Satish Arora

Everolimus initiation and early calcineurin inhibitor withdrawal in heart transplant recipients: a randomized trial.

In a randomized, open‐label trial, everolimus was compared to cyclosporine in 115 de novo heart transplant recipients. Patients were assigned within 5 days posttransplant to low‐exposure everolimus (3–6 ng/mL) with reduced‐exposure cyclosporine (n = 56), or standard‐exposure cyclosporine (n = 59), with both mycophenolate mofetil and corticosteroids. In the everolimus group, cyclosporine was withdrawn after 7–11 weeks and everolimus exposure increased (6–10 ng/mL). The primary efficacy end point, measured GFR at 12 months posttransplant, was significantly higher with everolimus versus cyclosporine (mean ± SD: 79.8 ± 17.7 mL/min/1.73 m2 vs. 61.5 ± 19.6 mL/min/1.73 m2; p < 0.001). Coronary intravascular ultrasound showed that the mean increase in maximal intimal thickness was smaller (0.03 mm [95% CI 0.01, 0.05 mm] vs. 0.08 mm [95% CI 0.05, 0.12 mm], p = 0.03), and the incidence of cardiac allograft vasculopathy (CAV) was lower (50.0% vs. 64.6%, p = 0.003), with everolimus versus cyclosporine at month 12. Biopsy‐proven acute rejection after weeks 7–11 was more frequent with everolimus (p = 0.03). Left ventricular function was not inferior with everolimus versus cyclosporine. Cytomegalovirus infection was less common with everolimus (5.4% vs. 30.5%, p < 0.001); the incidence of bacterial infection was similar. In conclusion, everolimus‐based immunosuppression with early elimination of cyclosporine markedly improved renal function after heart transplantation. Since postoperative safety was not jeopardized and development of CAV was attenuated, this strategy may benefit long‐term outcome.

Prognostic importance of renal function 1 year after heart transplantation for all-cause and cardiac mortality and development of allograft vasculopathy.

Background. Impaired renal function is associated with increased mortality among heart failure patients. Although a significant proportion of heart transplant (HTx) recipients have reduced renal function at 1 year post-HTx, no previous study has evaluated the associated risk for both all-cause and cardiac mortality. Hence, we assessed the relationship between glomerular filtration rate (GFR) at 1 year post-HTx and all-cause and cardiac mortality and development of cardiac allograft vasculopathy (CAV). Methods. We evaluated 381 patients with a minimum survival of 1 year post-HTx and the Modification of Diet in Renal Disease Study formula was used to calculate estimated GFR. Mortality and angiographic CAV were defined as separate endpoints, and median follow-up was 7.4 and 4.0 years, respectively. Results. During the follow-up period, 122 patients died and 154 patients developed CAV. Reduced GFR pre-HTx was not a risk factor for either endpoint. Overall, 193 (51%) patients had GFR <60 ml/min/1.73 m2 at one year post-HTx and this was an independent predictor of all-cause mortality with an adjusted hazard ratio of 1.7 (P=0.01) for a GFR between 30–60 and 3.2 (P=0.006) for GFR <30 ml/min/1.73 m2. GFR <60 ml/min/1.73 m2 at 1 year post-HTx was also associated with a higher risk of cardiac mortality (HR=1.9; P=0.04) but did not predict the development of CAV. Conclusions. Renal impairment is evident in a majority of HTx recipients at 1 year post-HTx. It is an important risk factor for both all-cause and cardiac mortality but does not predict the development of angiographic CAV.

Effect of everolimus introduction on cardiac allograft vasculopathy--results of a randomized, multicenter trial.

Background. Everolimus reduces the progression of cardiac allograft vasculopathy (CAV) in de novo heart transplant (HTx) recipients, but the influence on established CAV is unknown. Methods. In this Nordic Certican Trial in Heart and lung Transplantation substudy, 111 maintenance HTx recipients (time post-HTx 5.8±4.3 years) randomized to everolimus+reduced calcineurin inhibitor (CNI) or standard CNI had matching (intravascular ultrasound) examinations at baseline and 12 months allowing accurate assessment of CAV progression. Results. No significant difference in CAV progression was evident between the treatment groups (P=0.30). When considering patients receiving concomitant azathioprine (AZA) therapy (n=39), CAV progression was attenuated with everolimus versus standard CNI (&Dgr;maximal intimal thickness 0.00±0.04 and 0.04±0.04 mm, &Dgr;percent atheroma volume 0.2%±3.0% and 2.6%±2.5%, and &Dgr;total atheroma volume 0.25±14.1 and 19.8±20.4 mm3, respectively [P<0.05]). When considering patients receiving mycophenolate mofetil (MMF), accelerated CAV progression occurred with everolimus versus standard CNI (&Dgr;maximal intimal thickness 0.06±0.12 vs. 0.02±0.06 mm and &Dgr;percent atheroma volume 4.0%±6.3% vs. 1.4%±3.1%, respectively; P<0.05). The levels of C-reactive protein and vascular cell adhesion molecule-1 declined significantly with AZA+everolimus, whereas MMF+everolimus patients demonstrated a significant increase in levels of C-reactive protein, vascular cell adhesion molecule-1, and von Willebrand factor. Conclusions. Conversion to everolimus and reduced CNI does not influence CAV progression among maintenance HTx recipients. However, background immunosuppressive therapy is important as AZA+everolimus patients demonstrated attenuated CAV progression and a decline in inflammatory markers, whereas the opposite pattern was seen with everolimus+MMF. The different effect of everolimus when combined with AZA versus MMF could potentially reflect hitherto unknown interactions.

Early Postoperative Left Ventricular Function by Echocardiographic Strain is a Predictor of 1-Year Mortality in Heart Transplant Recipients

BACKGROUND Left ventricular (LV) function can be accurately assessed using two-dimensional speckle-tracking echocardiography. The association between reduced LV global longitudinal strain (LVGLS) magnitude and risk for mortality in heart transplant recipients is unclear. The aim of this study was to test the hypothesis that LVGLS could predict 1-year mortality in heart transplant recipients. METHODS A total of 176 consecutive adult primary single-organ orthotopic heart transplant recipients were retrospectively evaluated. Of these, 167 had acceptable echocardiographic image quality and were included in the study. N-terminal pro-B-type natriuretic peptide, creatinine, C-reactive protein, and invasive hemodynamic parameters were measured, and echocardiography was performed 1 to 3 weeks after heart transplantation. LVGLS was averaged from regional strain in 16 LV segments. RESULTS During the first year, 15 patients (9%) died 86 ± 72 days after heart transplantation. LVGLS and LV ejection fraction were decreased in magnitude in nonsurvivors (P < .05). They were older and had higher donor ages. Mean pulmonary capillary wedge pressures were similar in the two groups, while all other hemodynamic parameters were increased in nonsurvivors (P < .05). LVGLS was the only significant (P = .02) noninvasive independent predictor, with a hazard ratio of 1.42 (95% confidence interval, 1.07-1.88; P = .02) per 1% decrease in strain magnitude, while pulmonary vascular resistance was a significant (P < .001) invasive predictor, with a hazard ratio of 3.98 (95% confidence interval, 2.01-7.87) of 1-year mortality in multivariate Cox regression analysis. CONCLUSIONS Reduced LV function and increased pulmonary vascular resistance are related to poor prognosis in heart transplant recipients. Early assessment of LVGLS might be a noninvasive predictor of 1-year mortality in these patients.

Benefit of early conversion from CNI-based to everolimus-based immunosuppression in heart transplantation

BACKGROUND Calcineurin inhibitor (CNI)-induced nephrotoxicity is a feared adverse effect after heart transplantation (HTx). In patients with advanced renal failure we performed an overnight conversion from cyclosporine (CsA) to everolimus within the first year after HTx and compared changes in renal function to a similar switch performed in a group of long-term HTx survivors with 24-month follow up. METHODS Sixteen HTx recipients (Group 1), including 5 patients undergoing dialysis, were switched overnight from CsA to everolimus at 5.5 (range 1.3 to 8.5) months post-operatively, whereas 15 patients completed 24 months of follow-up. Fifteen long-term survivors (Group 2) were recruited at 96 (58 to 148) months post-HTx. Due to 3 withdrawals and 2 deaths, 10 of these 15 patients remained available for follow-up assessment. RESULTS In Group 1 patients, creatinine level improved from 211 (186 to 263) to 112 (98 to 140) mumol/liter and estimated glomerular filtration rate (eGFR) from 29 (20 to 35) to 62 (43 to 69) ml/min/1.73 m(2) (p < 0.001). In Group 2, creatinine decreased from 227 (188 to 255) to 193 (150 to 250) micromol/liter (p = 0.299), and eGFR increased from 26 (21 to 31) to 28 (22 to 35) ml/min/1.73 m(2) (p = 0.225). Four cellular rejections were treated successfully in Group 1. All together, 24 adverse events occurred. CONCLUSIONS These preliminary data are the first to suggest that the improvement in renal function after switching to CNI-free everolimus treatment has the greatest potential within the first year post-HTx. While we await randomized, controlled trials, it appears that conversion can be performed with acceptable safety in selected patients.

Improvement in renal function after everolimus introduction and calcineurin inhibitor reduction in maintenance thoracic transplant recipients: The significance of baseline glomerular filtration rate

BACKGROUND The NOCTET (NOrdic Certican Trial in HEart and lung Transplantation) trial demonstrated that everolimus improves renal function in maintenance thoracic transplant (TTx) recipients. Nevertheless, introduction of everolimus is not recommended for patients with advanced renal failure. We evaluated NOCTET data to assess everolimus introduction amongst TTx recipients with advanced renal failure. METHODS This 12-month multicenter Scandinavian study randomized 282 maintenance TTx recipients to everolimus introduction with calcineurin inhibitor (CNI) reduction or standard CNI therapy. The measured glomerular filtration rate (mGFR) was noted at baseline and after 1-year using Cr-ethylenediaminetetraacetic acid clearance. RESULTS In 21 patients with a baseline mGFR of 20 to 29 ml/min/1.73 m(2), renal function improved in the everolimus group compared with the control group ((ΔmGFR 6.7 ± 9.0 vs -1.6 ± 5.1 ml/min/1.73 m(2); p = 0.03). Amongst 173 patients with moderate renal impairment (mGFR 30-59 ml/min/1.73 m(2)), renal function improvement was also greater amongst everolimus patients than in controls (ΔmGFR 5.1 ± 11.1 vs -0.5 ± 8.7 ml/min/1.73 m(2); p < 0.01). In 55 patients with mGFR 60 to 89 ml/min/1.73 m(2), mGFR did not change significantly in either group. Improvement in mGFR was limited to patients with a median time since TTx of less than 4.6 years and was also influenced by CNI reduction during the study period. CONCLUSIONS Everolimus introduction and reduced CNI significantly improved renal function amongst maintenance TTx patients with pre-existing advanced renal failure. This beneficial effect was limited to patients undergoing conversion in less than 5 years after TTx, indicating a window of opportunity that is appropriate for pharmacologic intervention with everolimus.

Everolimus Initiation With Early Calcineurin Inhibitor Withdrawal in De Novo Heart Transplant Recipients: Three-Year Results From the Randomized SCHEDULE Study.

In a randomized, open‐label trial, de novo heart transplant recipients were randomized to everolimus (3–6 ng/mL) with reduced‐exposure calcineurin inhibitor (CNI; cyclosporine) to weeks 7–11 after transplant, followed by increased everolimus exposure (target 6–10 ng/mL) with cyclosporine withdrawal or standard‐exposure cyclosporine. All patients received mycophenolate mofetil and corticosteroids. A total of 110 of 115 patients completed the 12‐month study, and 102 attended a follow‐up visit at month 36. Mean measured GFR (mGFR) at month 36 was 77.4 mL/min (standard deviation [SD] 20.2 mL/min) versus 59.2 mL/min (SD 17.4 mL/min) in the everolimus and CNI groups, respectively, a difference of 18.3 mL/min (95% CI 11.1–25.6 mL/min; p < 0.001) in the intention to treat population. Multivariate analysis showed treatment to be an independent determinant of mGFR at month 36. Coronary intravascular ultrasound at 36 months revealed significantly reduced progression of allograft vasculopathy in the everolimus group compared with the CNI group. Biopsy‐proven acute rejection grade ≥2R occurred in 10.2% and 5.9% of everolimus‐ and CNI‐treated patients, respectively, during months 12–36. Serious adverse events occurred in 37.3% and 19.6% of everolimus‐ and CNI‐treated patients, respectively (p = 0.078). These results suggest that early CNI withdrawal after heart transplantation supported by everolimus, mycophenolic acid and steroids with lymphocyte‐depleting induction is safe at intermediate follow‐up. This regimen, used selectively, may offer adequate immunosuppressive potency with a sustained renal advantage.

Probrain natriuretic peptide and C-reactive protein as markers of acute rejection, allograft vasculopathy, and mortality in heart transplantation

Background. N-terminal probrain natriuretic peptide (NT-proBNP) and C-reactive protein (CRP) are useful in risk stratification of patients with congestive heart failure. They could also be markers of distinctly altered hormonal and immunological milieus, but the combined prognostic value of these biomarkers in heart transplant (HTx) recipients has not been assessed previously. Methods. We sought to assess the individual and combined value of NT-proBNP and CRP as markers of acute rejection, cardiac allograft vasculopathy (CAV) and all-cause mortality in HTx recipients. We evaluated 101 patients for acute rejection and 210 patients for CAV and all-cause mortality. Patients evaluated for rejection had serial endomyocardial biopsies and plasma sampling performed during the first year postHTx. All other patients had plasma samples taken upon inclusion at an annual visit. Median follow-up for CAV and all-cause mortality was 2.2 years and 5.4 years, respectively. Results. Altogether, 1131 biopsy procedures were performed, and increased NT-proBNP and CRP levels were not useful markers of acute cellular rejection. In total, 78 (37%) patients developed CAV, and 39 (19%) patients died. Neither biomarker was a predictor of CAV, but both were independent predictors of mortality. When combining both biomarkers, elevated levels of both NT-proBNP and CRP identified patients at highest risk for CAV (HR 2.10, P=0.01) and all-cause mortality (HR 3.14, P=0.01). Conclusions. In HTx recipients, NT-proBNP and CRP are not useful as markers of acute cellular rejection during the first year postHTx, but combined analysis adds significantly to their predictive value for development of CAV and all-cause mortality.

Effect of high-intensity interval training on progression of cardiac allograft vasculopathy

BACKGROUND Cardiac allograft vasculopathy (CAV) is a progressive form of atherosclerosis occurring in heart transplant (HTx) recipients, leading to increased morbidity and mortality. Given the atheroprotective effect of exercise on traditional atherosclerosis, we hypothesized that high-intensity interval training (HIIT) would reduce the progression of CAV among HTx recipients. METHODS Forty-three cardiac allograft recipients (mean ± SD age 51 ± 16 years; 67% men; time post-HTx 4.0 ± 2.2 years), all clinically stable and >18 years old, were randomized to either a HIIT group or control group (standard care) for 1 year. The effect of training on CAV progression was assessed by intravascular ultrasound (IVUS). RESULTS IVUS analysis revealed a significantly smaller mean increase [95% CI] in atheroma volume (PAV) of 0.9% [95% CI -;0.3% to 1.9%] in the HIIT group as compared with the control group, 2.5% [1.6% to 3.5%] (p = 0.021). Similarly, the mean increase in total atheroma volume (TAV) was 0.3 [0.0 to 0.6] mm(3)/mm in the HIT group vs 1.1 [0.6 to 1.7] mm(3)/mm in the control group (p = 0.020), and mean increase in maximal intimal thickness (MIT) was 0.02-0.01 to 0.04] mm in the HIIT group vs 0.05 [0.03 to 0.08] mm in the control group (p = 0.054). Qualitative plaque progression (virtual histology parameters) and inflammatory activity (biomarkers) were similar between the 2 groups during the study period. CONCLUSIONS HIIT among maintenance HTx recipients resulted in a significantly impaired rate of CAV progression. Future larger studies should address whether exercise rehabilitation strategies should be included in CAV management protocols.

Intra-aortic balloon counterpulsation as a bridge to heart transplantation does not impair long-term survival.

There are few studies of the use of intra‐aortic balloon pump (IABP) treatment as a bridge to heart transplantation (HTx). This is the first study to compare long‐term clinical and haemodynamic outcomes in IABP‐treated HTx patients and electively transplanted patients.