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Objectives: New dual antiplatelet therapies (DAPTs) have been introduced in clinical practice for patients with acute coronary syndrome (ACS). This nationwide study investigated DAPT patterns over time and patient characteristics associated with the various treatments in a population with ACS. Design: This observational cohort study linked morbidity, mortality and medication data from Swedish national registries. Results: Overall, 91% (104 012 patients) of all patients admitted to the hospital with an ACS (2009-2013) were alive after discharge and included in this study. Compared with 2009, in 2013 patients investigated with angiography increased by 10%, patients revascularized with percutaneous coronary intervention (PCI) increased by 11% and patients prescribed DAPT increased by 8%. Mean DAPT duration increased from 225 to 298 days in patients investigated with angiography, and from 155 to 208 days in patients who were not investigated with angiography. Furthermore, in patients undergoing angiography a treatment switch from clopidogrel to ticagrelor was observed. DAPT with prasugrel was used to a low extent. Approximately 10% of patients initiated on prasugrel or ticagrelor switched to clopidogrel during the first year of treatment. Conclusion: During the study more patients underwent angiography and PCI. There was an increase in the proportion of ACS patients receiving DAPT, as well as longer duration of DAPT in line with ESC guidelines. Among DAPT-treated patients, ticagrelor has emerged as the preferred P2Y12 antagonist in patients undergoing angiography, whereas clopidogrel tended to be prescribed to patients treated non-invasively. [ABSTRACT FROM AUTHOR]

Background There are little data on diverticular disease and cancer development other than colorectal cancer. Methods We conducted a population-based, matched cohort study with linkage of nationwide registers to the Epidemiology Strengthened by histoPathology Reports in Sweden histopathology cohort. We included 75 704 patients with a diagnosis of diverticular disease and colorectal histopathology and 313 480 reference individuals from the general population matched on age, sex, calendar year, and county. Cox proportional hazards models estimated multivariable-adjusted hazard ratios (HRs) for associations between diverticular disease and overall cancer and specific cancers. Results Over a median follow-up of 6 years, we documented 12 846 incident cancers among patients with diverticular disease and 43 354 incident cancers among reference individuals from the general population. Compared with reference individuals, patients with diverticular disease had statistically significantly increased overall cancer incidence (24.5 vs 18.1 per 1000 person-years), equivalent to 1 extra cancer case in 16 individuals with diverticular disease followed-up for 10 years. After adjusting for covariates, having a diagnosis of diverticular disease was associated with a 33% increased risk of overall cancer (95% confidence interval [CI] = 1.31 to 1.36). The risk increases also persisted compared with siblings as secondary comparators (HR = 1.26, 95% CI = 1.21 to 1.32). Patients with diverticular disease also had an increased risk of specific cancers, including colon cancer (HR = 1.71, 95% CI = 1.60 to 1.82), liver cancer (HR = 1.72, 95% CI = 1.41 to 2.10), pancreatic cancer (HR = 1.62, 95% CI = 1.42 to 1.84), and lung cancer (HR = 1.50, 95% CI = 1.39 to 1.61). The increase in colorectal cancer risk was primarily restricted to the first year of follow-up, and especially early cancer stages. Conclusions Patients with diverticular disease who have colorectal histopathology have an increased risk of overall incident cancer. [ABSTRACT FROM AUTHOR]

Introduction: There are limited population cohort data on overall and cause-specific mortality in colonic diverticular disease.Objective: To measure overall and cause-specific mortality in colonic diverticular disease, compared to matched reference individuals and siblings.Methods: Population-based cohort study ("the ESPRESSO study") in Sweden. There were 97,850 cases with a medical diagnosis of diverticular disease (defined by international classification of disease codes) and colorectal histology identified in 1987-2017 from histopathology reports. The mortality risk between individuals with colonic diverticular disease and matched reference individuals (n = 453/634) from the general population was determined. Cox regression models adjusted for comorbidity estimated hazard ratios (HRs) for all-cause mortality.Results: During follow-up, there were 32,959 deaths in individuals with colonic diverticular disease (44/1000 person-years) compared with 127,153 in matched reference individuals (34/1000 person-years), resulting in an HR of 1.27 (95%CI 1.25-1.29). Also compared to siblings, colonic diverticular disease patients were at increased risk of death, HR 1.39 (95%CI 1.33-1.45). Mortality risks were further increased in colonic diverticular disease patients with a colorectal biopsy showing any mucosal inflammation HR 1.36; (95%CI 1.33-1.38), with the most significant increase during the first year after diagnosis HR 2.18; (95%CI 2.05-2.32).Conclusions: Mortality in colonic diverticular disease is increased over reference individuals in the general population. The presence of mucosal inflammation on colorectal biopsies is a predictor of increased risk of mortality. [ABSTRACT FROM AUTHOR]

Background We compared kidney and cardiorenal protection in patients without type 2 diabetes across urine albumin–creatinine ratio (UACR) levels after initiation on dapagliflozin for the treatment of chronic kidney disease (CKD). Methods OPTIMISE-CKD is an observational study describing dapagliflozin treatment for CKD. Adult patients with CKD without type 2 diabetes were included in the primary analysis. Baseline UACR was grouped as normal/mildly elevated (0–29 mg/g), low (30–200 mg/g) and high (>200 mg/g). Outcomes were estimated glomerular filtration rate (eGFR) trajectories/slopes, cardiorenal complications and all-cause mortality. Results In total, 1480 patients had low (n  = 796) and high (n  = 684) UACR. The two groups were similar at baseline, aged 75 and 74 years, and 42% and 39% female, respectively. After dapagliflozin initiation, an acute eGFR dip of 3 mL/min/1.73 m2 was observed, followed by a flat development in both groups. The eGFR slope [95% confidence interval (CI)] for patients with low UACR was 0.79 mL/min/1.73 m2 per year (–0.59, 2.56), and similar to patients with high UACR [0.40 mL/min/1.73 m2 per year (–0.46, 1.38)]. Risks of cardiorenal complications and all-cause mortality were similar, with adjusted hazard ratios of 0.89 (95% CI 0.66, 1.19) and 1.10 (95% CI 0.63, 1.92), respectively. Analogous results were found in those with normal/mildly elevated UACR. Conclusions Dapagliflozin in patients without type 2 diabetes for the treatment of CKD demonstrated similar kidney protection, cardiorenal and all-cause mortality risk across UACR levels. This suggests that the efficacy of dapagliflozin found in clinical trials expands to real-world patients with CKD, regardless of albuminuria levels. [ABSTRACT FROM AUTHOR]

Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is a precursor of pancreatic cancer. While earlier research has shown a high prevalence of synchronous/metachronous extrapancreatic tumors in IPMN patients, these studies have often been small with retrospective data collection. The aim of the study was to examine absolute and relative risks of non-pancreatic gastrointestinal (GI) cancer precursors and mortality in histologically confirmed IPMN. Through the nationwide ESPRESSO histopathology cohort, we retrieved data on IPMN between 1965 and 2016. Each index case was matched to ≤5 general population controls. Through Cox regression, we estimated hazard ratios (HRs) for future GI cancer precursors and death. A total of 117 patients with IPMN and 539 age- and sex-matched controls were included. Over a median of 2.1 years of follow up, we confirmed two (1.7%) incident GI cancer precursors in IPMN vs. four (0.7%) in controls, corresponding to an HR of 1.89 (95%CI = 0.34–10.55). By contrast, IPMN patients were at increased risk of death (HR 3.61 (95%CI = 1.79–7.27)). The most common cause of death in IPMN was pancreatic cancer (n = 14; 45.2% of all deaths). We found no association between IPMN and other GI cancer precursors. This argues against comprehensive routine surveillance for other GI cancer precursors in IPMN patients. Mortality was increased in IPMN with pancreatic cancer being the most common cause of death, indicating the need for lifelong follow up in all resected and non-resected patients with IPMN. However, results should be confirmed in larger cohorts. [ABSTRACT FROM AUTHOR]

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) improve cardiovascular and renal outcomes in patients with type 2 diabetes through distinct mechanisms. However, evidence on clinical outcomes in patients treated with both GLP-1 RA and SGLT2i is lacking. We aim to provide insight into the effects of open-label SGLT2i use in parallel with or shortly after once-weekly GLP-1 RA exenatide (EQW) on cardiorenal outcomes. Methods: In the EXSCEL cardiovascular outcomes trial EQW arm, SGLT2i drop-in occurred in 8.7% of participants. These EQW+SGLT2i users were propensity-matched to: (1) placebo-arm participants not taking SGLT2i (n = 572 per group); and to (2) EQW-arm participants not taking SGLT2i (n = 575), based on their last measured characteristics before SGLT2i initiation, and equivalent study visit in comparator groups. Time-to-first major adverse cardiovascular event (MACE) and all-cause mortality (ACM) were compared using Cox regression analyses. eGFR slopes were quantified using mixed model repeated measurement analyses. Results: In adjusted analyses, the risk for MACE with combination EQW+SGLT2i use was numerically lower compared with both placebo (adjusted hazard ratio 0.68, 95% CI 0.39–1.17) and EQW alone (0.85, 0.48–1.49). Risk of ACM was nominally significantly reduced compared with placebo (0.38, 0.16–0.90) and compared with EQW (0.41, 0.17–0.95). Combination EQW+SGLT2i use also nominally significantly improved estimated eGFR slope compared with placebo (+ 1.94, 95% CI 0.94–2.94 mL/min/1.73 m2/year) and EQW alone (+ 2.38, 1.40–3.35 mL/min/1.73 m2/year). Conclusions: This post hoc analysis supports the hypothesis that combinatorial EQW and SGLT2i therapy may provide benefit on cardiovascular outcomes and mortality. Trial registration Clinicaltrials.gov, Identifying number: NCT01144338, Date of registration: June 15, 2010. [ABSTRACT FROM AUTHOR]

Available epidemiological data on primary biliary cholangitis (PBC) in Sweden originate from regional studies in the 1980s and may not reflect modern day PBC. We aimed to estimate incidence and prevalence, survival and death causes, and gender differences in PBC. We used international classification of disease (ICD) codes to identify patients with PBC in inpatient and outpatient registries 1987–2014 who were then linked to the Swedish cause of death, cancer and prescribed drug registries. Each PBC patient was matched with 10 reference individuals from the general population. In sensitivity analyses, we examined PBC patients identified through clinical patient records from Karolinska, Sahlgrenska and Örebro University Hospitals. We identified 5,350 adults with PBC. Prevalence of PBC increased steadily from 5.0 (1987) to 34.6 (2014) per 100,000 inhabitants whereas the yearly incidence rate was relatively constant with a median of 2.6 per 100,000 person-years, with a female:male gender ratio of 4:1. Compared to reference individuals, PBC individuals aged 15–39 years at diagnosis had a substantially higher risk of death (Hazard Ratio [HR] 12.7, 95% Confidence Interval [CI] 8.3–19.5) than those diagnosed between 40–59 (HR 4.1, 95% CI 3.7–4.5) and >60 (HR 3.7, 95% CI 3.5–3.9) years of age. Relative risks of mortality were highest in men. In conclusion, we found that recorded prevalence of PBC in Sweden has increased substantially during the last 30 years although incidence has been stable. Patients diagnosed in young adulthood were at a 12.7-fold increased risk of death, and male PBC patients had worse prognosis. [ABSTRACT FROM AUTHOR]

Melphalan flufenamide (melflufen), a first‐in‐class alkylating peptide‐drug conjugate, plus dexamethasone demonstrated superior progression‐free survival (PFS), but not overall survival (OS), versus pomalidomide plus dexamethasone in relapsed/refractory multiple myeloma in the OCEAN study. Time to progression (TTP) <36 months after a prior autologous stem cell transplantation (ASCT) was a negative prognostic factor for OS with melflufen. This post hoc exploratory analysis evaluated patients refractory to prior alkylators (e.g., cyclophosphamide and melphalan) in OCEAN. In 153 patients refractory to prior alkylators (melflufen, n = 78; pomalidomide, n = 75), the melflufen and pomalidomide arms had similar median PFS (5.6 months [95% CI, 4.2–8.3] vs. 4.7 months [95% CI, 3.1–7.3]; hazard ratio [HR], 0.92 [95% CI, 0.63–1.33]) and OS (23.4 months [95% CI, 14.4–31.7] vs. 20.0 months [95% CI, 12.0–28.7]; HR, 0.92 [95% CI, 0.62–1.38]). Among alkylator‐refractory patients with a TTP ≥ 36 months after a prior ASCT or no prior ASCT (melflufen, n = 54; pomalidomide, n = 53), the observed median PFS and OS were longer in the melflufen arm than the pomalidomide arm. The safety profile of melflufen was consistent with previous reports. These results suggest that melflufen is safe and effective in patients with alkylator‐refractory disease, suggesting differentiated activity from other alkylators. [ABSTRACT FROM AUTHOR]

Background: Patients with severe uncontrolled asthma may receive oral corticosteroid (OCS) treatment regularly. The present study investigated the health care resource utilization and cost in regularly OCS treated Swedish asthma patients.Methods: Primary care medical records data were linked to data from Swedish national health registries. Patients ≥18 years with a drug claim for obstructive pulmonary diseases during 2007-2009 (index date) and a prior asthma diagnosis, were classified by their OCS claims during the 12-months' post index period: regular OCS equals ≥5 mg per day; periodic OCS less than 5 mg per day; or non-OCS users. Cost of asthma- and OCS-morbidity-related health care resource utilization were calculated.Results: A total of 15,437 asthma patients (mean age 47.8, female 62.6%), whereof 223 (1.44%) were regular OCS users, 3054 (19.7%) were periodic, and 12,160 (78.7%) were non-OCS users. Regular OCS users were older and more often females, had lower lung function, greater eosinophil count and more co-morbidities at baseline compared with the other groups. Age-adjusted annual total health care cost was three-times greater in the regular OCS group (€5615) compared with the non-OCS users (€1980) and twice as high as in the periodic OCS group (€2948). The major cost driver in the non-OCS and periodic OCS groups were primary care consultations, whereas inpatient costs were the major cost driver in the regular OCS group. The asthma related costs represented 10-12% of the total cost in all three groups.Conclusion: In this real-life asthma study in Sweden, the total yearly cost of health care resource utilization for a regular OCS user was three times greater than for a patient with no OCS use, indicating substantial economic and health care burden for asthma patients on regular oral steroid treatment. [ABSTRACT FROM AUTHOR]

4 Dave CV, Kim SC, Goldfine AB, Glynn RJ, Tong A, Patorno E. Risk of cardiovascular outcomes in patients with type 2 diabetes after addition of SGLT2 inhibitors versus sulfonylureas to baseline GLP-1RA therapy. Before matching, patients in the SGLT2 inhibitor group were younger, more likely to be on metformin/glucagon-like peptide-1 receptor agonists/insulin, and had lower rates of comorbid heart failure, microvascular disease, stroke and chronic kidney disease (Table S2). Keywords: cardiovascular disease; real-world evidence; SGLT2 inhibitor; sulphonylureas; type 2 diabetes EN cardiovascular disease real-world evidence SGLT2 inhibitor sulphonylureas type 2 diabetes 2402 2409 8 07/04/23 20230801 NES 230801 INTRODUCTION Sulphonylureas (SUs) are widely used in type 2 diabetes (T2D), particularly in resource-constrained regions. Lower risk of cardiovascular events and death associated with initiation of sodium-glucose cotransporter-2 inhibitors versus sulphonylureas: Analysis from the CVD-REAL 2 study. [Extracted from the article]

Background: The risk of severe coronavirus disease 2019 (COVID-19) is increased in people with diabetes, but effects of diabetes type and other risk factors remain incompletely characterized. We studied this in a Swedish cohort of hospitalized patients with type 1 and type 2 diabetes (T1D and T2D), also including comparisons with influenza epidemics of recent years. Methods: Nationwide healthcare registries were used to identify patients. A total of 11,005 adult patients with diabetes (T1D, n = 373; T2D, n = 10,632) were hospitalized due to COVID-19 from January 1, 2020 to September 1, 2021. Moreover, 5111 patients with diabetes (304 T1D, 4807 T2D) were hospitalized due to influenza from January 1, 2015 to December 31, 2019. Main outcomes were death within 28 days after admission and new hospitalizations for heart failure (HF), chronic kidney disease (CKD), cardiorenal disease (CRD; composite of HF and CKD), myocardial infarction (MI) and stroke during 1 year of follow-up. Results: Number of deaths and CRD events were 2025 and 442 with COVID-19 and 259 and 525 with influenza, respectively. Age- and sex-adjusted Cox regression models in COVID-19 showed higher risk of death and HF in T1D vs. T2D, hazard ratio (HR) 1.77 (95% confidence interval 1.41–2.22) and 2.57 (1.31–5.05). With influenza, T1D was associated with higher risk of death compared with T2D, HR 1.80 (1.26–2.57). Older age and previous CRD were associated with higher risks of death and hospitalization for CRD. After adjustment for prior comorbidities, mortality differences were still significant, but there were no significant differences in cardiovascular and renal outcomes. COVID-19 relative to influenza was associated with higher risk of death in both T1D and T2D, HR 2.44 (1.60–3.72) and 2.81 (2.59–3.06), respectively. Conclusions: In Sweden, patients with T1D as compared to T2D had a higher age- and sex-adjusted risk of death within 28 days and HF within one year after COVID-19 hospitalization, whereas the risks of other non-fatal cardiovascular and renal disease events were similar. Patients with T1D as well as T2D have a greater mortality rate when hospitalized due to COVID-19 compared to influenza, underscoring the importance of vaccination and other preventive measures against COVID-19 for diabetes patients. [ABSTRACT FROM AUTHOR]

Aim: To examine how the development of cardiovascular and renal disease (CVRD) translates to hospital healthcare costs in individuals with type 2 diabetes (T2D) initially free from CVRD. Methods: Data were obtained from the digital healthcare systems of 12 nations using a prespecified protocol. A fixed country‐specific index date of 1 January was chosen to secure sufficient cohort disease history and maximal follow‐up, varying between each nation from 2006 to 2017. At index, all individuals were free from any diagnoses of CVRD (including heart failure [HF], chronic kidney disease [CKD], coronary ischaemic disease, stroke, myocardial infarction [MI], or peripheral artery disease [PAD]). Outcomes during follow‐up were hospital visits for CKD, HF, MI, stroke, and PAD. Hospital healthcare costs obtained from six countries, representing 68% of the total study population, were cumulatively summarized for CVRD events occurring during follow‐up. Results: In total, 1.2 million CVRD‐free individuals with T2D were identified and followed for 4.5 years (mean), that is, 4.9 million patient‐years. The proportion of individuals indexed before 2010 was 18% (n = 207 137); 2010‐2015, 31% (361 175); and after 2015, 52% (609 095). Overall, 184 420 (15.7%) developed CVRD, of which cardiorenal disease was most frequently the first disease to develop (59.7%), consisting of 23.0% HF and 36.7% CKD, and more common than stroke (16.9%), MI (13.7%), and PAD (9.7%). The total cumulative cost for CVRD was US$1 billion, of which 59.0% was attributed to cardiorenal disease, 3‐, 5‐, and 6‐fold times greater than the costs for stroke, MI, and PAD, respectively. Conclusion: Across all nations, HF or CKD was the most frequent CVRD manifestation to develop in a low‐risk population with T2D, accounting for the highest proportion of hospital healthcare costs. These novel findings highlight the importance of cardiorenal awareness when planning healthcare. [ABSTRACT FROM AUTHOR]

Background: Randomized trials demonstrated a lower risk of cardiovascular (CV) events with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) in patients with type 2 diabetes (T2D) at high CV risk. Prior real-world data suggested similar SGLT-2i effects in T2D patients with a broader risk profile, but these studies focused on heart failure and death and were limited to the United States and Europe.Objectives: The purpose of this study was to examine a broad range of CV outcomes in patients initiated on SGLT-2i versus other glucose-lowering drugs (oGLDs) across 6 countries in the Asia Pacific, the Middle East, and North American regions.Methods: New users of SGLT-2i and oGLDs were identified via claims, medical records, and national registries in South Korea, Japan, Singapore, Israel, Australia, and Canada. Propensity scores for SGLT-2i initiation were developed in each country, with 1:1 matching. Hazard ratios (HRs) for death, hospitalization for heart failure (HHF), death or HHF, MI, and stroke were assessed by country and pooled using weighted meta-analysis.Results: After propensity-matching, there were 235,064 episodes of treatment initiation in each group; ∼27% had established CV disease. Patient characteristics were well-balanced between groups. Dapagliflozin, empagliflozin, ipragliflozin, canagliflozin, tofogliflozin, and luseogliflozin accounted for 75%, 9%, 8%, 4%, 3%, and 1% of exposure time in the SGLT-2i group, respectively. Use of SGLT-2i versus oGLDs was associated with a lower risk of death (HR: 0.51; 95% confidence interval [CI]: 0.37 to 0.70; p < 0.001), HHF (HR: 0.64; 95% CI: 0.50 to 0.82; p = 0.001), death or HHF (HR: 0.60; 95% CI: 0.47 to 0.76; p < 0.001), MI (HR: 0.81; 95% CI: 0.74 to 0.88; p < 0.001), and stroke (HR: 0.68; 95% CI: 0.55 to 0.84; p < 0.001). Results were directionally consistent across both countries and patient subgroups, including those with and without CV disease.Conclusions: In this large, international study of patients with T2D from the Asia Pacific, the Middle East, and North America, initiation of SGLT-2i was associated with a lower risk of CV events across a broad range of outcomes and patient characteristics. (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors [CVD-REAL]; NCT02993614). [ABSTRACT FROM AUTHOR]

Background: An increased risk of cardiovascular disease (CVD) has been reported in patients with diverticular disease (DD). However, there are knowledge gaps about specific risks of each major adverse cardiovascular event (MACE) component., Methods: This nationwide cohort study included Swedish adults with DD (1987-2017, N=52,468) without previous CVD. DD was defined through ICD codes in the National Patient Register and colorectal histopathology reports from the ESPRESSO study. DD cases were matched by age, sex, calendar year and county of residence to ≤5 population reference individuals (N=194,525). Multivariable-adjusted hazard ratios (aHRs) for MACE up until December 2021 were calculated using stratified Cox proportional hazard models., Results: Median age at DD diagnosis was 62 years and 61% were females. During a median follow-up of 8.6 years, 16,147 incident MACE occurred in individuals with DD, and 48,134 in reference individuals (incidence rates (IRs)=61.4 vs. 43.8/1,000 person-years) corresponding to an aHR of 1.24 (95%CI=1.22-1.27), equivalent to one extra case of MACE for every 6 DD patients followed for 10 years. The risk was increased for ischemic heart disease (IR=27.9 vs. 18.6; aHR=1.36, 95%CI=1.32-1.40), congestive heart failure (IR=23.2 vs. 15.8; aHR=1.26, 95%CI=1.22-1.31), and stroke (IR=18.0 vs. 13.7; aHR=1.15, 95%CI=1.11-1.19). DD was not associated with cardiovascular mortality (IR=18.9 vs. 15.3; aHR=1.01, 95%CI=0.98-1.05). Results remained robust in sibling-controlled analyses., Conclusions: Patients with DD had a 24% increased risk of MACE compared with reference individuals, but no increased cardiovascular mortality. Future research should confirm these data and examine underlying mechanisms and shared risk factors between DD and CVD., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objective: Major adverse limb events (MALEs) are frequent in patients with lower extremity peripheral arterial disease (PAD). However, routine care MALE rate estimations after revascularisation are scarce. This study aimed to determine post-procedural MALE rates in revascularised patients with PAD and identify predictors of post-procedural MALEs., Methods: This was a population based observational study on merged national registry data. Patients with PAD undergoing lower limb revascularisation between 2008 and 2016 were retrieved from the Swedish National Registry for Vascular Surgery. Information on comorbidities, medications, and post-procedural MALE endpoints were identified in national healthcare registries. Primary outcomes of interest were categorised as 2 - 4 point MALE composites that included limb amputation, acute lower limb ischaemia, progression to or relapse of chronic limb threatening ischaemia (CLTI), and ipsilateral re-interventions regardless of indication. Patients with intermittent claudication (IC) and CLTI were analysed separately using Kaplan-Meier estimates. Stepwise Cox proportional hazard models were used for predictor candidate analysis., Results: Overall, 28 021 revascularised patients with PAD were analysed (IC, n = 10 506, 37.5%; CLTI, n = 17 515, 62.5%). During a mean follow up ± standard deviation of 3.2 ± 2.4 years, 5 226 (18.7%), 9 423 (33.6%), and 12 696 (45.3%) patients experienced a 2, 3, and 4 point MALE, respectively. The estimated one year 4 point MALE rates were 21.4% (95% confidence interval [CI] 20.6 - 22.2%) in IC and 46.9% (95% CI 46.1 - 47.7%) in CLTI. Adjusted predictors for experiencing a 4 point MALE in IC were chronic kidney disease (CKD) (hazard ratio [HR] 1.33, 95% CI 1.12 - 1.59) and previous lower limb revascularisation (HR 1.29, 95% CI 1.19 - 1.40). In CLTI, previous contralateral lower limb amputation (HR 1.60, 95% CI 1.47 - 1.73) and CKD (HR 1.25, 95% CI 1.17 - 1.34) were adjusted predictors., Conclusion: This study emphasises the very high MALE rates in revascularised patients with lower limb PAD, especially in CLTI. Prior lower limb revascularisation correlated with increased MALE rates in IC patients, while prior lower limb amputation was linked to subsequent MALEs in CLTI. In both IC and CLTI, CKD was associated with poorer outcomes, regardless of applied MALE definition., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective:  Necrotizing enterocolitis (NEC) classically is diagnosed by radiographic demonstration of pneumatosis intestinalis/portal venous gas (PI/PVG). This study examines clinical characteristics of NEC confirmed by independent evaluation of abdominal radiographs, taken for clinical signs of NEC, or by pathologic findings at laparotomy or autopsy (confirmed NEC [cNEC])., Study Design:  The investigated cohort included 1,382 extremely low birth weight (BW) infants (BW range: 500-1,000 g) with median 27 weeks (range: 23-32) gestational age (GA) at birth. They were randomized into the placebo-controlled "Connection Trial" of the new biological drug candidate IBP-9414 with cNEC as one primary endpoint., Results:  Total 119 infants (8.6%) had cNEC diagnosed at median 14 days of age by confirming PI/PVG at X-ray adjudication ( n  = 111) and/or by surgery/autopsy ( n  = 21). Sixteen percent of cNEC cases died. Adverse events of NEC were reported in 8.5% of infants and 4.1% had NEC diagnosed by radiology and surgery/autopsy at the participating centers. Regression analyses showed that the risk of cNEC decreased by 11 to 30% for every 100-g increment in BW and single-week increment in GA and associated cNEC with odds ratios (ORs) > 2.0 for gastrointestinal (GI) perforation and obstruction, hypotension, hypokalemia, hypophosphatemia, and death. Comparing risks of cNEC in infants below and above 750-g BW showed higher ORs (2.7-4.3) for GI perforation, hypotension, hypokalemia, and renal complications in the smaller infants, whereas the bigger infants had higher ORs (1.9-3.2) for serious non-GI events, late-onset sepsis (LOS), and death. Predictors of cNEC (hazard ratio, HR > 1.5) included serious non-GI events (mainly infections), hyponatremia, and hyperglycemia, whereas the HR was 0.52 for intravenous antibiotics. After cNEC diagnosis, there were higher rates of GI perforation and obstruction, hypotension, hypokalemia, and LOS., Conclusion:  Independent adjudication of abdominal radiographs increased radiological recognition of NEC and proved to be feasible in a multicenter study setting as well as able to diagnose clinically relevant NEC., Key Points: · Independent adjudication of abdominal radiographs in ELBW infants increased NEC recognition.. · Risk of NEC decreased by 11 to 30% with every 100-g increment in BW and GA week.. · In infants with BW 750 to 1,000 g, the risk of death from NEC was almost twice that in infants with BW 500 to 749 g. · Infants with NEC received antibiotics during one-third and parenteral nutrition during half of the first 7 postnatal weeks.., Competing Interests: J.N. is the global coordinating investigator of the Connection Trial sponsored by Infant Bacterial Therapeutics. R.S., M.D., J.F.-T., M.H., and J.A.Z. are principal investigators of the Connection Trial sponsored by Infant Bacterial Therapeutics. A.K., J.R., and S.S. are employees of the sponsor Infant Bacterial Therapeutics. M.T. is a consultant statistician employed by the sponsor Infant Bacterial Therapeutics., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background: Melflufen, a first-in-class alkylating peptide-drug conjugate, rapidly enters tumor cells and metabolizes to melphalan. In previous studies, melflufen was administered via central venous catheter (CVC). However, administration by peripheral venous catheter (PVC) may be preferable., Patients and Methods: PORT was a two-period, phase 2 crossover study of CVC versus PVC melflufen administration in patients with relapsed/refractory multiple myeloma. Adults with ≥ 2 prior therapies refractory to/intolerant of an immunomodulatory drug and a proteasome inhibitor were randomized 1:1 to weekly oral dexamethasone plus melflufen (40 mg) via CVC or PVC infusion on day 1 of 28-day cycle 1. In cycle 2, patients continued dexamethasone and crossed over to the other melflufen administration route. In cycle 3, all patients received melflufen until progression; PVC or CVC routes were allowed based upon investigator decision. Pharmacokinetic sampling was performed during and after melflufen infusion. Primary endpoints were melphalan pharmacokinetic parameters (C max , AUC (0-t) , and AUC (0-∞) ) and frequency and severity of PVC-related local reactions., Results: The 90% CIs for adjusted geometric mean ratios for pharmacokinetic parameters following CVC versus PVC administration were within the 0.8-1.25 bioequivalence range (C max 0.946 [90% CI: 0.849, 1.053]; AUC (0-t) 0.952 [90% CI: 0.861, 1.053]; AUC (0-∞) 0.955 [90% CI: 0.863, 1.058]). In both arms, adverse events were primarily hematological and similar; no phlebitis or local infusion-related reactions occurred., Conclusion: Melflufen PVC and CVC administrations are bioequivalent based on melphalan pharmacokinetic parameters. Melflufen via PVC was well tolerated, with no infusion-related reactions or new safety signals and may represent an alternative route of administration., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Investigate daily feeding volumes and their association with clinical variables in the early postnatal care of premature infants of the "Connection Trial.", Study Design: A total of 641 infants of 510 to 1,000-g birth weight (BW, mean: 847 g) and mean 27 weeks' gestational age at birth (GA) were analyzed for total daily enteral (TDE) feeding volumes of 10, 20, 40, 80, and 120 mL/kg/d and their association with 24 clinical variables. Uni- and multivariable Cox regression models were used to calculate hazard ratios (HR) with 95% confidence intervals as a measure of the chance of reaching each of the TDE volumes., Results: Daily feeding volumes were highly variable and the median advancement from 10 to 120 mL/kg/d was 11 mL/kg/d. Univariable analyses showed the lowest chance (HR, 0.22-0.81) of reaching the TDE volumes for gastrointestinal (GI) serious adverse events (SAEs), GI perforation, GI obstruction, and necrotizing enterocolitis, as well as respiratory SAEs, persistent ductus arteriosus, and hypotension. Each GA week, 100-g BW, and point in 5-minute Apgar score at birth associated with 8 to 20% increased chance of reaching the TDE volumes. Multivariable analyses showed independent effects for BW, GA, Apgar score, GI SAEs, abdominal symptoms/signs, respiratory SAEs, days on antibiotics, and hypotension., Conclusion: This observational analysis demonstrates the variable and cautious progression of enteral feedings in contemporary extremely low BW infants and the extent to which clinical variables associate with this progression., Key Points: · Total feedings of 10 and 120 mL/kg/d were reached at median 4 and 14 day of age, respectively, and at a daily increase of 11 mL/kg.. · Each incremental GA week, 100-g BW, and point in 5-minute Apgar score associated with 8 to 20% increased chance of reaching enteral feedings of 10 to 120 mL/kg/d.. · Progression of enteral feeding associated with several clinical events and was slower than advocated in common feeding protocols.., Competing Interests: J.N. is the global coordinating investigator of the Connection Trial sponsored by Infant Bacterial Therapeutics. P.A., V.C., A.L., P.P., R.R., B.S. are principal investigators of the Connection Trial sponsored by Infant Bacterial Therapeutics Inc. M.T. is a consultant statistician employed by Infant Bacterial Therapeutics Inc. A.K., S.S., and J.R. are all employees of Infant Bacterial Therapeutics Inc. sponsoring the Connection Trail., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone was approved in Europe for use in patients with triple-class refractory relapsed/refractory multiple myeloma (RRMM) with ≥3 prior lines of therapy and without prior autologous stem cell transplantation (ASCT) or with a time to progression >36 months after prior ASCT. The randomized LIGHTHOUSE study (NCT04649060) assessed melflufen plus daratumumab and dexamethasone (melflufen group) versus daratumumab in patients with RRMM with disease refractory to an immunomodulatory agent and a proteasome inhibitor or who had received ≥3 prior lines of therapy including an immunomodulatory agent and a proteasome inhibitor. A partial clinical hold issued by the US Food and Drug Administration for all melflufen studies led to financial constraints and premature study closure on February 23rd 2022 (data cut-off date). In total, 54 of 240 planned patients were randomized (melflufen group, N=27; daratumumab group, N=27). Median progression-free survival (PFS) was not reached in the melflufen group versus 4.9 months in the daratumumab group (Hazard Ratio: 0.18 [95% Confidence Interval, 0.05-0.65]; P=0.0032) at a median follow-up time of 7.1 and 6.6 months, respectively. Overall response rate (ORR) was 59% in the melflufen group versus 30% in the daratumumab group (P=0.0300). The most common grade ≥3 treatment-emergent adverse events in the melflufen group versus daratumumab group were neutropenia (50% vs. 12%), thrombocytopenia (50% vs. 8%), and anemia (32% vs. 19%). Melflufen plus daratumumab and dexamethasone demonstrated superior PFS and ORR versus daratumumab in RRMM and a safety profile comparable to previously published melflufen studies.

Background: There are few contemporary data on outcomes, costs, and treatment following a hospitalization for heart failure (hHF) in epidemiologically representative cohorts., Objectives: This study sought to describe rehospitalizations, hospitalization costs, use of guideline-directed medical therapy (GDMT) (renin-angiotensin system inhibitors, sacubitril/valsartan, beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter-2 inhibitors), and mortality after hHF., Methods: EVOLUTION HF (Utilization of Dapagliflozin and Other Guideline Directed Medical Therapies in Heart Failure Patients: A Multinational Observational Study Based on Secondary Data) is an observational, longitudinal cohort study using data from electronic health records or claims data sources in Japan, Sweden, the United Kingdom, and the United States. Adults with a first hHF discharge between 2018 and 2022 were included. The 1-year event rates per 100 patient-years (ERs) for death and rehospitalizations (with a primary diagnosis of heart failure (HF), chronic kidney disease [CKD], myocardial infarction, stroke, or peripheral artery disease) were calculated. Hospital health care costs were cumulatively summarized. Cumulative GDMT use was assessed using Kaplan-Meier estimates., Results: Of 263,525 patients, 28% died within the first year post-hHF (ER: 28.4 [95% CI: 27.0-29.9]). Rehospitalizations were mainly driven by HF (ER: 13.6 [95% CI: 9.8-17.4]) and CKD (ER: 4.5 [95% CI: 3.6-5.3]), whereas the ERs for myocardial infarction, stroke, and peripheral artery disease were lower. Health care costs were predominantly driven by HF and CKD. Between 2020 and 2022, use of renin-angiotensin system inhibitors, sacubitril/valsartan, beta-blockers, and mineralocorticoid receptor antagonists changed little, whereas uptake of sodium-glucose cotransporter-2 inhibitors increased 2- to 7-fold., Conclusions: Incident post-hHF rehospitalization risks and costs were high, and GDMT use changed little in the year following discharge, highlighting the need to consider earlier and greater implementation of GDMT to manage risks and reduce costs., Competing Interests: Funding Support and Author Disclosures EVOLUTION HF is funded by AstraZeneca. Dr Cleland was supported by a British Heart Foundation Centre of Research Excellence (grant number RE/18/6/34217). Dr Bozkurt has received consulting, advisory or research support from Abbott Vascular, Amgen, AstraZeneca, Baxter Healthcare Corporation, Boehringer Ingelheim, Bristol Myers Squibb, Cardurion, Liva Nova, Relypsa, Renovacor, Roche, Sanofi, scPharmaceuticals, and Vifor. Dr Savarese has received grants from AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Merck, Novartis, Pharmacosmos, and Vifor; and personal fees from AstraZeneca, Cytokinetics, Edwards Lifesciences, Medtronic, Novartis, Pharmacosmos, Roche, Laboratoires Servier, and Vifor. Drs Adamsson Eryd, Bodegård, Khordoc, and Zhang are employees of AstraZeneca. Dr Cleland has received grants and/or personal fees from Abbott Laboratories, Amgen, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Bristol Myer Squibb, Idorsia, Johnson & Johnson, Medtronic, MyoKardia, NI Medical, Novartis, Pharmacosmos, Pharma Nord, Respicardia, Laboratoires Servier, Torrent Pharmaceuticals, Vifor, and VisCardia. Dr Thuresson is an employee of Statisticon, which has received funding from AstraZeneca. Dr Vardeny has received personal or institutional research support from AstraZeneca. Dr Lund has received grant support, lecture fees, and/or consulting fees from Abbott Laboratories, Alleviant, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Edwards Lifesciences, Lexicon Pharmaceuticals, Medscape, Merck Sharp & Dohme, MyoKardia, Novartis, OrionPharma, Pharmacosmos, Sanofi, and Vifor. Dr Kishi has reported that he has no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone demonstrated superior progression-free survival (PFS) but directionally different overall survival (OS) favoring pomalidomide (hazard ratio [HR], 1.10) in OCEAN., Methods: These analyses further investigated prognostic subgroups impacting survival in updated data from the randomized, phase 3 OCEAN study (NCT03151811; date: February 3, 2022) and the phase 2 HORIZON study (NCT02963493; date: February 2, 2022)., Results: In OCEAN, subgroups prognostic for OS were age (P = .011; <65 years favored pomalidomide) and no previous autologous stem cell transplant (ASCT) or progression >36 months after ASCT (P = .001; favored melflufen). Overall, 245 of 495 (49%) patients randomized had received a previous ASCT, of which 202 (82%) had progressed within 36 months following their ASCT. When excluding patients who had progressed <36 months post-ASCT (melflufen group, n = 145; pomalidomide group, n = 148), median OS was 23.6 months with melflufen and 19.8 months with pomalidomide (HR, 0.83 [95% CI, 0.62-1.12]; P = .22). Among patients with triple-class refractory disease in HORIZON, patients who had progressed <36 months post-ASCT (n = 58) had a lower response rate and shorter duration of response and PFS than the remaining patients (n = 52). Safety was consistent with previous reports., Conclusion: These analyses demonstrate a consistent benefit for melflufen and dexamethasone in patients with relapsed/refractory multiple myeloma who have not received an ASCT or progressed >36 months after receiving an ASCT (ClinicalTrials.gov identifier: NCT03151811)., Competing Interests: Disclosure Funding was provided by Oncopeptides AB. P.S. has received payment or honoraria and research funding from Amgen, Celgene, Janssen, Karyopharm, and Takeda and payment or honoraria from Bristol Myers Squibb. P.G.R. has received consulting fees from AstraZeneca, Bristol Myers Squibb/Celgene, GlaxoSmithKline, Janssen, Karyopharm, Protocol Intelligence, Regeneron, Sanofi, Secura Bio, and Takeda and grants or contracts from Bristol Myers Squibb/Celgene, Karyopharm, Oncopeptides, and Takeda. H.L. has received grants or contracts from Amgen, Sanofi, and Takeda; consulting fees from Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen-Cilag, Pfizer, Sanofi, and Takeda; payment or honoraria from Amgen, Bristol Myers Squibb, Celgene, Janssen-Cilag, Pfizer, Sanofi, and Takeda; and has participated on a data safety monitoring board or advisory board for Amgen, Bristol Myers Squibb, Celgene, Sanofi, and Takeda. M.-A.D. has received payment or honoraria for participation on an advisory board for Amgen, BeiGene, Bristol Myers Squibb, Janssen, and Takeda. F.H.S. has received grants or contracts from Celgene, GlaxoSmithKline, Janssen, Oncopeptides, Targovax, and Sanofi; payment or honoraria from AbbVie, Amgen, Bristol Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Janssen, Novartis, Oncopeptides, Pfizer, Sanofi, SkyliteDX, and Takeda; and participated on a data safety monitoring board or advisory board for AbbVie, Celgene, GlaxoSmithKline, Janssen, Oncopeptides, Sanofi, and Takeda. R.H. has received grants or contracts from Novartis and Takeda; consulting fees and payment or honoraria from AbbVie, Amgen, Bristol Myers Squibb, Janssen, PharmaMAR, and Takeda; consulting fees from Novartis; support for attending meetings and/or travel from Takeda; and has participated on a data safety monitoring board or advisory board for Amgen and Takeda. H.A. has received payment or honoraria from Amgen, Alexion, and Oncopeptides and has participated on a data safety monitoring board or advisory board for Amgen, Bristol Myers Squibb, Genentech, Janssen, MorphoSys and Novartis. M.T. is a consultant of and receives stock or stock options from Oncopeptides. S.N. is an employee of, has participated on a data safety monitoring board or advisory board for, and receives stock or stock options from Oncopeptides. N.A.B. is an employee of and receives stock or stock options from Oncopeptides. M.-V.M. has received payment or honoraria for lectures, presentations, speakers’ bureau, manuscript writing, or education events from Amgen, Bristol Myers Squibb/Celgene, GlaxoSmithKline, Janssen, Pfizer, Sanofi, and Takeda; and has participated on a data safety monitoring board or advisory board for Amgen, Bristol Myers Squibb/Celgene, GlaxoSmithKline, Janssen, Oncopeptides, Pfizer, Sanofi, and Takeda., (Copyright © 2023. Published by Elsevier Inc.)

Objectives: To explore how cardiorenal disease (CRD; heart failure and/or chronic kidney disease) impacted mortality in men and women hospitalised for COVID-19 during the first three waves of the pandemic in Sweden in comparison to previous influenza outbreaks., Design: A registry-based, retrospective, case-control study., Setting: Hospital care in Sweden., Participants: All patients in Sweden with a main hospital diagnosis of COVID-19 (January 2020-September 2021) or influenza (January 2015-December 2019) with previous CRD were identified in registries and compared with a reference group free from CRD but with COVID-19 or influenza., Primary Outcome Measure: Associated risk of all-cause death during the first year was analysed using adjusted Cox proportional hazards models., Results: In COVID-19 patients with and without prior history of CRD (n=44 866), mean age was 79.8 years (SD 11.8) and 43% were women. In influenza patients (n=8897), mean age was 80.6 years (SD 11.5) and 45% were women. COVID-19 versus influenza was associated with higher mortality risk during the first two COVID-19 waves (HR 1.53; 95% CI 1.45 to 1.62, p<0.001 and HR 1.52; 95% CI 1.44 to 1.61, p<0.001), but not in the third wave (HR 1.07; 95% CI 0.99 to 1.14, p=0.072). CRD was an independent risk factor for all-cause death after COVID-19 in men and women (men: 1.37; 95% CI 1.31 to 1.44, p<0.001; women: 1.46; 95% CI 1.38 to 1.54, p<0.001). At ages <70 years, women with CRD had a similar mortality rate to men with CRD, while at ages ≥70 years, the mortality rate was higher in men., Conclusions: Outcome after COVID-19 is worse if CRD is present. In women at ages <70 years, the presence of CRD attenuates the protective effect of female sex. COVID-19 was associated with higher mortality risk than influenza during the first two pandemic waves., Competing Interests: Competing interests: The authors declared the following potential conflicts of interest with respect to the research, authorship and publication of this article: VR has received honoraria on expert group participation from Astra Zeneca, Novo Nordisk and Boehringer Ingelheim. AN has received honoraria from Astra Zeneca, Merck Sharp & Dohme, Eli Lilly and Company, Novo Nordisk and Boehringer Ingelheim on expert group participation. TN has received unrestricted grants from AstraZeneca and NovoNordisk and has served on national advisory boards of Abbot, Amgen, Novo Nordisk, Sanofi-Aventis, Eli Lilly, MSD and Boehringer Ingelheim. JE has received research support or honoraria from AstraZeneca, NovoNordisk, Bayer, Ilya Pharma, Merck-Sharp & Dohme, Boehringer-Ingelheim. RK and DN reports no conflicts of interest. JB holds a full-time position at AstraZeneca as an epidemiologist. MT holds a full-time position by an independent statistical consultant company, Statisticon AB, Uppsala, Sweden, of which AstraZeneca Nordic is a client., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Digital healthcare systems could provide insights into the global prevalence of heart failure (HF). We designed the CardioRenal and Metabolic disease (CaReMe) HF study to estimate the prevalence, key clinical adverse outcomes and costs of HF across 11 countries., Methods: Individual level data from a contemporary cohort of 6 29 624 patients with diagnosed HF was obtained from digital healthcare systems in participating countries using a prespecified, common study plan, and summarised using a random effects meta-analysis. A broad definition of HF (any registered HF diagnosis) and a strict definition (history of hospitalisation for HF) were used. Event rates were reported per 100 patient years. Cumulative hospital care costs per patient were calculated for a period of up to 5 years., Results: The prevalence of HF was 2.01% (95% CI 1.65 to 2.36) and 1.05% (0.85 to 1.25) according to the broad and strict definitions, respectively. In patients with HF (broad definition), mean age was 75.2 years (95% CI 74.0 to 76.4), 48.8% (40.9-56.8%) had ischaemic heart disease and 34.5% (29.4-39.6%) had diabetes. In 51 442 patients with a recorded ejection fraction (EF), 39.1% (30.3-47.8%) had a reduced, 18.8% (13.5-24.0%) had a mildly reduced and 42.1% (31.5-52.8%) had a preserved left ventricular EF. In 1 69 518 patients with recorded estimated glomerular filtration rate, 49% had chronic kidney disease (CKD) stages III-V. Event rates were highest for cardiorenal disease (HF or CKD) and all cause mortality (19.3 (95% CI 11.3 to 27.1) and 13.1 (11.1 to 15.1), respectively), and lower for myocardial infarction, stroke and peripheral artery disease. Hospital care costs were highest for cardiorenal diseases., Conclusions: We estimate that 1-2% of the contemporary adult population has HF. These individuals are at significant risk of adverse outcomes and associated costs, predominantly driven by hospitalisations for HF or CKD. There is considerable public health potential in understanding the contemporary burden of HF and the importance of optimising its management., Competing Interests: Competing interests: AN has received honoraria from MSD, AstraZeneca, Eli Lilly, Boehringer Ingelheim and Novo Nordisk. JB holds a full time position at AstraZeneca as an epidemiologist. NT reports grants and personal fees from AstraZeneca, grants and personal fees from Janssen, grants and personal fees from BI-Lilly, grants and personal fees from Otsuka, grants, personal fees and other from Tricida, personal fees and other from Pulsedata, personal fees and other from Mesentech, personal fees and other from Renibus, and other from ClinPredict, outside the submitted work; NT has a patent for a microfluidic device for point of care detection of urine albumin pending. AK has received research grants and speaking honoraria from Astrazeneca, Novonordisk and Boehringer Ingelheim. APM reports receiving fees for serving on study committees from AstraZeneca, Novartis, Bayer and Fresenius, outside the present work. TT-G declares speaker and consulting fees from AstraZeneca, BIAL, Daiichi-Sankyo, MSD, Medinfar and Novartis; TT-G holds shares in MTG. MB has received honoraria from Astra Zeneca, Janssen, Lilly, Boehringer Ingelheim, Sanofi, Amgen and Novo Nordisk. MT holds a full time position by an independent statistical consultant company, Statisticon AB, Uppsala, Sweden, of which AstraZeneca Nordic is a client. JS reports stock ownership in companies providing services to Itrim, Amgen, Janssen, Novo Nordisk, Eli Lilly, Boehringer, Bayer, Pfizer, Takeda and AstraZeneca, outside the submitted work. AB is supported by research funding from NIHR, British Medical Association, AstraZeneca and UK Research and Innovation. ABo is part of the BigData@Heart Consortium, funded by the Innovative Medicines Initiative-2 Joint Undertaking under grant agreement No 116074; this joint undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. KAS has received speaking honoraria from Astrazeneca, Novonordisk, Sanofi and Boehringer Ingelheim., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)