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An assessment of rapamycin for weakening binge-eating memories via reconsolidation: a pre-registered, double-blind randomised placebo-controlled experimental study.
Walsh, K, Iskandar, G, Kamboj, SK, Das, RK
Psychological medicine. 2021;(1):158-167
Abstract
BACKGROUND Maladaptive learning linking environmental food cues to high-palatability food reward plays a central role in overconsumption in obesity and binge eating disorders. The process of memory reconsolidation offers a mechanism to weaken such learning, potentially ameliorating over-eating behaviour. Here we investigated whether putatively interfering with synaptic plasticity using the mammalian target of rapamycin (mTOR) inhibitor, rapamycin, could weaken retrieved chocolate reward memories through blockade of reconsolidation. METHODS Seventy five healthy volunteers with a tendency to binge eat chocolate were randomised to retrieve chocolate reward memory under 10 mg rapamycin (RET + RAP, active condition), or placebo (RET + PBO), or they received 10 mg rapamycin without subsequent retrieval (NO RET + RAP). Indices of chocolate reward memory strength were assessed one week pre and post manipulation and at one month follow-up. RESULTS Contrary to hypotheses, the RET + RAP group did not show any greater reduction than control groups on indices of motivational salience of chocolate cues, motivation to consume chocolate or liking of chocolate. Mild evidence of improvement in the RET + RAP group was found, but this was limited to reduced chocolate binge episodes and improved healthy food choices. CONCLUSIONS We did not find convincing evidence of comprehensive naturalistic chocolate reward memory reconsolidation blockade by rapamycin. The effects on chocolate bingeing and food choices may warrant further investigation. These limited positive findings may be attributable to insufficient interference with mTOR signalling with 10 mg rapamycin, or failure to destabilise chocolate memories during retrieval.
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Randomized Comparison of the Polymer-Free Biolimus-Coated BioFreedom Stent With the Ultrathin Strut Biodegradable Polymer Sirolimus-Eluting Orsiro Stent in an All-Comers Population Treated With Percutaneous Coronary Intervention: The SORT OUT IX Trial.
Jensen, Lisette Okkels, Maeng, M, Raungaard, B, Kahlert, J, Ellert, J, Jakobsen, L, Villadsen, AB, Veien, KT, Kristensen, SD, Ahlehoff, O, et al
Circulation. 2020;(25):2052-2063
Abstract
BACKGROUND In patients with increased bleeding risk, the biolimus A9-coated BioFreedom stent, a stainless steel drug-coated stent free from polymer, has shown superiority compared with a bare-metal stent. The aim of this study was to investigate whether the BioFreedom stent is noninferior to a modern ultrathin strut biodegradable polymer cobalt-chromium sirolimus-eluting Orsiro stent in an all-comers patient population treated with percutaneous coronary intervention. METHODS The SORT OUT IX trial (Scandinavian Organization for Randomized Trials With Clinical Outcome IX), was a large-scale, registry-based, randomized, multicenter, single-blind, 2-arm, noninferiority trial. The primary end point, major adverse cardiovascular events, was defined as the composite of cardiac death, myocardial infarction not related to any segment other than the target lesion, or target lesion revascularization within 1 year, analyzed by intention-to-treat. The trial was powered to assess noninferiority for major adverse cardiovascular events of the BioFreedom stent compared with the Orsiro stent with a predetermined noninferiority margin of 0.021. RESULTS Between December 14, 2015 and April 21, 2017, 3151 patients were assigned to treatment with the BioFreedom stent (1572 patients, 1966 lesions) or to the Orsiro stent (1579 patients, 1985 lesions). Five patients were lost to follow-up because of emigration (99.9% follow-up rate). Mean age was 66.3±10.9, diabetes mellitus was seen in 19.3% of patients, and 53% of the patients had acute coronary syndromes. At 1 year, intention-to-treat analysis showed that 79 (5.0%) patients, who were assigned the BioFreedom stent, and 59 (3.7%), who were assigned the Orsiro stent, met the primary end point (absolute risk difference 1.29% [upper limit of one-sided 95% CI 2.50%]; Pnoninferiority=0.14). Significantly more patients in the BioFreedom stent group had target lesion revascularization than those in the Orsiro stent group (55 [3.5%] vs 20 [1.3%], rate ratio 2.77 [95% CI, 1.66-4.62]; P<0.0001). CONCLUSIONS The biolimus A9-coated BioFreedom polymer-free stent did not meet criteria for noninferiority for major adverse cardiovascular events at 12 months when compared with the ultrathin strut biodegradable polymer sirolimus-eluting Orsiro stent in an all-comers population Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02623140.
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Biodegradable polymer sirolimus-eluting stents versus durable polymer everolimus-eluting stents in patients with ST-segment elevation myocardial infarction (BIOSTEMI): a single-blind, prospective, randomised superiority trial.
Iglesias, JF, Muller, O, Heg, D, Roffi, M, Kurz, DJ, Moarof, I, Weilenmann, D, Kaiser, C, Tapponnier, M, Stortecky, S, et al
Lancet (London, England). 2019;(10205):1243-1253
Abstract
BACKGROUND Newer-generation drug-eluting stents that combine ultrathin strut metallic platforms with biodegradable polymers might facilitate vascular healing and improve clinical outcomes in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention (PCI) compared with contemporary thin strut second-generation drug-eluting stents. We did a randomised clinical trial to investigate the safety and efficacy of ultrathin strut biodegradable polymer sirolimus-eluting stents versus thin strut durable polymer everolimus-eluting stents in patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing primary PCI. METHODS The BIOSTEMI trial was an investigator-initiated, multicentre, prospective, single-blind, randomised superiority trial at ten hospitals in Switzerland. Patients aged 18 years or older with acute STEMI who were referred for primary PCI were eligible to participate. Patients were randomly allocated (1:1) to either biodegradable polymer sirolimus-eluting stents or durable polymer everolimus-eluting stents. Central randomisation was done based on a computer-generated allocation sequence with variable block sizes of 2, 4, and 6, which was stratified by centre, diabetes status, and presence or absence of multivessel coronary artery disease, and concealed using a secure web-based system. Patients and treating physicians were aware of group allocations, whereas outcome assessors were masked to the allocated stent. The experimental stent (Orsiro; Biotronik; Bülach, Switzerland) consisted of an ultrathin strut cobalt-chromium metallic stent platform releasing sirolimus from a biodegradable polymer. The control stent (Xience Xpedition/Alpine; Abbott Vascular, Abbott Park, IL, USA) consisted of a thin strut cobalt-chromium stent platform that releases everolimus from a durable polymer. The primary endpoint was target lesion failure, a composite of cardiac death, target vessel myocardial reinfarction (Q-wave and non-Q-wave), and clinically-indicated target lesion revascularisation, within 12 months of the index procedure. All analyses were done with the individual participant as the unit of analysis and according to the intention-to-treat principle. The trial was registered with ClinicalTrials.gov, number NCT02579031. FINDINGS Between April 26, 2016, and March 9, 2018, we randomly assigned 1300 patients (1623 lesions) with acute myocardial infarction to treatment with biodegradable polymer sirolimus-eluting stents (649 patients and 816 lesions) or durable polymer everolimus-eluting stents (651 patients and 806 lesions). At 12 months, follow-up data were available for 614 (95%) patients treated with biodegradable polymer sirolimus-eluting stents and 626 (96%) patients treated with durable polymer everolimus-eluting stents. The primary composite endpoint of target lesion failure occurred in 25 (4%) of 649 patients treated with biodegradable polymer sirolimus-eluting stents and 36 (6%) of 651 patients treated with durable polymer everolimus-eluting stents (difference -1·6 percentage points; rate ratio 0·59, 95% Bayesian credibility interval 0·37-0·94; posterior probability of superiority 0·986). Cardiac death, target vessel myocardial reinfarction, clinically-indicated target lesion revascularisation, and definite stent thrombosis were similar between the two treatment groups in the 12 months of follow-up. INTERPRETATION In patients with acute STEMI undergoing primary PCI, biodegradable polymer sirolimus-eluting stents were superior to durable polymer everolimus-eluting stents with respect to target lesion failure at 1 year. This difference was driven by reduced ischaemia-driven target lesion revascularisation in patients treated with biodegradable polymer sirolimus-eluting stents compared with durable polymer everolimus-eluting stents. FUNDING Biotronik.
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Twelve-month angiographic and clinical outcomes of the XINSORB bioresorbable sirolimus-eluting scaffold and a metallic stent in patients with coronary artery disease.
Wu, Y, Shen, L, Yin, J, Chen, J, Qian, J, Ge, L, Ge, J, ,
International journal of cardiology. 2019;:61-66
Abstract
BACKGROUND Recent studies showed bioresorbable scaffold (BRS) increased risks of late target lesion failure (TLF) and thrombosis. XINSORB scaffold is a poly-L-lactic acid based BRS. METHODS The study included randomization and registry parts. Eligible patients with one or two de novo lesions were randomly 1:1 assigned to XINSORB scaffold and sirolimus-eluting stent (SES) in randomization part. These patients were clinically and angiographically assessed. In registry part, patients were treated with XINSORB scaffold only and were clinically assessed. The primary endpoint was in-segment late luminal loss (LLL) at 12-month in randomization part. The secondary endpoint was 12-month TLF in all XINSORB-treated patients. RESULTS Total 395 and 798 patients were enrolled in randomization and registry part, respectively. Device success was 98.0% (1069/1091) in all XINSORB-treated and 100% (221/221) in SES-treated lesions. The primary endpoint of in-segment LLL at 12-month was 0.19 ± 0.32 mm in XINSORB and 0.31 ± 0.41 mm in SES (P = 0.003), which met the noninferior margin of 0.195 mm (95% CI: -0.20, -0.04, P ≪ 0.0001). No difference was found in TLF between two devices. In all XINSORB-treated patients, 12-month TLF was 0.8% (8/998), which also met the noninferior margin of 9.0% (95% CI: 0.3%, 1.4%, P ≪ 0.0001). Only one device thrombosis was recorded in all XINSORB-treated patients while none in SES. CONCLUSIONS In the multicenter clinical trial, XINSORB BRS was noninferior to sirolimus-eluting stent for the primary endpoint of in-segment LLL at 12-month in patients with simple and moderate complex de novo coronary lesions. TLF at 12-month was low and comparable.
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Sirolimus in patients with clinically active systemic lupus erythematosus resistant to, or intolerant of, conventional medications: a single-arm, open-label, phase 1/2 trial.
Lai, ZW, Kelly, R, Winans, T, Marchena, I, Shadakshari, A, Yu, J, Dawood, M, Garcia, R, Tily, H, Francis, L, et al
Lancet (London, England). 2018;(10126):1186-1196
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BACKGROUND Patients with systemic lupus erythematosus have T-cell dysfunction that has been attributed to the activation of the mammalian target of rapamycin (mTOR). Rapamycin inhibits antigen-induced T-cell proliferation and has been developed as a medication under the generic designation of sirolimus. We assessed safety, tolerance, and efficacy of sirolimus in a prospective, biomarker-driven, open-label clinical trial. METHODS We did a single-arm, open-label, phase 1/2 trial of sirolimus in patients with active systemic lupus erythematosus disease unresponsive to, or intolerant of, conventional medications at the State University of New York Upstate Medical University (Syracuse, NY, USA). Eligible participants (aged ≥18 years) had active systemic lupus erythematosus fulfilling four or more of 11 diagnostic criteria defined by the American College of Rheumatology. We excluded patients with allergy or intolerance to sirolimus, patients with life-threatening manifestations of systemic lupus erythematosus, proteinuria, a urine protein to creatinine ratio higher than 0·5, anaemia, leucopenia, or thrombocytopenia. Patients received oral sirolimus at a starting dose of 2 mg per day, with dose adjusted according to tolerance and to maintain a therapeutic range of 6-15 ng/mL. Patients were treated with sirolimus for 12 months. Safety outcomes included tolerance as assessed by the occurrence of common side-effects. The primary efficacy endpoint was decrease in disease activity, assessed using the British Isles Lupus Assessment Group (BILAG) index and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Blood samples of 56 matched healthy individuals were obtained as controls for immunobiological outcomes monitored at each visit. The primary efficacy endpoint was assessed in all patients who completed 12 months of treatment, and all patients who received at least one dose of treatment were included in the safety analyses. This trial is registered with ClinicalTrials.gov, number NCT00779194. FINDINGS Between March 9, 2009, and Dec 8, 2014, 43 patients were enrolled, three of whom did not meet eligibility criteria. 11 of the 40 eligible patients discontinued study treatment because of intolerance (n=2) or non-compliance (n=9). SLEDAI and BILAG disease activity scores were reduced during 12 months of treatment in 16 (55%) of 29 patients who completed treatment. Mean SLEDAI score decreased from 10·2 (SD 5·6) at enrolment to 4·8 (4·5) after 12 months of treatment (p<0·001) and the mean total BILAG index score decreased from 28·4 (12·4) at enrolment to 17·4 (10·7) after 12 months of treatment (p<0·001). The mean daily dose of prednisone required to control disease activity decreased from 23·7 mg (SD 9·6) to 7·2 mg (2·3; p<0·001) after 12 months of treatment. Sirolimus expanded CD4+CD25+FoxP3+ regulatory T cells and CD8+ memory T-cell populations and inhibited interleukin-4 and interleukin-17 production by CD4+ and CD4-CD8- double-negative T cells after 12 months. CD8+ memory T cells were selectively expanded in SRI-responders. Patient liver function and lymphocyte counts were unchanged. Although HDL-cholesterol (Z=-2·50, p=0·012), neutrophil counts (Z=-1·92, p=0·054), and haemoglobin (Z=-2·83, p=0·005) were moderately reduced during treatment, all changes occurred within a range that was considered safe. Platelet counts were slightly elevated during treatment (Z=2·06, p=0·0400). INTERPRETATION These data show that a progressive improvement in disease activity is associated with correction of pro-inflammatory T-cell lineage specification in patients with active systemic lupus erythematosus during 12 months of sirolimus treatment. Follow-up placebo-controlled clinical trials in diverse patient populations are warranted to further define the role of mTOR blockade in treatment of systemic lupus erythematosus. FUNDING Pfizer, the National Institutes of Health, and the Central New York Community Foundation.
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Safety and efficacy of a bioabsorbable polymer-coated, everolimus-eluting coronary stent in patients with diabetes: the EVOLVE II diabetes substudy.
Kereiakes, DJ, Meredith, IT, Masotti, M, Carrié, D, Moreno, R, Erglis, A, Mehta, SR, Elhadad, S, Berland, J, Stein, B, et al
EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology. 2017;(16):1987-1994
Abstract
AIMS: Bioabsorbable polymer drug-eluting stents (DES) may reduce the inflammation and delayed healing associated with some permanent polymer-coated DES. Whether late clinical outcomes are improved, particularly among patients with medically treated diabetes, is unknown. Therefore, we analysed outcomes from a pre-specified substudy of the EVOLVE II trial to evaluate the safety and effectiveness of the SYNERGY stent in patients with diabetes mellitus. METHODS AND RESULTS SYNERGY is a thin-strut, platinum-chromium everolimus-eluting stent with an ultra-thin bioabsorbable poly(DL-lactide-co-glycolide) abluminal polymer. The EVOLVE II randomised, controlled trial proved the non-inferiority of the SYNERGY versus the PROMUS Element Plus stent for one-year target lesion failure (TLF: ischaemia-driven target lesion revascularisation [ID-TLR], target vessel myocardial infarction [TVMI], or cardiac death). The pre-specified EVOLVE II diabetes substudy prospectively pooled randomised patients with diabetes (N=263) with a sequential single-arm diabetic cohort (n=203). The substudy primary endpoint was one-year TLF compared with a pre-specified performance goal (14.5%). The primary endpoint occurred in 7.5% of SYNERGY-treated patients with diabetes, significantly less than the performance goal (p<0.0001). The two-year rate of TLF was 11.2% (cardiac death 1.5%, TVMI 6.4%, ID-TLR 6.8%) and definite/probable stent thrombosis occurred in 1.1% of patients. CONCLUSIONS The EVOLVE II diabetes substudy demonstrates the efficacy and safety of the SYNERGY stent in patients with medically treated diabetes.
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Comparison of the Absorbable Polymer Sirolimus-Eluting Stent (MiStent) to the Durable Polymer Everolimus-Eluting Stent (Xience) (from the DESSOLVE I/II and ISAR-TEST-4 Studies).
Lansky, AJ, Kastrati, A, Edelman, ER, Parise, H, Ng, VG, Ormiston, J, Wijns, W, Byrne, RA
The American journal of cardiology. 2016;(4):532-538
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We compared the outcomes of a novel, thin-strut, cobalt-chromium, absorbable, polymer sirolimus-eluting stent (APSES; MiStent) to the durable polymer cobalt-chromium everolimus-eluting stent (EES; Xience). A propensity-matched analysis was performed comparing data from the DES With Sirolimus and a Bioabsorbable Polymer for the Treatment of Patients With De Novo Lesions in the Native Coronary Arteries (DESSOLVE) I and II studies, evaluating the APSES to the EES arm of the Intracoronary Stenting and Angiographic Results: Test Efficacy of 3 Limus-Eluting Stents-4 study. Target lesion failure (TLF) and its components were evaluated at 12 months and annually to 3 years; 805 patients (APSES = 153; EES = 652) were included with propensity matching in 204 patients (APSES = 102; EES = 102). APSES compared with EES had lower TLF at 1 year (3.0% vs 8.0%, p = 0.12) driven by a difference in target lesion revascularization (TLR; 1% vs 6%, p = 0.05), with no difference in target vessel myocardial infarction (p = 0.56) or stent thrombosis (p = 0.31). At 3 years, TLF (5.0% vs 12.5%, p = 0.07) and TLR (2.0% vs 8.4%, p = 0.04) remained lower with APSES. By landmark analysis, there was no significant difference in TLF between 1 and 3 years (p = 0.36). In conclusion, in a propensity-matched analysis, the APSES demonstrated reduced clinically indicated TLR rates at 1 and 3 years compared with the durable polymer EES, with minimal accrual of events between 1 and 3 years.
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Comparison of sirolimus eluting stent with bioresorbable polymer to everolimus eluting stent with permanent polymer in bifurcation lesions: Results from CENTURY II trial.
Orvin, K, Carrie, D, Richardt, G, Desmet, W, Assali, A, Werner, G, Ikari, Y, Fujii, K, Goicolea, J, Dangoisse, V, et al
Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions. 2016;(6):1092-100
Abstract
OBJECTIVE To demonstrate the safety and efficacy of a new sirolimus eluting stent with bioresorbable polymer, Ultimaster, (BP-SES) compared with everolimus-eluting, permanent polymer, Xience stent (PP-EES) in bifurcation lesions with respect to the freedom from Target Lesion Failure at 1-year. METHODS Within 1,119 patients enrolled in the CENTURY II randomized controlled multicenter trial, 194 patients were treated for bifurcation lesions and randomized to either BP-SES (n = 95) or PP-EES (n = 99). The primary endpoint was freedom from target lesion failure (TLF) composite endpoint [cardiac death, MI not clearly attributable to a non-target vessel, and clinically driven target lesion revascularization (TLR)] at 1-year. RESULTS Baseline patient demographic, angiographic, and stenting characteristics were similar in both study arms. A single stent technique with provisional or "cross over" stenting were the most widely used in both arms (93.2% BP-SES vs. 92.4% PP-EES). Freedom from TLF at 1-year was 94.7% for BP-SES and 91.9% for PP-EES (P for noninferiority 0.031). The rate of clinically driven target lesion revascularization (TLR) at 1-year was 3.2% for BP-SES and 3.0% for PP-EES (P = 0.95). There were no significant differences detected in any of the individual clinical endpoints or other secondary clinical endpoints between the study arms at 1-year follow up. CONCLUSIONS The new bioresorbable polymer sirolimus-eluting stent showed safety and efficacy profiles similar to durable polymer everolimus-eluting in the treatment of patients with bifurcation lesions at 1-year follow up. © 2015 Wiley Periodicals, Inc.
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Vascular response to bioresorbable polymer sirolimus-eluting stent vs. permanent polymer everolimus-eluting stent at 9-month follow-up: an optical coherence tomography sub-study from the CENTURY II trial.
Kuramitsu, S, Kazuno, Y, Sonoda, S, Domei, T, Jinnouchi, H, Yamaji, K, Soga, Y, Shirai, S, Ando, K, Saito, S
European heart journal. Cardiovascular Imaging. 2016;(1):34-40
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AIMS: The Ultimaster bioresorbable polymer sirolimus-eluting stent (BP-SES) is a newly developed drug-eluting stent (DES) that consists of a thin-strut, cobalt chromium with bioresorbable polymer coated only albuminally. We sought to compare tissue coverage in coronary lesions treated with BP-SES with the XIENCE permanent polymer everolimus-eluting stent (PP-EES) using optical coherence tomography (OCT). METHODS AND RESULTS A total of 36 patients participated in the CENTURY II trial in our institution and were randomly assigned to BP-SES (n = 15) and PP-EES (n = 21). Of these, 27 patients (13 BP-SES and 14 PP-EES) underwent OCT at 9-month follow-up. Tissue coverage and apposition were assessed on each strut, and the results in both groups were compared using multilevel logistic or linear regression models with random effects at three levels: patient, lesion, and struts. A total of 6450 struts (BP-SES, n = 2951; PP-EES, n = 3499) were analysed. Thirty and 79 uncovered struts (1.02 and 2.26%, P = 0.35), and 3 and 4 malapposed struts (0.10 and 0.11%, P = 0.94) were found in BP-SES and PP-EES groups, respectively. Mean neointimal thickness did not significantly differ between both groups (110 ± 10 vs. 93 ± 10 µm, P = 0.22). No significant differences in per cent neointimal volume obstruction (13.2 ± 4.6 vs. 10.5 ± 4.9%, P = 0.14) or other areas-volumetric parameters were detected between both groups. CONCLUSION BP-SES shows an excellent vascular healing response at 9-month follow-up, which is similar to PP-EES.
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Effect of Ramipril on Urinary Protein Excretion in Maintenance Renal Transplant Patients Converted to Sirolimus.
Mandelbrot, DA, Alberú, J, Barama, A, Marder, BA, Silva, HT, Flechner, SM, Flynn, A, Healy, C, Li, H, Tortorici, MA, et al
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2015;(12):3174-84
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This prospective, randomized, double-blind, placebo-controlled study evaluated the effects of ramipril on urinary protein excretion in renal transplant patients treated with sirolimus following conversion from a calcineurin inhibitor. Patients received ramipril or placebo for up to 6 weeks before conversion and 52 weeks thereafter. Doses were increased if patients developed proteinuria (urinary protein/creatinine ratio ≥0.5); losartan was given as rescue therapy for persistent proteinuria. The primary end point was time to losartan initiation. Of 295 patients randomized, 264 met the criteria for sirolimus conversion (ramipril, 138; placebo, 126). At 52 weeks, the cumulative rate of losartan initiation was significantly lower with ramipril (6.2%) versus placebo (23.2%) (p < 0.001). No significant differences were observed between ramipril and placebo for change in glomerular filtration rate from baseline (p = 0.148) or in the number of patients with biopsy-confirmed acute rejection (13 vs. 5, respectively; p = 0.073). One patient in the placebo group died due to cerebrovascular accident. Treatment-emergent adverse events were consistent with the known safety profile of sirolimus and were not potentiated by ramipril co-administration. Ramipril was effective in reducing the incidence of proteinuria for up to 1 year following conversion to sirolimus in maintenance renal transplant patients.