[Show abstract][Hide abstract] ABSTRACT: 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.
Full-text · Article · Jan 2016 · American Journal of Transplantation
[Show abstract][Hide abstract] ABSTRACT: Objective:
Dilated cardiomyopathy (DCM) is characterised by left ventricular dilation and dysfunction not caused by coronary disease, valvular disease or hypertension. Owing to the considerable aetiological and prognostic heterogeneity in DCM, an extensive diagnostic work-up is recommended. We aimed to assess the value of diagnostic testing beyond careful physical examination, blood tests, echocardiography and coronary angiography.
From October 2008 to November 2012, we prospectively recruited 102 patients referred to our tertiary care hospital with a diagnosis of 'idiopathic' DCM based on patient history, physical examination, routine blood tests, echocardiography and coronary angiography. Extended work-up included cardiac MRI, exercise testing, right-sided catheterisation with biopsies, 24 h ECG and genetic testing.
In 15 patients (15%), a diagnosis other than 'idiopathic' DCM was made based on additional tests. In 10 patients (10%), a possibly disease-causing mutation was detected. 2 patients were found to have non-compaction cardiomyopathy based on MRI findings; 2 patients had systemic inflammatory disease with cardiac involvement; and in 1 patient, cardiac amyloidosis was diagnosed by endomyocardial biopsy. Only in 5 cases did the results of the extended work-up have direct therapeutic consequences.
In patients with DCM, in whom patient history and routine work-up carry no clues to the aetiology, the diagnostic and therapeutic yield of extensive additional testing is modest.
[Show abstract][Hide abstract] ABSTRACT: Elevated levels of soluble ST2 (sST2) are associated with adverse outcome in heart failure. A change in sST2 levels has also been shown to presage outcome. In vitro, ST2 expression is induced by myocardial stress and pro-inflammatory stimuli. The determinants of sST2 levels in vivo, and how they vary with clinical status over time, have not been well described. In a cohort of patients with non-ischemic heart failure, we aimed to assess the association between sST2-levels and hemodynamic parameters reflecting right and left ventricular pre- and afterload, and how these vary with time and clinical status.Methods
We prospectively recruited 102 patients with a left ventricular ejection fraction of 26 ± 10% and a diagnosis of idiopathic dilated cardiomyopathy based on patient history, clinical examination, echocardiography and coronary angiography. Patients went through extensive baseline work-up and were re-examined after one year. Subsequently, heart transplantations and deaths were recorded. Determinants of sST2 were analyzed at baseline and after one year. Soluble ST2 was measured with a highly sensitive immunoassay.ResultsSoluble ST2 levels were associated with hemodynamic parameters, but these associations were attenuated with clinical improvement. Soluble ST2 was elevated in patients with severe symptoms, but did not vary with etiology, viral presence or the amount of myocardial fibrosis. Heart rate and right atrial pressure remained independent predictors of sST2 on multiple regression analysis.Conclusions
Our results imply that in non-ischemic heart failure, sST2 reflects hemodynamic stress rather than pathogenic processes in the myocardium.
No preview · Article · Nov 2014 · International Journal of Cardiology
[Show abstract][Hide abstract] ABSTRACT: 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.
Full-text · Article · Jul 2014 · American Journal of Transplantation
[Show abstract][Hide abstract] ABSTRACT: Calcineurin inhibitors have constituted the cornerstone of immunosuppressive regime following heart transplantation. The transplanted heart is subjected to increased hypertrophy and the risk of developing graft vasculopathy. To what extent these negative effects are influenced by different immunosuppressive drugs, is largely unknown. We conducted a randomised, open-label, parallel group clinical trial to assess early introduction of everolimus followed by withdrawal of cyclosporine (EVE) in de novo heart transplant recipients, compared to a standard protocol of cyclosporine-based immunosuppression (CYA). In a substudy we investigated cardiac reserve by invasive hemodynamics during rest and exercise, early (7 weeks) and later (52 weeks) after heart transplantation, in 28 (EVE) and 34 (CYA) patients. The aim was to compare cardiac reserve in the two treatment arms.
Methods: Patients had a right heart catheterisation at rest and during submaximal supine bicycle exercise. Pressures and cardiac output (CO) were measured.
Results: At baseline (7 w) PCWP and CO increased from rest to exercise. After 52 w the hemodynamic pattern was similar, with a non-significant trend towards higher CO during exercise. There were no significant differences between treatment groups.
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Full-text · Article · Apr 2014 · The Journal of Heart and Lung Transplantation
[Show abstract][Hide abstract] ABSTRACT: Purpose: Calcineurin inhibitors remain the mainstay of immunosuppression following heart transplantation, but are associated with significant long term complications. We conducted a randomized, open-label, parallel group clinical trial to assess whether early introduction of everolimus followed by withdrawal of cyclosporine would lead to superior renal function in de novo heart transplant (HTx) recipients, compared to a standard protocol of cyclosporine-based immunosuppression.
Methods: A total of 115 patients were randomly assigned within 5 days postoperatively to low dose everolimus and reduced dose cyclosporine (n=56) or standard cyclosporine dosage (n=59). All received mycophenolate mofetil and corticosteroids. In the former group, cyclosporine was withdrawn and full-dose everolimus initiated after 7-11 weeks. The primary efficacy end point was renal function assessed by measured glomerular filtration rate (mGFR) after 12 months. Secondary objectives included progression of cardiac-allograft vasculopathy (as assessed by intravascular ultrasound (IVUS)), left ventricular function (assessed by echocardiography and NT-proBNP), number of rejections and serious adverse effects.
Results: At 12 months, mGFR was significantly higher in the everolimus group compared to those receiving standard cyclosporine-based immunosuppression (80 mL/kg/1.73 m2 vs. 62 mL/kg/1.73 m2; p<0.0001; Intention To Treat population)). A significantly higher incidence of acute cellular rejection was observed in the everolimus group, while left ventricular dimension and function as assessed by echocardiography and NT-proBNP, were similar between the two groups. With similar rates of bacterial infection, cytomegalovirus infection was significantly less common among everolimus treated patients (n=3 (5.4%) vs.n=18 (30.5%); p<0.001). IVUS data, not yet ready, will be presented.
Conclusions: Early elimination of cyclosporine and replacement with an everolimus-based immunosuppressive strategy was associated with significant and clinically important improvement in renal function in HTx patients.
Preview · Article · Aug 2013 · European Heart Journal