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Statistical analysis | REGRESSION | Statistical analyses were performed using R software (version 4.0.3)A multivariable logistic regression model was used to estimate the OR and the 95 per cent c.i. associated with the use of patches and CR-POPF. POPF survival rates were plotted for treatment groups using Kaplan–Meier analysis and were compared using a log rank test. A | PMC10077024 | |
Results | fistula | SECONDARY, LEAKAGE | Among the total 72 patients who were randomized (36 in each group), five subjects in the patch group and three in the control group underwent a total pancreatectomy and were excluded from the analyses. The final analyses included 64 patients (31 in the patch group and 33 in the control group) (CONSORT diagramBaseline clinical and demographic characteristicsValues are Surgical time was shorter in the patch group (median 265 Overview of the intraoperative characteristics of the study sampleValues are POPF rate, including biochemical leakage, was 38 per cent (24/64 patients) in the overall study sample, with nine (14 per cent) patients presenting grade B/C POPF. Regarding the overall POPF rate, there was no significant difference between the patch group (29 per cent) and the control group (52 per cent) (Overview of the secondary outcomes of the study within 90 days after surgery in the overall study population, the patch group, and the control groupValues are The risk of CR-POPF was reduced by 90 per cent (OR 0.10, 95 per cent c.i. 0.01 to 0.89, Unadjusted and adjusted OR of the role of the polyethylene glycol-coated haemostatic patch in the risk of clinically relevant-postoperative pancreatic fistulaModel 1: adjusted by age and sex. Model 2: adjusted by age, sex, and fistula risk score (low The length of hospital stay and length of ICU stay were similar in the patch and control groups. The incidence of other secondary outcomes did not significantly differ between the study groups ( | PMC10077024 |
Discussion | PD, POPF | ADVERSE EVENTS, SECONDARY, COMPLICATIONS, POSTOPERATIVE COMPLICATIONS | The results of this study suggested that in patients who underwent PD with a PJ, the use of the PEG-coated collagen patch reduces the incidence of CR-POPF. Moreover, the capacity of the PEG-coated patch to prevent the onset of POPF was dependent on the FRS: the higher the FRS, the higher the protection. The incidences of adverse events were lower in the patch group compared with the control group, although no significant differences were observed in the specific postoperative complications analysed.Although different surgical approaches are currently used for PD, there does not seem to be an optimal technique that significantly decreases POPF ratesFrom a clinical point of view, POPF may be divided into ‘clinically relevant’ (grade B/C) and ‘not clinically relevant’ (biochemical leakage)The current study reported an overall POPF rate of 38 per cent (24/64 patients), which lies within the range of the published seriesAs far as the authors know, this is the first RCT evaluating the effectiveness of a PEG-coated haemostatic patch in PD, which makes it difficult to compare these results with the current evidence. Pisapia The decrease in CR-POPF rate observed in this study was not associated with a significant reduction in the incidence of other specific postoperative outcomes or a lower mortality rate.The use of sealants may be an option to reduce the incidence of POPF and, therefore, reducing life-threatening complications and healthcare costsNo evidence is currently available regarding the association of the use of the fibrin sealant patch (TachoSil™) in patients who undergo a PD with a lowering of the incidence of POPF or a reduction of its severityHemopatch™ is a PEG-covered collagen matrix, which has been proven to be an effective haemostat and sealant in different surgical proceduresThis study has some limitations that need to be taken into consideration. The main one is that it is a single-centre study, which included a small number of patients. The lack of differences in secondary outcomes may be due to the fact that the study was underpowered for detecting such differences. This study only used one type of reconstruction technique and appropriate caution is therefore recommended when extending the results to other reconstruction techniques. Finally, it should be mentioned that the use of interrupted suture in eight patients may have biased the results. Nevertheless, the incidence rate of POPF was similar for both suture techniques.Further research is needed to elucidate the role of different baseline factors in the effectiveness of the patch and the incidence of CR-POPF in larger, prospective multicentre controlled trials. | PMC10077024 |
Supplementary Material | Click here for additional data file. | PMC10077024 | ||
Acknowledgements | This study was done by an independent, interdisciplinary academic non-profit research organization in Spain. We received an Investigator Initiated Research Grant from Baxter Healthcare SA, Switzerland, to augment study funding. Medical writing and editorial assistant services were provided by Antonio Martinez (MD) of Ciencia y Deporte S.L. (Spain). | PMC10077024 | ||
Funding | This study received an Investigator Initiated Research Grant from Baxter Healthcare Corporation SA, Switzerland. | PMC10077024 | ||
Author contributions | Mario Serradilla-Martín (Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Supervision, Writing—original draft, Writing—review & editing), Sandra Paterna-López (Data curation, Investigation, Writing—review & editing), Ana Palomares-Cano (Data curation, Writing—review & editing), Miguel Cantalejo-Díaz (Data curation, Writing—review & editing), Teresa Abadía-Forcén (Data curation, Writing—review & editing), Marta L. Gutiérrez-Díaz (Data curation, Writing—review & editing), Consuelo Artigas-Marco (Data curation, Writing—review & editing), and Alejandro Serrablo-Requejo (Data curation, Writing—review & editing). | PMC10077024 | ||
Disclosure | Mario Serradilla-Martín receives fees from Baxter International Inc. (Deerfield, IL, USA) as a consultant. Mario Serradilla-Martín declares no other conflict of interest. The rest of the authors declare no conflict of interest. | PMC10077024 | ||
Supplementary material | PMC10077024 | |||
Data availability | The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. | PMC10077024 | ||
References | PMC10077024 | |||
Background | T2D, type 2 diabetes, cardiovascular disease | TYPE 2 DIABETES, CARDIOVASCULAR DISEASE | In clinical practice, anthropometric measures other than BMI are rarely assessed yet may be more predictive of cardiovascular (CV) risk. We analyzed the placebo group of the REWIND CV Outcomes Trial to compare several anthropometric measures as baseline risk factors for cardiovascular disease (CVD)-related outcomes in participants with type 2 diabetes (T2D). | PMC9999507 |
Methods | T2D | EVENT | Data from the REWIND trial placebo group (N = 4952) were analyzed. All participants had T2D, age ≥ 50 years, had either a previous CV event or CV risk factors, and a BMI of ≥ 23 kg/m | PMC9999507 |
Results | deaths, HC | EVENTS | Participants in the placebo group experienced 663 MACE-3 events, 346 CVD-related deaths, 592 all-cause deaths, and 226 events of HF requiring hospitalization during the median follow-up of 5.4 years. WHR and WC, but not BMI, were identified as independent risk factors of MACE-3 (hazard ratio [HR] for WHR: 1.11 [95% CI 1.03 to 1.21]; p = 0.009; HR for WC: 1.12 [95% CI 1.02 to 1.22]; p = 0.012). WC adjusted for hip circumference (HC) showed the strongest association with MACE-3 compared to WHR, WC, or BMI unadjusted for each other (HR: 1.26 [95% CI 1.09 to 1.46]; p = 0.002). Results for CVD-related mortality and all-cause mortality were similar. WC and BMI were risk factors for HF requiring hospitalization, but not WHR or WC adjusted for HC (HR for WC: 1.34 [95% CI 1.16 to 1.54]; p < 0.001; HR for BMI: 1.33 [95% CI 1.17 to 1.50]; p < 0.001). No significant interaction with sex was observed. | PMC9999507 |
Conclusions | In this post hoc analysis of the REWIND placebo group, WHR, WC and/or WC adjusted for HC were risk factors for MACE-3, CVD-related mortality, and all-cause mortality; while BMI was only a risk factor for HF requiring hospitalization. These findings indicate the need for anthropometric measures that consider body fat distribution when assessing CV risk. | PMC9999507 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s12933-023-01757-z. | PMC9999507 | ||
Keywords | PMC9999507 | |||
Background | Obesity, obesity, adiposity | OBESITY, OBESITY, CVD, ADIPOSITY, EVENTS, TYPE 2 DIABETES | Obesity, defined as excess adiposity that is detrimental to health, is a major risk factor for type 2 diabetes and other comorbidities [Obesity can be assessed using different measures. In the absence of imaging modalities, which are typically not used in routine clinical practice, BMI, waist-to-hip ratio (WHR), and waist circumference (WC) are commonly used clinical measures. BMI can be readily calculated to estimate overall body fat, and WHR and WC can be measured during the office visit to estimate distribution of fat which may have varied pathophysiological effects. BMI measures weight to height squared ratio and is inclusive of total body fat and lean mass. WC and WHR measure central adiposity: WC examines the circumference of the abdomen at the level of the umbilicus, and WHR is a ratio of the circumference of the waist to that of the hips with higher ratios indicating more central adiposity [Different measures of obesity have been associated with CVD and all-cause mortality. While some studies indicate that measures of central adiposity are superior to BMI when evaluating patients’ risk of cardiovascular (CV) events [The REWIND CV Outcomes Trial evaluated CVD-related events, including MACE-3, CVD-related mortality, all-cause mortality, and HF requiring hospitalization, over a median of 5.4 years [The aim of the current study was to evaluate and contrast measures of general and central adiposity as potential risk factors for MACE-3, CVD-related mortality, all-cause mortality, and HF requiring hospitalization in the placebo group of the REWIND CV Outcomes Trial. | PMC9999507 |
Methods | PMC9999507 | |||
Study design and patients | obesity, death, HC, stroke, deaths | OBESITY, STROKE, MYOCARDIAL INFARCTION, CREST | Data from the placebo group of the REWIND trial were used for this analysis. Details of the REWIND trial are published elsewhere [Weight measurements were taken at baseline and throughout the trial annually as well as at the final study visit. Height, waist circumference, and hip circumference were measured at baseline and every 24 months throughout the trial as well as at the final study visit. To calculate BMI, body weight and height were measured. Body weight was measured using a calibrated scale (mechanical or digital). BMI was calculated as weight in kilograms divided by the square of height in meters. WC and hip circumference (HC) measurements were obtained with the patient in the standing position. WC was measured immediately above the iliac crest and HC at the maximal circumference of the buttocks, both in centimeters. WHR was calculated by dividing WC by HC.The current analysis examined obesity measures, measured at baseline, as potential risk factors for four outcomes: MACE-3 (non-fatal myocardial infarction, non-fatal stroke, or death from CV causes including unknown causes), CVD-related mortality, all-cause mortality, and HF requiring hospitalization or urgent care. Potential CV outcomes and all deaths were adjudicated by an independent clinical endpoint committee that was masked to treatment assignment. Further adjudication criteria are published elsewhere [ | PMC9999507 |
Results | PMC9999507 | |||
Baseline characteristics and demographics | There were 4952 participants in the REWIND placebo group. The average age was 66.2 years, 46.1% were female, and 75.6% were White (Table | PMC9999507 | ||
Incidence of health outcomes | deaths | EVENTS | During follow-up in the placebo group, there were 663 MACE-3 events, 346 CVD-related deaths, 592 all-cause deaths, and 226 events of HF requiring hospitalization or urgent care. | PMC9999507 |
Association of obesity measures with health outcomes | obesity | OBESITY | The list of variables included in the Stepwise Variable Selection can be found in Table Additional file Association of BMI, WHR, WC, and WC adjusted for HC with (For MACE-3, WHR was found to be a significant independent risk factor (HR = 1.11; 95% CI 1.03 to 1.21; p = 0.009), as was WC (HR = 1.12; 95% CI 1.02 to 1.22; p = 0.012) in the fully adjusted model. The analysis of WC adjusted for HC emerged as the strongest risk factor for MACE-3 (HR = 1.26; 95% CI 1.09 to 1.46; p = 0.002). When either BMI, WHR, and WC or BMI, WC, and HC were included together, the resulting multivariable models did not identify any obesity measure (including WC adjusted for HC) as being significantly associated with MACE-3.For CVD-related mortality, WHR was identified as a significant risk factor (HR = 1.19; 95% CI 1.04 to 1.36; p = 0.010). WC was not significant when included alone (p = 0.057) but became significant when adjusted for HC, with the strongest association of the four measures for CVD-related mortality (HR = 1.33; 95% CI 1.08 to 1.64; p = 0.007). In the model investigating BMI, WHR, and WC together, only WHR was included via the selection process, resulting in the same final model as the respective single model (HR = 1.19; 95%-CI 1.04 to 1.36; p = 0.010). In the model investigating BMI, WC, and HC together, none of the obesity measures were selected. However, when HC was forced into the model, WC was selected, resulting in the same final model as above (HR = 1.33; 95% CI 1.08 to 1.64; p = 0.007).For all-cause mortality, WC emerged as a significant risk factor (HR = 1.10; 95% CI 1.00 to 1.20; p = 0.047) and remained significant when adjusted for HC, with the largest HR (HR = 1.17; 95% CI 1.00 to 1.38; p = 0.049). In both models investigating a combination of three obesity measures, none of them were included via the selection process. This did not change in the latter model when HC was a forced factor.BMI was a significant independent risk factor for HF requiring hospitalization (Fig. In all models no significant interaction with sex was observed. | PMC9999507 |
Discussion | obesity, HC | CVD, OBESITY, TYPE 2 DIABETES | This post hoc analysis of the placebo group of the REWIND CV Outcomes Trial showed that the anthropometric measures WHR and/or WC, but not BMI, were risk factors for MACE-3, CVD-related mortality, and all-cause mortality in patients with type 2 diabetes and CV risk factors or established CVD. BMI was a significant risk factor only for HF requiring hospitalization. WHR and/or WC were risk factors for all four outcomes, with varying strengths of associations when analyzed in a combination model with other obesity measures. WC adjusted for HC was one of the strongest risk factors for MACE-3, CVD-related mortality, and all-cause mortality, indicating that both WC and HC have independent information pertaining to CV risk which is not completely captured by WHR. | PMC9999507 |
General adiposity poorly reflects the risk of CV outcomes | obesity, overweight, overweight or obesity | OBESITY, MODERATE OBESITY | While used routinely in clinical practice, increasing BMI is not a reliable universal risk factor for CV-related outcomes in patients with overweight or obesity. Data from the ORIGIN trial showed that obesity, categorized using BMI, had a U-shaped association with mortality and CV outcomes, and patients with overweight and moderate obesity (BMI 25–35 kg/m | PMC9999507 |
Central adiposity measures as recommended risk factors for CV outcomes | obesity | OBESITY, PATHOLOGY, CVD, ADIPOSITY, EVENTS, TYPE 2 DIABETES | Our results showed that either WHR or WC were risk factors for MACE-3, CVD-related mortality, and all-cause mortality. Given that different measures of obesity indicate general adiposity versus specific areas of fat depots, such as central fat, this may translate to different physiological effects and therefore varied associations with different outcomes. Although reports differ, most studies suggest that central obesity, measured by WHR or WC, is a risk factor for CVD [Given the strong evidence that central adiposity can inform patients’ risk of CV events, guidelines should include detail on collecting these measures in addition to weight and BMI. It is increasingly more widely acknowledged that central adiposity can not only contribute to CV risk but also to type 2 diabetes pathology [ | PMC9999507 |
Strengths and limitations | type 2 diabetes | CVD, EVENTS, TYPE 2 DIABETES, ADIPOSITY | This study had several strengths. The REWIND placebo group was a large cohort of patients with type 2 diabetes and CV risk factors or established CVD. The follow-up period was long (median 5.4 years). The REWIND study protocol did not prescribe interventions on body weight or weight change advice. The REWIND trial data provided detailed information such as general and central adiposity in addition to multiple risk factors which are not typically available in other settings.This study also had limitations. This was a post hoc analysis that was not prespecified. Participants in the REWIND trial had a history of CVD or CV risk factors so results may not be generalizable to patients with no history or risk factors. Likewise, REWIND participants had type 2 diabetes which limits generalisability to other populations. The full spectrum of BMI was unlikely to be represented. Despite multivariable adjustments, some baseline differences may be unaccounted for which limits conclusions. For outcomes other than MACE, the power is low since there were much fewer events. No causal inference can be concluded from the observed associations. | PMC9999507 |
Conclusions | obesity | CVD, OBESITY, EVENTS, TYPE 2 DIABETES | In a cohort of patients with type 2 diabetes with high risk for CVD, different general and central measures of obesity better reflected patients’ risk of CV events. There was no single obesity measure that was a risk factor for all outcomes (MACE-3, CVD-related or all-cause mortality, or HF requiring hospitalization), however WHR, WC and/or WC adjusted for HC were risk factors for most outcomes. Measuring BMI, WC, and HC collectively may be the most appropriate when assessing the risk of CV events in patients with type 2 diabetes and obesity. | PMC9999507 |
Author contributions | NNA, MK, and HK designed the study. EF, PP, and HCG were involved in the collection of the data. EF, PP, JB, CN, SR, AH, NNA, MK, HK, and HCG were involved in the analysis of the data and/or interpretation of the results. All authors were involved in the drafting or critical revising of the manuscript. All authors read and approved the final manuscript. | PMC9999507 | ||
Funding | This study was sponsored by Eli Lilly and Company. | PMC9999507 | ||
Availability of data and materials | Eli Lilly and Company provides access to all individual participant data collected during the trial, after anonymization, with the exception of pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the US and EU and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, blank or annotated case report forms, will be provided in a secure data sharing environment. For details on submitting a request, see the instructions provided at | PMC9999507 | ||
Declarations | PMC9999507 | |||
Ethics approval and consent to participate | The REWIND protocol was approved by research ethics boards for all sites. All participants provided written informed consent. The trial was carefully monitored by members of an independent data monitoring committee who reviewed accruing and unblinded data every 6 months. | PMC9999507 | ||
Consent for publication | Not applicable. | PMC9999507 | ||
Competing interests | Diabetes | DIABETES | EF has acted as an advisor to AstraZeneca, Boehringer Ingelheim, Novo Nordisk, and Polfa Tarchomin, and reports honoraria for speaking from AstraZeneca, Bioton, Boehringer Ingelheim, Eli Lilly and Company, Novo Nordisk, Polfa Tarchomin, Sanofi, and Servier. PP discloses no conflicts of interest. JB declares research grants from Eli Lilly and Company, ReCor, and Ablative Solutions; and consultant fees from Medtronic and Up-to-Date. CN, SR, AH, NNA, MK, and HK are employees and shareholders of Eli Lilly and Company. HCG holds the McMaster-Sanofi Population Health Institute Chair in Diabetes Research and Care. He reports research grants from Eli Lilly and Company, AstraZeneca, Merck, Novo Nordisk, and Sanofi; honoraria for speaking from AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Novo Nordisk, DKSH, Zuellig, Sanofi, Jiangsu Hanson, and Carbon Brand; and consulting fees from Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Novo Nordisk, Sanofi, Kowa, Pfizer, Hanmi and Viatris. | PMC9999507 |
References | PMC9999507 | |||
Background | pain | The aim of this study was to compare pain-scores in three targeted treatment-strategies in JIA-patients and to identify characteristics predicting persistent pain. | PMC10464062 | |
Methods | pain | In the BeSt-for-Kids-study 92 DMARD-naïve JIA-patients were randomized in 3 treatment-strategies: 1) initial sequential DMARD-monotherapy 2) initial methotrexate (MTX)/prednisolone-bridging or 3) initial MTX/etanercept. Potential differences in VAS pain scores (0-100 mm) over time between treatment-strategies were compared using linear mixed models with visits clustered within patients. A multivariable model was used to assess the ability of baseline characteristics to predict the chance of high pain-scores during follow-up. | PMC10464062 | |
Results | pain | Pain-scores over time reduced from mean 55.3 (SD 21.7) to 19.5 (SD 25.3) mm after 24 months. On average, pain-scores decreased significantly with β -1.37 mm (95% CI -1.726; -1.022) per month. No significant difference was found between treatment-strategies (interaction term treatment arm*time (months) β (95% CI) arm 1: 0.13 (-0.36; 0.62) and arm 2: 0.37 (-0.12; 0.86) compared to arm 3). Correction for sex and symptom duration yielded similar results. Several baseline characteristics were predictive for pain over time. Higher VAS pain [β 0.44 (95% CI 0.25; 0.65)] and higher active joint count [0.77 (0.19; 1.34)] were predictive of higher pain over time, whereas, low VAS physician [ -0.34 (-0.55; -0.06)], CHQ Physical [ -0.42 (-0.72; -0.11)] and Psychosocial summary Score [ -0.42 (-0.77; -0.06)] were predictive of lower pain. | PMC10464062 | |
Conclusions | pain | CHRONIC PAIN | Treatment-to-target seems effective in pain-reduction in non-systemic JIA-patients irrespective of initial treatment-strategy. Several baseline-predictors for pain over time were found, which could help to identify patients with a high risk for development of chronic pain. | PMC10464062 |
Trial registration | Dutch Trial Registry number 1574. | PMC10464062 | ||
Keywords | PMC10464062 | |||
Background | JIA, pain, auto-immune disease | DISEASE, REMISSION, JUVENILE IDIOPATHIC ARTHRITIS | Juvenile Idiopathic Arthritis (JIA) is the most common auto-immune disease in children, with an estimated prevalence of 33 per 100.000 children [In JIA, treatment to target (T2T) with clinical remission as a treatment goal has been widely recommended [The aim of this subanalysis is to compare pain scores over two years in three treatment strategies in non-systemic JIA patients who were treated to target aimed at inactive disease [ | PMC10464062 |
Methods | PMC10464062 | |||
Patients | juvenile psoriatic arthritis, JIA, uveitis, polyarticular JIA | DISEASE, UVEITIS, JUVENILE PSORIATIC ARTHRITIS | The BeSt for Kids study (NTR 1574) is a Dutch multicenter randomized single-blinded trial. It was designed to investigate the effectiveness of three different treat to target strategies for non-systemic JIA patients. Newly diagnosed patients between 2 and 16 years old with JIA (oligoarticular JIA, RF negative polyarticular JIA and juvenile psoriatic arthritis) were included. Exclusion criteria were a disease duration of more than 18 months, uveitis at enrolment and prior DMARD therapy.Patients were randomized between three strategy arms. Patients in arm 1 were initially treated with methotrexate(MTX) or sulfasalazine(SSZ) monotherapy. Patients in arm 2 initially received MTX and 6 weeks prednisolone bridging. Patients in arm 3 were initially treated with etanercept (ETN) and MTX. Patients were treated to target, with inactive disease (as defined by Wallace [The BeSt for Kids study was approved by the Institutional Review Board at Leiden University Medical Center and written informed consent was obtained from all participants before enrolment. | PMC10464062 |
Outcome measures | [Inactive disease, pain | The primary outcome measure was pain intensity. This was assessed using a 100 mm visual analogue scale (VAS), where 0 mm is ‘no pain’ and 100 mm is ‘unbearable pain’. Patients were asked to rate their pain over the last 7 days. Under the age of 12, pain was estimated by the parents. A VAS pain of ≤ 35mm is considered ‘mild pain’, whereas ‘moderate pain’ is defined as 36–60 mm and ≥ 61mm as ‘severe pain’ [Inactive disease was defined by the adjusted Wallace criteria [ | PMC10464062 | |
Statistical methods | Juvenile Arthritis, active joints, JIA, pain | JUVENILE ARTHRITIS, DISEASE, DISEASE, PGA | Descriptive statistics were used with mean and standard deviations (SDs) for continuous variables and absolute frequency percentage for categorical variables. Potential differences in VAS pain scores over time between treatment arms were compared using linear mixed models with random intercept and random slope for visits clustered within patients. The third arm was treated as reference arm since we hypothesized that arm 3 would be superior compared with arm 1 or arm 2, based on earlier research [Additionally, a third mixed model was used in an exploratory analysis to assess the ability of several baseline characteristics to predict the chance of high pain levels during follow-up. For this model multiple imputation was used to deal with missing values of variables with missing data from patients who were still in follow-up, as well as data from the 2 patients that were lost to follow-up and performed based on predictive mean matching (with 5 observations to draw from, resulting in 30 imputation sets). Imputation variables were treatment group, age at inclusion, sex, NSAID use, VAS pain, PGA, VAS patient/parent general wellbeing, VAS disease activity, symptom duration at diagnosis, Juvenile Arthritis Disease Activity Score 10 (JADAS10), number of active joints, number of limited joints, Child Health Assessment Questionnaire (CHAQ) score, CHQ- PhS, CHQ-PsS, JIA category, Erythrocyte Sedimentation Rate (ESR), baseline ESR and all baseline outcome measures. We first evaluated the possible predictive variables in a univariable model and subsequently added them to a multivariable model and evaluated its predictive value for reaching a lower VAS pain during follow-up.For all statistical analyses | PMC10464062 |
Results | PMC10464062 | |||
VAS pain | active disease, Pain, pain | DISEASE | Mean (SD) pain at 24 months was 17.3 (25.5) mm in arm 1, 25.6 (28.5) mm in arm 2 and 15.8 (21.0) mm in arm 3 (overall 19.5(25.3)). When comparing pain scores over time per treatment arm, pain decreased significantly in every arm with β -1.37 mm (95% CI -1.73;-1.02) per month. No significant difference was found in pain over 24 months between treatment arms (interaction term treatment arm*time (months) in arm 1 with β (95% CI) 0.13 (-0.36; 0.62) and in arm 2 with β 0.37 (-0.12; 0.86) compared to arm 3). Correction for age and sex yielded similar results. Pain trajectories over time are depicted in Fig. VAS pain outcomes over 24 months in the three treatment arms, based on linear mixed models with random intercept and random slope on unimputed data. Errors bar indicate 95% confidence intervalWhen performing the model for the first three months separately, pain decreased at a similar rate in each treatment group with β(95% CI) -7.82 mm (-11.12; -4.53) per month. Arm 1 compared to arm 3 with β(95% CI) 1.45(-3.14; -6.03) and arm 2 with β(95% CI) 2.33(-2.19; 6.85).Over 24 months, more than 70 percent of patients reached inactive disease [VAS pain active and inactive disease. VAS pain in children with active disease and inactive disease at 12 and 24 months with median and interquartile range. Inactive disease was determined based on adjusted Wallace criteria. At 12 months inactive disease | PMC10464062 |
Baseline predictors | active joints, pain | Several baseline characteristics were selected beforehand and tested for predictive value for pain over time, first in a univariable and subsequently in a multivariable prediction model. In the multivariable model, higher VAS pain and number of active joints at baseline were significantly predictive of higher pain over time, whereas higher VAS physician, CHQ PhS and PsS were predictive of lower pain. Baseline symptom duration, NSAID use and VAS patient/parent were not predictive of pain during follow-up (Table Effect of baseline characteristics on pain over timeEffect of baseline characteristics on pain over time. Included baseline variables in univariate and multivariate analysis; VAS pain, VAS physician, VAS patient/parent general wellbeing, diagnosis, number of active joints, PhS, PsS, symptom duration and NSAID use. | PMC10464062 | |
Discussion | JIA, active joints, pain | DISEASE, PGA | The BeSt for Kids is one of the first treat-to-target studies in newly diagnosed, DMARD naïve, non-systemic JIA patients investigating pain as outcome measure. In the current subanalysis, three frequently used initial treatment strategies were compared for effectiveness in treating pain [Although few studies have addressed pain over time as an outcome, we know from cross sectional data and reports from trials and prospective observational studies that pain scores can remain high after treatment. These high pain levels are reported after treatment according to clinical practice before the availability of biologic treatment [Even though we saw a decrease of active disease and pain in the BeSt for kids study, still some of our patients who did achieve inactive disease continued to have pain. It is this group of patients that deserves additional attention [In addition to this, we could consider adding an extra patient reported outcome, to investigate whether the clinical improvement we find corresponds to what our patients regard as a satisfactory improvement in pain levels [We performed an exploratory analysis to identify baseline factors that predict pain over time. In univariable analyses we identified VAS pain, PGA, VAS patient/parent, number of active joints, PhS and PsS as significant predictors of pain over time. In a multivariable model including all previously tested variables, identified VAS pain, PGA, number of active joints, PhS and PsS remained predictive. This is in accordance with previous literature [Counterintuitively and in contrast to previous studies, in our multivariable model, a lower PGA at baseline was associated with more pain during the two years follow up [Contrary to previous studies we did not find symptom duration as a significant baseline predictor for more pain over time. This could be due to lack of power, as these studies included more patients and the effect that was found was very small [In our previous publication [There are some limitations to our study. The sample size of our study was limited, therefore more subtle differences might have been found in a larger study cohort. Second, pain is multifactorial in nature and affected by many psychosocial patient factors [ | PMC10464062 |
Acknowledgements | DER | We would like to thank Bastiaan van Dijk and Joy van der Pol for their support in formatting the graphs. | PMC10464062 | |
Authors’ contributions | All authors were involved in drafting the article or revising it critically for important intellectual content. All authors approved the final version to be published. Ms Spekking and dr Hissink Muller had full access to all data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design: KS, PB, SB, DB, CA, RC, LS, MR, PHM. Acquisition of data: PHM, DB, CA, DS, YK, MR, LS, MB. Critically revising the manuscript; KS, JA, PB, SB, MB, DS, YK, MR, LS, CA, RC, DB, PHM. | PMC10464062 | ||
Funding | The BeSt for Kids study is an investigator-initiated study which received financial support from Pfizer, who had no role in study design, data collection, data analysis, data interpretation, writing of an abstract, or decision to submit a manuscript for submission. | PMC10464062 | ||
Availability of data and materials | The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. | PMC10464062 | ||
Declarations | PMC10464062 | |||
Ethics approval and consent to participate | Approval of the Medical Ethical Committee of the Leiden University Medical Center and local Ethical Committees was obtained prior to start at each study site. Written Informed consent was obtained from patients above 12 years of age and parents of all participating patients. | PMC10464062 | ||
Consent for publication | Not applicable. | PMC10464062 | ||
Competing interests | The authors declare that they have no competing interests. | PMC10464062 | ||
References | PMC10464062 | |||
Research Design and Methods: | T1D, Diabetes | DIABETES | This multicenter 12-week 1:1 randomized, controlled, parallel-arm trial included 100 participants with established T1D aged 4–13 years (mean 10.9 ± 2.3 years) naive to isCGM and with elevated HbA1c 7.5%–12.2% [58–110 mmol/mol] [mean HbA1c was 9.05 (1.3)%] [75.4 (13.9) mmol/mol]. Participants were allocated to 12-week intervention (isCGM; FreeStyle Libre 2.0; Abbott Diabetes Care, Witney, United Kingdom) ( | PMC10698781 |
Results: | −0.21 | There was no evidence of a difference between groups for change in HbA1c at 12 weeks (0.23 [95% confidence interval; CI: −0.21 to 0.67], | PMC10698781 | |
Conclusions: | For children aged 4–13 years with elevated Hba1c isCGM led to improvements in glucose testing frequency and reduced time below range. However, isCGM did not translate into reducing Hba1c or psychosocial outcomes compared to usual care over 12-weeks. The trial is registered within the Australian New Zealand Trial Registry on February 19, 2020 (ACTRN12620000190909p; | PMC10698781 | ||
Introduction | TYPE 1 DIABETES | Self-monitoring of glucose levels, whether by self-monitored capillary blood glucose (SMBG), real-time continuous glucose monitoring (rtCGM), or intermittently scanned continuous glucose monitoring [isCGM]), is strongly recommended for children with type 1 diabetes (T1D).When compared with first-generation isCGM, rtCGM systems are superior in terms of glucose control, specifically time in range (TIR) and glycated hemoglobin (HbA1c).However, in children aged 4–13 years, there are no published randomized controlled trials (RCTs) on either first- or second-generation isCGM. These data are required, as when compared with adult data, pediatric technology outcomes are not always comparable. | PMC10698781 | |
Methods | comorbidity, Diabetes, ketoacidosis, hypoglycemia, Diabetes Self-Management (SEDM).Data, diabetes | KETOACIDOSIS, ADVERSE EVENTS, EVENT, RECRUITMENT, HYPOGLYCEMIA, DIABETES, DIABETES, HYPOGLYCEMIA | This 12-week multisite 1: 1 randomized, 2-arm, parallel, controlled open-label study was conducted across five diabetes centers in New Zealand: Northland (NDHB), Auckland (ADHB), Bay of Plenty (BOPDHB), Capital and Coast (CCDHB), and Southern (SDHB) from October 2020 to August 2022. For full details, see the published study protocol.Eligibility criteria were children aged 4–13 years (inclusive), diabetes duration of ≥6 months, and HbA1c between 7.5% and 12.2% (58–110 mmol/mol) (at time of enrollment and insulin dose >0.5 U/[kg·d]). Exclusion criteria included continuous use of any CGM in the previous 3 months (excluding in-hospital), was defined by use of any CGM for ongoing week-to-week home use in the past 3 months—as opposed to a sensor provided by the clinic to capture 1–2 weeks of data as a one-off in the past 3 months, participation in any other study that could affect measurements, or any severe psychiatric/physical comorbidity, which may have treatment disrupted by agreeing to take part in the trial. Potentially eligible children from the participating sites were invited to participate, and interest was also taken from families at satellite sites following advertising on social media.Following consent, basic demographic information about children and their parents was collected at the screening visit with outcome measurements assessed at baseline and 12 weeks. HbA1c was measured using a calibrated point-of-care device (DCA Vantage analyzer; Siemens Healthcare Diagnostic Ireland). All consented and eligible participants were asked to wear a blinded sensor (Freestyle Libre Pro; Abbott) for up to 14 days (7 days minimum). While wearing the blinded sensor and before randomization, children and parents were asked to complete age-appropriate psychosocial questionnaires examining quality of life (PedsQL Diabetes Module 3.2 young child/child/teen version, as appropriate), fear of hypoglycemia (Hypoglycemia Fear Survey), and participants aged 10–14 years (inclusive) were also asked to complete the Self Efficacy for Diabetes Self-Management (SEDM).Data on adverse events, including severe cutaneous reactions and severe hypoglycemia and ketoacidosis were self-reported by phone or text messages, but no further contact was made between research staff and the participants in either group during the study period. All medical advice continued with their usual diabetes service (diabetes clinics are attended regularly [at least every 3 months] by a multidisciplinary team [pediatric endocrinologist/diabetologist/pediatrician, diabetes nurse specialist, dietitian, psychologist]).The treatment group allocation was revealed at visit 2, which coincided with the end of the 2-week blinded continuous interstitial glucose collection period. Participants were randomized in a 1:1 ratio to either the control (SMBG) group or the intervention (isCGM) group by research staff using a randomization module in REDcap.The first sensor was applied by research staff. Participants inserted the next sensor 14 days later themselves at home, and for the remainder of the study, and contacted research staff for technical support as required. Participants were instructed to scan a minimum of 6–10 times each day with no longer than 8 h between two scans, but no upper limit was set. The initial recommended reader alert settings were 3.9 mmol/L (70 mg/dL) and 15.0 mmol/L (270 mg/dL). These could be modified as required. As a safety precaution, participants were recommended to perform SMBG to confirm their glucose level before therapeutic interventions for hypoglycemia levels. To prevent sensor loss before the end of the 14-day sensor session, participants were shown examples of cohesive tape to be used to attach the sensor securely in the event the adhesive becomes loose.Control group participants continued SMBG using conventional finger-stick blood glucose (BG) testing with a glucometer but were recalled at week 10 to be refitted with a second blinded isCGM sensor, which they wore for weeks 10–12 of the study. This was used to compare with the isCGM data from the intervention group for the same 2 weeks.To maximize study recruitment, all participants received a second-generation isCGM in an open and supported 12-week extension phase after the RCT. | PMC10698781 |
Ethics | RECRUITMENT | The protocol underwent Māori (indigenous New Zealanders) consultation, which fostered input into this study. The study protocol was approved by the Northern A Health and Disability Ethics Committee (ethics reference: 20/NTA/12). All district health boards approved recruitment and conduct of the study at their site. The isCGM manufacturer was not involved with the planning, funding, or the conduct of the study. | PMC10698781 | |
Statistical analysis and data management | DKA | HYPOGLYCEMIA, RECRUITMENT, DIABETIC KETOACIDOSIS | As described in our published methodology, a sample size of 88 (44 participants in each group) was estimated to provide 80% power to detect a difference in changes in HbA1c of 7 mmol/mol (0.75%) between the intervention and control groups using standard deviation (SD) of 15 mmol/mol and correlation of 0.7 between repeated observations on the same person and a two-sided test at the 0.05 level.The primary analysis followed intention to-treat principles with all participants analyzed in the group to which they were randomized, regardless of actual sensor wear. Additional analyses included standard glycemic metrics, glucose monitoring frequency and adherence, episodes of severe hypoglycemia, episodes of diabetic ketoacidosis (DKA), and psychosocial variables. Mean differences and Recruitment was from July 1, 2021, to June 1, 2022, with all subjects completing the 12-week RCT by September 1, 2022. | PMC10698781 |
Results | capillary blood glucose | Baseline characteristics are presented in Demographic and Clinical Characteristics of the Participants at BaselineThe participants (or parents/guardians) could select more than one ethnic group. However, they were assigned to a single ethnic group for statistical evaluation with the list prioritized in the standardized order of Māori; Pacific Islander; Asian; Middle Eastern, Latin American, or African; and New Zealand European or other.Māori are the indigenous people of New Zealand.NZDep13, The New Zealand Deprivation Index is an area-based measure of socioeconomic deprivation (in which 1 represents the least socioeconomic deprivation and 10 the most deprived). Post office box and some rural addresses cannot be derived from this index, and thus, there are NZDep13 scores available for 45/50 (90%) in the intervention group and 45/52 (86.5%) in the control group.BMI, body mass index; CSII, continuous subcutaneous insulin infusion; HbA1c, glycated hemoglobin; MDI, multiple daily injections; SD, standard deviation; SMBG, Self Monitoring of capillary blood glucose. | PMC10698781 | |
Glucose monitoring | In the isCGM group, there was an increase in mean (SD) glucose checks performed per day from 4.7 (2.7) SMBG at baseline to 10.7 (4.6) combined interstitial and SMBG per day at 12 weeks. In the SMBG group, the baseline glucose checks decreased from 3.9 (2.2)/day to 3.2 (1.6)/day at 12 weeks. This translated to the isCGM group with combined interstitial and SMBG checking over 6 times more/day at +6.77 checks per day (CI: 4.81–8.72), | PMC10698781 | ||
Other glucose metrics | 3.9–10, −2.7 | % Time in target 70–180 mg/dL (3.9–10 mmol/L) showed an absolute increase in the isCGM group (28.7% [16.6] at baseline to 36.4% [13.2]) at 12 weeks, and remained similar in the SMBG group (27.3% [16] and 25.1% [13]), however, this did not translate to a statistically significant difference between groups, +4.7% (CI: −2.7 to 13.4), Percentage of time spent in various glucose target ranges at baseline and at 12 weeks in the intervention and control groups. Red is percentage TBR or less than 70 mg/dL (<3.9 mmol/L), green is percentage TIR 70–180 mg/dL (3.9–10.0 mmol/L), and orange is percentage TAR over 180 mg/dL (>10.0 mmol/L). Values shown are mean percentage for the intervention and control groups. TAR, time above range; TBR, time below range; TIR, time in range.% Time spent <70 mg/dL (<3.9 mmol/L) showed a difference between groups favoring reduced time <70 mg/dL (<3.9 mmol/L) in the isCGM group (isCGM −6.4% and control +1.0% [CI: −10.6 to −4.2], % Time above 180 mg/dL (>10 mmol/mol) remained unchanged with no difference between groups at 12 weeks (−1.6% for isCGM and −3.8% for control group, respectively [CI: −6.6 to 11.1, There was no difference in mean glucose or glucose Coefficient of Variation percentage between groups at baseline or at 12 weeks. | PMC10698781 | |
Psychosocial assessments | diabetes symptoms, HFS, hypoglycemia, diabetes, Diabetes, Hypoglycemia | HYPOGLYCEMIA, DIABETES, HYPOGLYCEMIA, DIABETES | At 12 weeks there was no difference in PedsQL Diabetes Module Total score (or 5 subscales), Fear of Hypoglycemia (2 subscales), nor in Self-efficacy for Diabetes Self-Management score (see Comparison of Psychological Outcomes Between Groups at Baseline and at 12 Weeks: Children's and Parent's ScoresData are mean ± SD unless otherwise indicated. PedsQL Diabetes subscale scores range from 0 to 100; higher scores indicate lower problems with diabetes symptoms. PedsQL Treatment subscale scores range from 0 to 100; higher scores indicate lower problems with diabetes-specific barriers. PedsQL Adherence subscale scores range from 0 to 100; higher scores indicate lower problems with adherence. PedsQL Worry subscale scores range from 0 to 100; higher scores indicate lower problems with diabetes-specific worry. PedsQL Communication subscale scores range from 0 to 100; higher scores indicate lower problems with diabetes-specific communication. PedsQL Diabetes Total scores range from 0 to 100; higher scores indicate better diabetes-specific quality of life. Fear of hypoglycemia (HFS) Behavior subscale mean item scores range from 0 to 4; higher scores indicate a greater tendency to avoid hypoglycemia. HFS-Worry subscale scores range from 0 to 4; higher scores indicate more worry concerning episodes of hypoglycemia and its consequences. Self: The SEDM is a 10-item self-report questionnaire for youth aged 10–16 years that examines confidence to carry out self-care behaviors and covers all the key areas of diabetes self-management. Participants are asked “How sure are you that you can do each of the following, almost all the time” and items are rated from 1 (not at all sure) to 10 (completely sure) and averaged.Within groups: A positive number means the mean score was higher at week 12.For children older than 10 years.HFS, Hypoglycemia Fear Survey; SEDM, Self-Efficacy for Diabetes Self-Management.There was no difference in parents' fear of hypoglycemia (Behavior and Worry subscales) at baseline or 12 weeks, and no between-group difference at 12 weeks ( | PMC10698781 |
Adverse events | hypoglycemia, hyperthyroidism, DKA | HYPOGLYCEMIA, DRUG-INDUCED HEPATITIS, HYPERTHYROIDISM | There was one episode of DKA in the control group and none in the intervention group. There were no episodes of severe hypoglycemia in either group, or any reported hospitalizations for other reasons. There was one case in the intervention group of acquired hyperthyroidism and subsequent drug-induced hepatitis requiring radioactive iodine treatment, resulting in withdrawal from the study. | PMC10698781 |
Cutaneous reactions | cutaneous reaction, erythema, dryness | ERYTHEMA | There was one local reaction (erythema, dryness, and irritation) to a baseline blinded Libre pro, data not repeated due to subject choice. There was one reported episode of cutaneous reaction to a skin tape fixation in the intervention group, not repeated once the tape fixation was removed, and no reaction to subsequent sensors. There was one repeated sensor failure in the intervention group (8 sensors “fell off” in the first 4 weeks, and the child discontinued the study). Overall, <1% of Libre 2.0 sensors resulted in a reported cutaneous reaction. | PMC10698781 |
Discussion | hypoglycemia, T1D, diabetes | HYPOGLYCEMIA, RECRUITMENT, DIABETES | This study investigated second-generation isCGM in children with elevated glycemic control who were naive to any form of CGM. This is the first RCT to be conducted in children aged <13 years worldwide and importantly was carried out independently (i.e., was not industry funded). The main findings are that despite a clear increase in glucose-checking frequency, there were no benefits over 12-weeks seen in the primary outcome HbA1c using isCGM 2.0 compared to SMBG. However, time spent in the hypoglycemic range was considerably improved, and TIR was clinically improved, but this finding did not reach clinical significance.This lack of improvement (in both the control and intervention groups) in the primary outcome (HbA1c) is consistent with the only other study conducted in pediatric and youth aged children using isCGM (1.0),Similarly, both studies were impacted by COVID effects on procedures and delays in recruitment. Clearly in those struggling with diabetes control and burden, as seen in both pediatric studies to date, sensors alone are less likely to result in substantial improvement in longer term glycemic values as measured by HBA1c.Interestingly, while HBA1c did not change, there were important glycemic findings when assessing CGM metrics. First, and of considerable clinical relevance, time in hypoglycemia was improved using isCGM 2.0, similar to published studies.In children with T1D and elevated HbA1c, these results will reinforce caution in extrapolating data from adults with T1D.Despite the increased use of glucose checking with isCGM, no psychosocial gains were seen on the traditional measures collected. | PMC10698781 |
Strengths and limitations | T1D, fits, diabetes | DIABETES | To our knowledge, this is the only trial to date of isCGM 2.0 in children, and it is important to validate diabetes technology although it is an ever-changing and emerging field.The study deliberately targeted those with elevated HbA1c levels who (for whatever reason: cost, social support, or other) have not been on isCGM. Comparatively, they are not the “first movers” in technology, or children/families that are able to exhibit high levels of diabetes management in combination with the challenges of broader socioeconomic deprivation.Our age range is both a strength and weakness; from our data, children in this age group are spanning development ages, and very reliant on family structure and support (unlike the studies in adults with T1D). Compared with previous studies on first-generation Libre, we were able to also have the TIR metrics to strengthen this study. LibreView software unfortunately did not provide data on alarm settings and use, and limiting any insights into participant behavior and potential benefits on sensor use or alarms.A weakness is the ever-changing nature of technological improvement in T1D, and we are aware that at present Libre 2.0 is not the latest version now available, however, much of the world is still using isCGM 2.0, and some locations still 1.0 or are reliant on finger-stick glucose testing. So, this study still has considerable value, especially as the first study of its kind in children, with only one in adults, and also that there are so few worldwide on any form of isCGM. Understanding the evolution of technology and where each type is placed or fits in our management “arsenal” is vital. | PMC10698781 |
Conclusion | T1D, diabetes | HYPOGLYCEMIA, DIABETES | This RCT highlights that isCGM 2.0 is appealing and engages families and children with T1D and elevated HbA1c, as shown by the increased glucose monitoring behavior, and reduced time in hypoglycemia. However, in this study, the use of isCGM (Libre 2.0) did not translate into reducing HbA1c compared with usual care SMBG over a 12-week period. Ongoing efforts to find solutions that improve outcomes both glycemic and psychosocial are required in children experiencing the greatest difficulties and burdens with their diabetes. | PMC10698781 |
Supplementary Material | PMC10698781 | |||
Supplemental data | PMC10698781 | |||
Supplemental data | PMC10698781 | |||
Authors' Contributions | C.A.J.: Conceptualization (colead), methodology (colead), supervision, visualization, and writing—original and editing. A.B. and S.E.S.: Investigation, project administration, resources, software, supervision, and writing—review and editing. B.C.: Investigation, visualization, software, and validation. V.R.M.: Visualization, software, and validation. H.R.C. and A.S.S.: Investigation, methodology, and writing—review and editing. M.D.L.: Data curation, methodology, and software. A.L. and V.C.: Investigation and writing—review and editing. E.J.W.: Methodology and writing—review and editing. B.J.W.: Conceptualization (colead), methodology (colead), supervision, visualization, and writing—original and editing. All the authors contributed to the refinement of the study protocol and approved the final article. | PMC10698781 | ||
Consent to Participate | Written informed consent was obtained from parents, written informed assent was obtained from participants aged 7 to 13 years, and verbal assent was obtained from participants aged 4 to 6 years. | PMC10698781 | ||
Author Disclosure Statement | No competing financial interests exist. | PMC10698781 | ||
Funding Information | The study funder is The Starship Foundation A +8211 (Auckland, New Zealand). The funder and the isCGM manufacturer had no roles or responsibilities in the study design, conduct, data analysis and interpretation, or article writing. Intervention supplies and blinded glucose sensors were purchased commercially from the isCGM manufacturer. C.A.J. is the recipient of a New Zealand Health Research Council (HRC) clinical practitioner research fellowship 20/026. | PMC10698781 | ||
Supplementary Material | PMC10698781 | |||
References | PMC10698781 | |||
Key Points | PMC10551818 | |||
Question | CARDIOVASCULAR DISEASE | Does enteric coating on aspirin reduce effectiveness or increase safety in patients with cardiovascular disease? | PMC10551818 | |
Findings | atherosclerotic cardiovascular disease, death, stroke | BLEEDING, MYOCARDIAL INFARCTION, STROKE, SECONDARY, ATHEROSCLEROTIC CARDIOVASCULAR DISEASE | In this post hoc secondary analysis of 10 678 participants with atherosclerotic cardiovascular disease from the ADAPTABLE randomized clinical trial, there were no significant differences in the primary effectiveness (death, hospitalization for myocardial infarction, or hospitalization for stroke) or safety (major bleeding) end points between enteric-coated aspirin and uncoated aspirin among participants, regardless of which dose of aspirin they were assigned. | PMC10551818 |
Meaning | EVENTS, SECONDARY | These findings suggested that enteric coating on aspirin is not associated with changes in the effectiveness or safety of aspirin for secondary prevention of cardiovascular events, allowing patients to determine the aspirin formulation. | PMC10551818 | |
Importance | gastrointestinal bleeding, coronary artery disease | GASTROINTESTINAL BLEEDING, CORONARY ARTERY DISEASE, SECONDARY | Clinicians recommend enteric-coated aspirin to decrease gastrointestinal bleeding in secondary prevention of coronary artery disease even though studies suggest platelet inhibition is decreased with enteric-coated vs uncoated aspirin formulations. | PMC10551818 |
Objective | To assess whether receipt of enteric-coated vs uncoated aspirin is associated with effectiveness or safety outcomes. | PMC10551818 | ||
Design, Setting, and Participants | atherosclerotic cardiovascular disease | ATHEROSCLEROTIC CARDIOVASCULAR DISEASE, SECONDARY | This is a post hoc secondary analysis of ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-term Effectiveness), a pragmatic study of 15 076 patients with atherosclerotic cardiovascular disease having data in the National Patient-Centered Clinical Research Network. Patients were enrolled from April 19, 2016, through June 30, 2020, and randomly assigned to receive high (325 mg) vs low (81 mg) doses of daily aspirin. The present analysis assessed the effectiveness and safety of enteric-coated vs uncoated aspirin among those participants who reported aspirin formulation at baseline. Data were analyzed from November 11, 2019, to July 3, 2023. | PMC10551818 |
Intervention | ADAPTABLE participants were regrouped according to aspirin formulation self-reported at baseline, with a median (IQR) follow-up of 26.2 (19.8-35.4) months. | PMC10551818 | ||
Main Outcomes and Measures | death, bleeding | BLEEDING, MYOCARDIAL INFARCTION, STROKE, INTRACRANIAL HEMORRHAGE, EVENT, EVENTS | The primary effectiveness end point was the cumulative incidence of the composite of myocardial infarction, stroke, or death from any cause, and the primary safety end point was major bleeding events (hospitalization for a bleeding event with use of a blood product or intracranial hemorrhage). Cumulative incidence at median follow-up for primary effectiveness and primary safety end points was compared between participants taking enteric-coated or uncoated aspirin using unadjusted and multivariable Cox proportional hazards models. All analyses were conducted for the intention-to-treat population. | PMC10551818 |
Results | Baseline aspirin formulation used in ADAPTABLE was self-reported for 10 678 participants (median [IQR] age, 68.0 [61.3-73.7] years; 7285 men [68.2%]), of whom 7366 (69.0%) took enteric-coated aspirin and 3312 (31.0%) took uncoated aspirin. No significant difference in effectiveness (adjusted hazard ratio [AHR], 0.94; 95% CI, 0.80-1.09; | PMC10551818 | ||
Conclusions and Relevance | death, bleeding | SECONDARY, MYOCARDIAL INFARCTION, STROKE, BLEEDING | In this post hoc secondary analysis of the ADAPTABLE randomized clinical trial, enteric-coated aspirin was not associated with significantly higher risk of myocardial infarction, stroke, or death or with lower bleeding risk compared with uncoated aspirin, regardless of dose, although a reduction in bleeding with enteric-coated aspirin cannot be excluded. More research is needed to confirm whether enteric-coated aspirin formulations or newer formulations will improve outcomes in this population. | PMC10551818 |
Trial Registration | ATHEROSCLEROTIC CARDIOVASCULAR DISEASE, SECONDARY | ClinicalTrials.gov Identifier: This post hoc secondary analysis of a randomized clinical trial compares the effectiveness and safety of enteric-coated aspirin vs uncoated aspirin among patients with atherosclerotic cardiovascular disease. | PMC10551818 | |
Introduction | cardiovascular disease | SECONDARY, CARDIOVASCULAR DISEASE | Aspirin has been one of the most widely used medications since its introduction in the 1890s.The association of enteric-coated aspirin with secondary prevention of cardiovascular disease is controversial. Several studies have proposed that the enteric coating reduces the bioavailability of aspirin due to reduced dissolution and absorption. | PMC10551818 |
Methods | death, bleeding, Gastrointestinal tract bleeding, GI bleed, stroke, ASCVD, coronary artery disease | PERIPHERAL ARTERIAL DISEASE, BLEEDING, TRANSIENT ISCHEMIC ATTACK, GI BLEED, EVENT, STROKE, SECONDARY, DIABETES TYPE 1, ASCVD, CEREBROVASCULAR DISEASE, CORONARY ARTERY DISEASE | The ADAPTABLE study design has been previously described in detail.Overall, 15 076 participants 18 years or older with known ASCVD and at least 1 enrichment factor (age >65 years, serum creatinine >1.5 mg/dL [to convert milligrams per deciliter to micromoles per liter, multiply by 88.4], diabetes type 1 or type 2, 3-vessel coronary artery disease, cerebrovascular disease or peripheral arterial disease, left ventricular ejection fraction lower than 50%, and current cigarette smoker), no history of significant GI bleed within the last 12 months, and not currently treated with an oral anticoagulant or with ticagrelor were enrolled. The primary effectiveness end point was the time to a first occurrence of any event in the composite of death from any cause, hospitalization for MI, or hospitalization for stroke. The secondary effectiveness end points were the individual components of the primary end point, all-cause mortality, revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass graft [CABG]), and transient ischemic attack. The primary safety end point was hospitalization for major bleeding with an associated blood product transfusion. Gastrointestinal tract bleeding was also evaluated as a safety end point. For this analysis, participants were divided into subgroups based on randomized aspirin dose and self-reported aspirin formulation (enteric-coated aspirin or uncoated aspirin) at the time of randomization. Participants who did not answer the question related to aspirin formulation, or reported that they did not know the formulation, were excluded from the analyses. It was assumed that the participants remained on the same aspirin formulation throughout the study, as information on enteric coating was not collected past baseline. | PMC10551818 |
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