| 1. |
- Arora, Satish, et al.
(författare)
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Effect of Everolimus Initiation and Calcineurin Inhibitor Elimination on Cardiac Allograft Vasculopathy in De Novo Heart Transplant Recipients
- 2018
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Ingår i: Circulation. Heart failure. - 1941-3297. ; 11:9, s. 004050-004050
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Tidskriftsartikel (refereegranskat)abstract
- Background Cardiac allograft vasculopathy (CAV) limits survival after heart transplantation, and the effect of different immunosuppressive regimens on CAV is not fully understood. The randomized SCHEDULE trial (Scandinavian Heart Transplant Everolimus De Novo Study With Early Calcineurin Inhibitors Avoidance) evaluated whether initiation of the proliferation signal inhibitor everolimus and early cyclosporine elimination can reduce CAV development. Methods and Results The SCHEDULE trial was a multicenter Scandinavian trial, where 115 de novo heart transplantation recipients were randomized to everolimus with complete cyclosporine withdrawal 7 to 11 weeks after heart transplantation or standard cyclosporine-based immunosuppression. Seventy-six (66%) patients had matched intravascular ultrasound examinations at baseline and 12 and 36 months. Intravascular ultrasound analysis evaluated maximal intimal thickness, percent atheroma volume, and total atheroma volume. Qualitative plaque analysis using virtual histology assessed fibrous, fibrofatty, and calcified tissue as well as necrotic core. Serum inflammatory markers were measured in parallel. The everolimus group (n=37) demonstrated significantly reduced CAV progression as compared with the cyclosporine group (n=39) at 36 months (Δ maximal intimal thickness, 0.09±0.05 versus 0.15±0.16 mm [ P=0.03]; Δ percent atheroma volume, 5.3±2.8% versus 7.6±5.9% [ P=0.03]; and Δ total atheroma volume, 33.9±71.2 versus 54.2±96.0 mm3 [ P=0.34], respectively]. At 36 months the number of everolimus patients with rejection graded ≥2R was 15 (41%) as compared with 5 (13%) in the cyclosporine group ( P=0.01). Everolimus did not affect CAV morphology or immune marker activity during the follow-up period. Conclusions The SCHEDULE trial demonstrates that everolimus initiation and early cyclosporine elimination significantly reduces CAV progression at 12 months, and this beneficial effect is clearly sustained at 36 months. Clinical trial registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT01266148.
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| 2. |
- Arora, Satish, et al.
(författare)
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Effect of Everolimus Introduction on Cardiac Allograft Vasculopathy-Results of a Randomized, Multicenter Trial
- 2011
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Ingår i: Transplantation. - : Williams and Wilkins. - 0041-1337 .- 1534-6080. ; 92:2, s. 235-243
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Tidskriftsartikel (refereegranskat)abstract
- 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 (Delta maximal intimal thickness 0.00 +/- 0.04 and 0.04 +/- 0.04 mm, Delta percent atheroma volume 0.2%+/- 3.0% and 2.6%+/- 2.5%, and Delta total atheroma volume 0.25 +/- 14.1 and 19.8 +/- 20.4 mm(3), respectively [Pless than0.05]). When considering patients receiving mycophenolate mofetil (MMF), accelerated CAV progression occurred with everolimus versus standard CNI (Delta maximal intimal thickness 0.06 +/- 0.12 vs. 0.02 +/- 0.06 mm and Delta percent atheroma volume 4.0%+/- 6.3% vs. 1.4%+/- 3.1%, respectively; Pless than0.05). 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.
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| 3. |
- Arora, Satish, et al.
(författare)
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Improvement in renal function after everolimus introduction and calcineurin inhibitor reduction in maintenance thoracic transplant recipients: The significance of baseline glomerular filtration rate
- 2012
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Ingår i: The Journal of Heart and Lung Transplantation. - : Elsevier. - 1053-2498 .- 1557-3117. ; 31:3, s. 259-265
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The NOCTET (NOrdic Certican Trial in HEart and lung Transplantation) trial demonstrated that everolimus improves renal function in maintenance thoracic transplant (FIX) 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. less thanbrgreater than less thanbrgreater thanMETHODS: 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-ethylenediarninetetraacetic acid clearance. less thanbrgreater than less thanbrgreater thanRESULTS: 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 ((Delta mGFR 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 (Delta mGFR 5.1 +/- 11.1 vs -0.5 +/- 8.7 ml/min/1.73 m(2); p andlt; 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 CM reduction during the study period. less thanbrgreater than less thanbrgreater thanCONCLUSIONS: 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.
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| 4. |
- Ekberg, Henrik, et al.
(författare)
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Clinicians underestimate gastrointestinal symptoms and overestimate quality of life in renal transplant recipients: A multinational survey of nephrologists
- 2007
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Ingår i: Transplantation. - 1534-6080. ; 84:8, s. 1052-1054
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Tidskriftsartikel (refereegranskat)abstract
- Gastrointestinal (GI) symptoms are common in renal transplant recipients and are associated with impaired health-related quality of life (HRQoL). We investigated clinician attitudes to GI symptoms and HRQoL in these patients by surveying 145 nephrologists from Sweden, Denmark, Finland, and Norway. In total, 79 clinicians responded. They estimated that 20% of their patients experienced GI discomfort and that 36% had impaired HRQoL. We previously conducted a survey of the renal transplant recipients treated-by-these clinicians, inwhich 92% reported troublesome GI symptoms and 53% had impaired HRQoL compared with the general population. Nephrologists were more likely to manage GI symptoms by reducing immunosuppressant dose (87%) than by switching medication to one with fewer GI side effects (66%). We conclude that clinicians appear to underestimate the prevalence of GI symptoms and impaired HRQoL. Improving patient-clinician communication could lead to more informed management, resulting in better HRQoL and increased graft survival.
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| 5. |
- Ekberg, Henrik, et al.
(författare)
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Increased prevalence of gastrointestinal symptoms associated with impaired quality of life in renal transplant recipients.
- 2007
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Ingår i: Transplantation. - : Ovid Technologies (Wolters Kluwer Health). - 1534-6080 .- 0041-1337. ; 83:3, s. 282-289
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Tidskriftsartikel (refereegranskat)abstract
- Background. Immunosuppressive therapies have been associated with gastrointestinal (GI) side effects, which may impair health-related quality of life (HRQoL). Methods. In this survey, 4,232 renal transplant recipients from Denmark, Finland, Nor-way, and Sweden completed the Short-Form 36 (SF-36) questionnaire and the Gastrointestinal Symptom Rating Scale (GSRS). SF-36 scores were compared with country norm values. Multiple logistic regression analysis was used to identify immunosuppressants associated with GI symptoms. Results. The prevalence of troublesome GI symptoms (GSRS > 1) was 83% for indigestion, 69% for abdominal pain, 58% for constipation, 53% for diarrhea, 47% for reflux, and 92% for any GI symptom. Compared with the general population, HRQoL was most commonly meaningfully impaired in the general health dimension (53% of patients). The presence and severity of GI symptoms were associated with worse HRQoL. Tacrolimus showed a significant association with diarrhea (odds ratio [OR]: 1.7; 95% confidence interval [CI]: 1.4-2.0) and constipation (OR: 1.3; 95% Cl: 1.1-1.6), and sirolimus with indigestion (OR: 2.9; 95% Cl: 1.0-8.1) and abdominal pain (OR: 2.2; 95% Cl: 1.1-4.4). Conclusions. GI symptoms are associated with impaired HRQoL in the renal transplant population. Managing GI symptoms by careful choice of immunosuppressants should be a focus for improving HRQoL in renal transplant recipients
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| 6. |
- Gullestad, Lars, et al.
(författare)
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Everolimus With Reduced Calcineurin Inhibitor in Thoracic Transplant Recipients With Renal Dysfunction: A Multicenter, Randomized Trial
- 2010
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Ingår i: Transplantation. - : Williams and Wilkins. - 0041-1337 .- 1534-6080. ; 89:7, s. 864-872
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Tidskriftsartikel (refereegranskat)abstract
- Background. The proliferation signal inhibitor everolimus offers the potential to reduce calcineurin inhibitor (CNI) exposure and alleviate CNI-related nephrotoxicity. Randomized trials in maintenance thoracic transplant patients are lacking. Methods. In a 12-month, open-labeled, multicenter study, maintenance thoracic transplant patients (glomerular filtration rate greater than= 20 mL/min/1.73m(2) and less than90 mL/min/1.73 m(2)) greater than1 year posttransplant were randomized to continue their current CNI-based immunosuppression or start everolimus with predefined CNI exposure reduction. Results. Two hundred eighty-two patients were randomized (140 everolimus, 142 controls; 190 heart, 92 lung transplants). From baseline to month 12, mean cyclosporine and tacrolimus trough levels in the everolimus cohort decreased by 57% and 56%, respectively. The primary endpoint, mean change in measured glomerular filtration rate from baseline to month 12, was 4.6 mL/min with everolimus and -0.5 mL/min in controls (Pless than0.0001). Everolimus-treated heart and lung transplant patients in the lowest tertile for time posttransplant exhibited mean increases of 7.8 mL/min and 4.9 mL/min, respectively. Biopsy-proven treated acute rejection occurred in six everolimus and four control heart transplant patients (P=0.54). In total, 138 everolimus patients (98.6%) and 127 control patients (89.4%) experienced one or more adverse event (P=0.002). Serious adverse events occurred in 66 everolimus patients (46.8%) and 44 controls (31.0%) (P=0.02). Conclusion. Introduction of everolimus with CNI reduction offers a significant improvement in renal function in maintenance heart and lung transplant recipients. The greatest benefit is observed in patients with a shorter time since transplantation.
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| 7. |
- Gullestad, Lars, et al.
(författare)
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Long-term outcomes of thoracic transplant recipients following conversion to everolimus with reduced calcineurin inhibitor in a multicenter, open-label, randomized trial
- 2016
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Ingår i: Transplant International. - : Wiley-Blackwell Publishing Inc.. - 0934-0874 .- 1432-2277. ; 29:7, s. 819-829
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Tidskriftsartikel (refereegranskat)abstract
- The NOCTET study randomized 282 patients ≥1 year after heart or lung transplantation to continue conventional calcineurin inhibitor (CNI) therapy or to start everolimus with reduced-exposure CNI. Last follow-up, at ≥5 years postrandomization (mean: 5.6 years) was attended by 72/140 everolimus patients (51.4%) and 91/142 controls (64.1%). Mean measured GFR remained stable in the everolimus group from randomization (51.3 ml/min) to last visit (51.4 ml/min) but decreased in controls (from 50.5 ml/min to 45.3 ml/min) and was significantly higher with everolimus at last follow-up (P = 0.004). The least squares mean (SE) change from randomization was -1.5 (1.7)ml/min with everolimus versus -7.2 (1.7)ml/min for controls (difference: 5.7 [95% CI 1.7; 9.6]ml/min; P = 0.006). The difference was accounted for by heart transplant patients (difference: 6.9 [95% 2.3; 11.5]ml/min; P = 0.004). Lung transplant patients showed no between-group difference at last follow-up. Rates of rejection, death, and major cardiac events were similar between groups, as was graft function. Pneumonia was more frequent with everolimus (18.3% vs. 6.4%). In conclusion, introducing everolimus in maintenance heart transplant patients, with reduced CNI, achieves a significant improvement in renal function which is maintained for at least 5 years, but an early renal benefit in lung transplant patients was lost. Long-term immunosuppressive efficacy was maintained.
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| 8. |
- Gullestad, Lars, et al.
(författare)
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Two-Year Outcomes in Thoracic Transplant Recipients After Conversion to Everolimus With Reduced Calcineurin Inhibitor Within a Multicenter, Open-Label, Randomized Trial.
- 2010
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Ingår i: Transplantation. - : Williams and Wilkins. - 1534-6080 .- 0041-1337. ; 90:12, s. 1581-1589
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND.: Use of the mammalian target of rapamycin inhibitor everolimus with an accompanying reduction in calcineurin inhibitor (CNI) exposure has shown promise in preserving renal function in maintenance thoracic transplant patients, but robust, long-term data are required. METHODS.: In a prospective, open-label, multicenter study, thoracic transplant recipients more than or equal to 1 year posttransplant with mild-to-moderate renal insufficiency were randomized to continue their current CNI-based immunosuppression or convert to everolimus with predefined CNI exposure reduction. After a 12-month core trial, patients were followed up to month 24 after randomization. RESULTS.: Of 245 patients who completed the month 12 visit, 235 patients (108 everolimus and 127 controls) entered the 12-month extension phase. At month 24, mean measured glomerular filtration rate had increased by 3.2±12.3 mL/min from the point of randomization in everolimus-treated patients and decreased by 2.4±9.0 mL/min in controls (P<0.001), a difference that was significant within both the heart and lung transplant subpopulations. During months 12 to 24, 5.6% of everolimus patients and 3.1% of controls experienced biopsy-proven acute rejection (P=0.76). There were no significant differences in the rate of adverse events or serious adverse events (including pneumonia) between groups during months 12 to 24. CONCLUSIONS.: Converting maintenance thoracic transplant recipients to everolimus with low-exposure CNI results in a renal benefit that is sustained to 2 years postconversion, with significantly improved measured glomerular filtration rate in both heart and lung transplant patients. Despite reductions of more than 50% in CNI exposure, there was no marked loss of efficacy. The safety profile of the everolimus-based regimen was acceptable.
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| 9. |
- Gustafsson, Finn, et al.
(författare)
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Everolimus Initiation With Early Calcineurin Inhibitor Withdrawal in De Novo Heart Transplant Recipients : Long-term Follow-up From the Randomized SCHEDULE Study
- 2020
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Ingår i: Transplantation. - : LIPPINCOTT WILLIAMS & WILKINS. - 1534-6080 .- 0041-1337. ; 104:1, s. 154-164
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A calcineurin inhibitor (CNI)-free immunosuppressive regimen has been demonstrated to improve renal function early after heart transplantation, but long-term outcome of such a strategy has not been well described. METHODS: In the randomized SCHEDULE trial, de novo heart transplant recipients received (1) everolimus with reduced-exposure CNI (cyclosporine) followed by CNI withdrawal at week 7-11 posttransplant or (2) standard-exposure cyclosporine, both with mycophenolate mofetil and corticosteroids; 95/115 randomized patients were followed up at 5-7 years posttransplant. RESULTS: Mean measured glomerular filtration rate was 74.7 mL/min and 62.4 mL/min with everolimus and CNI, respectively. The mean difference was in favor of everolimus by 11.8 mL/min in the intent-to-treat population (P = 0.004) and 17.2 mL/min in the per protocol population (n = 75; P < 0.001). From transplantation to last follow-up, the incidence of biopsy-proven acute rejection (BPAR) was 77% (37/48) and 66% (31/47) (P = 0.23) with treated BPAR in 50% and 23% (P < 0.01) in the everolimus and CNI groups, respectively; no episode led to hemodynamic compromise. Coronary allograft vasculopathy (CAV) assessed by coronary intravascular ultrasound was present in 53% (19/36) and 74% (26/35) of everolimus- and CNI-treated patients, respectively (P = 0.037). Graft dimensions and function were similar between the groups. Late adverse events were comparable. CONCLUSIONS: These results suggest that de novo heart transplant patients randomized to everolimus and low-dose CNI followed by CNI-free therapy maintain significantly better long-term renal function as well as significantly reduced CAV than patients randomized to standard CNI treatment. Increased BPAR in the everolimus group during year 1 did not impair long-term graft function.
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| 10. |
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