of Heart and Lung Transplantation in February 2009, Dr. M. Abdul Kashem, Adjunct Assistant Professor, Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania, and colleagues examined the effects of a switch from cyclosporine to tacrolimus on LVH as well as systolic and diastolic function. They found that among patients followed for 14 years in their cardiac transplant program who underwent the switch due to medically indicated conditions, there was a slight improvement in LV ejection fraction and a significant improvement in diastolic relaxation six months after the switch.

“Besides the advantage for renal function and possible graft atherosclerosis, switching from cyclosporine to tacrolimus is also likely to improve LV diastolic function and exercise tolerance in patients post-heart transplant,” the investigators concluded.

Summary

Clearly, the prognosis for heart transplant recipients has improved dramatically since Dr. Christian Barnard’s pioneering surgeries in the 1960s. The introduction of the CNIs and other less toxic immunosuppressive agents has given many years of life to patients who would otherwise die. Although CNIs, like all agents, have adverse effects, these effects are manageable and are outweighed by the benefits that the agents bring to patients, heart transplant experts here agreed.