Glucagon-like peptide-1 receptor agonists and risk of major adverse liver outcomes in patients with chronic liver disease and type 2 diabetes.

OBJECTIVE: Phase II trials suggest glucagon-like peptide-1 receptor (GLP1) agonists resolve metabolic dysfunction-associated steatohepatitis but do not affect fibrosis regression. We aimed to determine the long-term causal effect of GLP1 agonists on the risk of major adverse liver outcomes (MALO) in patients with any chronic liver disease and type 2 diabetes. DESIGN: We used observational data from Swedish healthcare registers 2010-2020 to emulate a target trial of GLP1 agonists in eligible patients with chronic liver disease and type 2 diabetes. We used an inverse-probability weighted marginal structural model to compare parametric estimates of 10-year MALO risk (decompensated cirrhosis, hepatocellular carcinoma, liver transplantation or MALO-related death) in initiators of GLP1 agonists with non-initiators. We randomly sampled 5% of the non-initiators to increase computational efficiency. RESULTS: GLP1 agonist initiators had a 10-year risk of MALO at 13.3% (42/1026) vs 14.6% in non-initiators (1079/15 633) in intention-to-treat analysis (risk ratio (RR)=0.91, 95% CI=0.50 to 1.32). The corresponding 10-year per-protocol risk estimates were 7.4% (22/1026) and 14.4% (1079/15 633), respectively (RR=0.51, 95% CI=0.14 to 0.88). The per-protocol risk estimates at 6 years were 5.4% (21/1026) vs 9.0% (933/15 633) (RR=0.60, 95% CI=0.29 to 0.90) and at 8 years 7.2% (22/1026) vs 11.7% (1036/15 633) (RR=0.61, 95% CI=0.21 to 1.01). CONCLUSION: In patients with chronic liver disease and type 2 diabetes who adhered to therapy over time, GLP1 agonists may result in lower risk of MALO. This suggests that GLP1 agonists are promising agents to reduce risk of chronic liver disease progression in patients with concurrent type 2 diabetes, although this needs to be corroborated in randomised trials.

Identifying target populations to align with decision makers' needs.

Randomized trials estimate the average treatment effect within individuals that are eligible, invited and agree to enroll. However, decision makers often require evidence that extends beyond the trial's enrolled population to inform policy or actions for their specific target population. Each decision maker has distinct target populations, the composition of which may not often align with that of the trial population. As researchers, we should identify a decision maker for whom we aim to generate evidence early in the research process. We can then specify a target population of their interest and determine if a policy or action can be informed using results from a trial alone, or if additional complementary real-world data and analysis are required. In this commentary, we outline five key groupings of decision makers: policymakers, payers, purchasers, providers, and patients. We then specify relevant target populations for decision makers interested in the effectiveness of beta-blockers following a myocardial infarction with preserved ejection fraction. Finally, we summarize the scenarios in which results from a randomized trial may or may not apply to these target populations and suggest relevant analytic approaches that can generate evidence to better align with a decision makers' needs.

Prospective benchmarking of an observational analysis in the SWEDEHEART registry against the REDUCE-AMI randomized trial.

Prospective benchmarking of an observational analysis against a randomized trial increases confidence in the benchmarking process as it relies exclusively on aligning the protocol of the trial and the observational analysis, while the trials findings are unavailable. The Randomized Evaluation of Decreased Usage of Betablockers After Myocardial Infarction (REDUCE-AMI, ClinicalTrials.gov ID: NCT03278509) trial started recruitment in September 2017 and results are expected in 2024. REDUCE-AMI aimed to estimate the effect of long-term use of beta blockers on the risk of death and myocardial following a myocardial infarction with preserved left ventricular systolic ejection fraction. We specified the protocol of a target trial as similar as possible to that of REDUCE-AMI, then emulated the target trial using observational data from Swedish healthcare registries. Had everyone followed the treatment strategy as specified in the target trial protocol, the observational analysis estimated a reduction in the 5-year risk of death or myocardial infarction of 0.8 percentage points for beta blockers compared with no beta blockers; effects ranging from an absolute reduction of 4.5 percentage points to an increase of 2.8 percentage points in the risk of death or myocardial infarction were compatible with our data under conventional statistical criteria. Once results of REDUCE-AMI are published, we will compare the results of our observational analysis against those from the trial. If this prospective benchmarking is successful, it supports the credibility of additional analyses using these observational data, which can rapidly deliver answers to questions that could not be answered by the initial trial. If benchmarking proves unsuccessful, we will conduct a "postmortem" analysis to identify the reasons for the discrepancy. Prospective benchmarking shifts the investigator focus away from an endeavour to use observational data to obtain similar results as a completed randomized trial, to a systematic attempt to align the design and analysis of the trial and the observational analysis.

Benchmarking Observational Analyses Before Using Them to Address Questions Trials Do Not Answer: An Application to Coronary Thrombus Aspiration.

To increase confidence in the use of observational analyses when addressing effectiveness questions beyond those addressed by randomized trials, one can first benchmark the observational analyses against existing trial results. We used Swedish registry data to emulate a target trial similar to the Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia (TASTE) randomized trial, which found no difference in the risk of death or myocardial infarction by 1 year with or without thrombus aspiration among individuals with ST-elevation myocardial infarction. We benchmarked the emulation against the trial at 1 year and then extended the emulation's follow-up to 3 years and estimated effects in subpopulations underrepresented in the trial. As in the TASTE trial, the observational analysis found no differences in risk of outcomes by 1 year between groups (risk difference = 0.7 (confidence interval, -0.7, 2.0) and -0.2 (confidence interval, -1.3, 1.0) for death and myocardial infarction, respectively), so benchmarking was considered successful. We additionally showed no difference in risk of death or myocardial infarction by 3 years, or within subpopulations by 1 year. Benchmarking against an index trial before using observational analyses to answer questions beyond those the trial could address allowed us to explore whether the observational data can be trusted to deliver valid estimates of treatment effects.

Risk of Cardiovascular Diseases Among Older Breast Cancer Survivors in the United States: A Matched Cohort Study.

BACKGROUND: It has been suggested that cardiovascular risks are increased in breast cancer survivors, but few studies have quantified the risks of a range of specific clinically important cardiovascular outcomes in detail. PATIENTS AND METHODS: Women aged >65 years with incident breast cancer from 2004 to 2013 in the SEER-Medicare linked database were matched with 5 cancer-free female counterparts (5:1 ratio). Prevalence of specific cardiovascular outcomes at baseline was measured, then Cox regression was used to calculate hazard ratios (HRs) and 95% confidence intervals for the risk of individual cardiovascular outcomes during follow-up. Modification of the effect was investigated by time since diagnosis, race/ethnicity, prior cardiovascular disease (CVD), and age. RESULTS: In all, 91,473 women with breast cancer and 454,197 without breast cancer were included. Women with breast cancer had lower baseline prevalence of all CVDs. Compared with cancer-free controls, breast cancer survivors had substantially increased risks of deep vein thrombosis (adjusted HR, 1.67; 95% CI, 1.62-1.73; 386,484 person-years of follow-up) and pericarditis (HR, 1.43; 95% CI, 1.38-1.49; 390,776 person-years of follow-up); evidence of smaller increased risks of sudden cardiac arrest, arrhythmia, heart failure, and valvular heart disease (adjusted HRs ranging from 1.05-1.09, lower CI limits all ≥1); and evidence of lower risk of incident angina, myocardial infarction, revascularization, peripheral vascular disease, and stroke (adjusted HRs ranging from 0.89-0.98, upper CI limits all ≤1). Increased risks of arrhythmia, heart failure, pericarditis, and deep vein thrombosis persisted >5 years after cancer diagnosis. CONCLUSIONS: Women with a history of breast cancer were at increased risk of several CVDs, persisting into survivorship. Monitoring and managing cardiovascular risk throughout the long-term follow-up of women diagnosed with breast cancer should be a priority.

Burden and prevalence of prognostic factors for severe COVID-19 in Sweden.

The World Health Organization and European Centre for Disease Prevention and Control suggest that individuals over the age of 70 years or with underlying cardiovascular disease, cancer, chronic obstructive pulmonary disease, asthma, or diabetes are at increased risk of severe COVID-19. However, the prevalence of these prognostic factors is unknown in many countries. We aimed to describe the burden and prevalence of prognostic factors of severe COVID-19 at national and county level in Sweden. We calculated the burden and prevalence of prognostic factors for severe COVID-19 based on records from the Swedish national health care and population registers for 3 years before 1st January 2016. 9,624,428 individuals were included in the study population. 22.1% had at least one prognostic factor for severe COVID-19 (2,131,319 individuals), and 1.6% had at least three factors (154,746 individuals). The prevalence of underlying medical conditions ranged from 0.8% with chronic obstructive pulmonary disease (78,516 individuals) to 7.4% with cardiovascular disease (708,090 individuals), and the county specific prevalence of at least one prognostic factor ranged from 19.2% in Stockholm (416,988 individuals) to 25.9% in Kalmar (60,005 individuals). We show that one in five individuals in Sweden is at increased risk of severe COVID-19. When compared with the critical care capacity at a local and national level, these results can aid authorities in optimally planning healthcare resources during the current pandemic. Findings can also be applied to underlying assumptions of disease burden in modelling efforts to support COVID-19 planning.

Antidepressant Use and Risk of Manic Episodes in Children and Adolescents With Unipolar Depression.

Importance: Antidepressants are increasingly prescribed to pediatric patients with unipolar depression, but little is known about the risk of treatment-emergent mania. Previous research suggests pediatric patients may be particularly vulnerable to this adverse outcome. Objective: To estimate whether pediatric patients treated with antidepressants have an increased incidence of mania/hypomania compared with patients not treated with antidepressants and to identify patient characteristics associated with the risk of mania/hypomania. Design, Setting, and Participants: In a cohort study applying the target trial emulation framework, nationwide inpatient and outpatient care in Sweden from July 1, 2006, to December 31, 2019, was evaluated. Follow-up was conducted for 12 and 52 weeks after treatment initiation, with administrative follow-up ending December 31, 2020. Data were analyzed between May 1, 2022, and June 28, 2023. Individuals aged 4 to 17 years with a diagnosis of depression, but without a prior diagnosis of mania/hypomania, bipolar disorder, or psychosis or treatment with mood stabilizer (lithium, valproate, or carbamazepine), prescriptions were included. Exposures: The treatment group included patients who initiated any antidepressant medication within 90 days of diagnosis. The control group included patients who did not initiate antidepressants within 90 days. Main Outcomes and Measures: Diagnosis of mania/hypomania or initiation of mood stabilizer therapy. Incidences were estimated with Kaplan-Meier estimator, and inverse probability of treatment weighting was used to adjust for group differences at baseline. Results: The cohort included 43 677 patients (28 885 [66%] girls); 24 573 in the treatment group and 19 104 in the control group. The median age was 15 (IQR, 14-16) years. The outcome occurred in 96 individuals by 12 weeks and in 291 by 52 weeks. The cumulative incidence of mania was 0.26% (95% CI, 0.19%-0.33%) in the treatment group and 0.20% (95% CI, 0.13%-0.27%) in the control group at 12 weeks, with a risk difference of 0.06% (95% CI, -0.04% to 0.16%). At 52 weeks, the cumulative incidence was 0.79% (95% CI, 0.68%-0.91%) in the treatment group and 0.52% (95% CI, 0.40%-0.63%) in the control group (risk difference, 0.28%; 95% CI, 0.12%-0.44%). Hospitalizations, parental bipolar disorder, and use of antipsychotics and antiepileptics were the most important predictors of mania/hypomania by 12 weeks. Conclusion: This cohort study found no evidence of treatment-emergent mania/hypomania by 12 weeks in children and adolescents. This corresponds to the time frame for antidepressants to exert their psychotropic effect. A small risk difference was found only with longer follow-up. Certain patient characteristics were associated with mania/hypomania, which warrants clinical attention.

Effect of selective serotonin reuptake inhibitor treatment following diagnosis of depression on suicidal behaviour risk: a target trial emulation.

There is concern regarding the impact of selective serotonin reuptake inhibitors (SSRIs) on suicidal behaviour. Using the target trial framework, we investigated the effect on suicidal behaviour of SSRI treatment following a depression diagnosis. We identified 162,267 individuals receiving a depression diagnosis aged 6-59 years during 2006-2018 in Stockholm County, Sweden, after at least 1 year without antidepressant dispensation. Individuals who initiated an SSRI within 28 days of the diagnosis were assigned as SSRI initiators, others as non-initiators. Intention-to-treat and per-protocol effects were estimated; for the latter, individuals were censored when they ceased adhering to their assigned treatment strategy. We applied inverse probability weighting (IPW) to account for baseline confounding in the intention-to-treat analysis, and additionally for treatment non-adherence and time-varying confounding in the per-protocol analysis. The suicidal behaviour risk difference (RD), and risk ratio (RR) between SSRI initiators and non-initiators were estimated at 12 weeks. In the overall cohort, we found an increased risk of suicidal behaviour among SSRI initiators (intention-to-treat RR = 1.50, 95% CI = 1.25, 1.80; per-protocol RR = 1.69, 95% CI = 1.20, 2.36). In age strata, we only found evidence of an increased risk among individuals under age 25, with the greatest risk among 6-17-year-olds (intention-to-treat RR = 2.90, 95% CI = 1.72, 4.91; per-protocol RR = 3.34, 95% CI = 1.59, 7.00). Our finding of an increased suicidal behaviour risk among individuals under age 25 reflects evidence from RCTs. We found no evidence of an effect in the high-risk group of individuals with past suicidal behaviour. Further studies with information on a wider array of confounders are called for.

Causal effect of shifting from precarious to standard employment on all-cause mortality in Sweden: an emulation of a target trial.

BACKGROUND: We aimed at estimating the causal effect of switching from precarious to standard employment on the 6-year and 12-year risk of all-cause mortality among workers aged 20-55 years in Sweden. METHODS: We emulated a series of 12 target trials starting every year between 2005 and 2016 using Swedish register data (n=251 273). We classified precariously employed individuals using a multidimensional approach at baseline as (1) remaining in precarious employment (PE) (73.8%) and (2) shifting to standard employment (26.2%). All-cause mortality was measured from 2006 to 2017. We pooled data for all 12 emulated trials and used covariate-adjusted pooled logistic regression to estimate intention-to-treat and per-protocol effects via risk ratios (RRs) and standardised risk curves (the parametric g-formula). RESULTS: Shifting from precarious to standard employment decreases the 12-year risk of death by 20% on the relative scale (RR: 0.82, 95% CI: 0.73; 0.93), regardless of what happens after the initial shift. However, we estimated a 12-year risk reduction of 30% on the relative scale for workers shifting from precarious to standard employment and staying within this employment category for the full 12 years (RR: 0.71, 95% CI: 0.54; 0.95). CONCLUSIONS: This study finds that shifting from low to higher-quality employment conditions (ie, stable employment, sufficient income levels and high coverage by collective agreements) decreases the risk of death. Remaining in PE increases the risk of premature mortality. Our results emphasise the necessity of ensuring decent work for the entire working population to accomplish the 2030 Agenda for Sustainable Development.

Does Cardiovascular Mortality Overtake Cancer Mortality During Cancer Survivorship?: An English Retrospective Cohort Study.

Background: Cancer survivors have a higher risk for developing cardiovascular diseases than the general population. Objectives: The aim of this study was to investigate whether cardiovascular mortality overtakes cancer-specific mortality during cancer survivorship and, if so, at what point cardiovascular disease becomes the dominant cause of death. Methods: This cohort study used linked English electronic health records, including death registration data. The study population included 104,028 adults ≥40 years of age whose first cancer diagnosis was for 1 of 9 common cancers and who were alive and followed up at least 1 year after diagnosis. Age-stratified mortality rates were estimated from cardiovascular disease or cancer by predicting from Poisson models incorporating categorical age at diagnosis and time since diagnosis. Where cardiovascular disease mortality overtook cancer mortality, the crossover point was estimated using interpolation. Results: Mortality from cardiovascular causes overtook mortality due to the primary cancer at 2 to 11 years after cancer diagnosis in survivors of all 9 cancer types ≥80 years of age at diagnosis and after 5 to 17 years in survivors of 7 cancer types 60 to 79 years of age at diagnosis. Cardiovascular mortality overtook all cancer mortality for 6 and 2 cancer sites in the ≥80-year and 60- to 79-year age groups, respectively, over a longer time period. Cardiovascular mortality did not overtake cancer mortality during the observation period in patients aged 40 to 59 years, except among survivors of uterine cancer. Conclusions: In older survivors of 9 common cancers, cardiovascular mortality becomes dominant over mortality from the primary cancer, though not always over total cancer mortality, as time passes since cancer diagnosis.

Endocrine therapy use and cardiovascular risk in postmenopausal breast cancer survivors.

OBJECTIVE: Examine the effect of tamoxifen and aromatase inhibitors (AIs) on the risk of 12 clinically relevant cardiovascular outcomes in postmenopausal female breast cancer survivors. METHODS: We carried out two prospective cohort studies among postmenopausal women with breast cancer in UK primary care and hospital data (2002-2016) and US Surveillance, Epidemiology and End Results-Medicare data (2008-2013). Using Cox adjusted proportional hazards models, we compared cardiovascular risks between AI and tamoxifen users; and in the USA, between users of both drug classes and women receiving no endocrine therapy. RESULTS: 10 005 (UK) and 22 027 (USA) women with postmenopausal breast cancer were included. In both countries, there were higher coronary artery disease risks in AI compared with tamoxifen users (UK age-standardised incidence rate: 10.17 vs 7.51 per 1000 person-years, HR: 1.29, 95% CI 0.94 to 1.76; US age-standardised incidence rate: 36.82 vs 26.02 per 1000 person-years, HR: 1.29, 95% C I1.06 to 1.55). However, comparisons with those receiving no endocrine therapy (US data) showed no higher risk for either drug class and a lower risk in tamoxifen users (age-standardised incidence rate tamoxifen vs unexposed: 26.02 vs 35.19 per 1000 person-years, HR: 0.74, 95% 0.60 to 0.92; age-standardised incidence rate AI vs unexposed: 36.82 vs 35.19, HR: 0.96, 95% CI 0.83 to 1.10). Similar patterns were seen for other cardiovascular outcomes (arrhythmia, heart failure and valvular heart disease). As expected, there was more venous thromboembolism in tamoxifen compared with both AI users and those unexposed. CONCLUSIONS: Higher risks of several cardiovascular outcomes among AI compared with tamoxifen users appeared to be driven by protective effects of tamoxifen, rather than cardiotoxic effects of AIs.

Comparing Effect Estimates in Randomized Trials and Observational Studies From the Same Population: An Application to Percutaneous Coronary Intervention.

Background To understand when results from observational studies and randomized trials are comparable, we performed an observational emulation of a target trial designed to ask similar questions as the VALIDATE (Bivalirudin Versus Heparin in ST-Segment and Non-ST-Segment Elevation Myocardial Infarction in Patients on Modern Antiplatelet Therapy) randomized trial. The VALIDATE trial compared the effect of bivalirudin and heparin during percutaneous coronary intervention on the risk of death, myocardial infarction, and bleeding across Sweden. Methods and Results We specified the protocol of a target trial similar to the VALIDATE trial, then emulated the target trial in the period before the VALIDATE trial took place using data from the SWEDEHEART (Swedish Web System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies) registry-the same registry in which the trial was undertaken. The target trial emulation and the VALIDATE trial both estimated little or no effect of bivalirudin versus heparin on the risk of death or myocardial infarction by 180 days (target trial emulation risk ratio for death, 1.21 [95% CI, 0.88 - 1.54]; VALIDATE trial hazard ratio for death, 1.05 [95% CI, 0.78 - 1.41]). The observational data, however, could not capture less severe cases of bleeding, resulting in an inability to define a bleeding outcome like the trial, and could not accurately estimate the comparative risk of death by 14 days, which may be the result of intractable confounding early in follow-up or the inability to precisely emulate the trial's eligibility criteria. Conclusions Using real-world data to emulate a target trial can deliver accurate effect estimates. Yet, even with rich observational data, it is not always possible to estimate the short-term effect of interventions or the effect on outcomes for which data are not routinely collected.

Indirect acute effects of the COVID-19 pandemic on physical and mental health in the UK: a population-based study.

BACKGROUND: There are concerns that the response to the COVID-19 pandemic in the UK might have worsened physical and mental health, and reduced use of health services. However, the scale of the problem is unquantified, impeding development of effective mitigations. We aimed to ascertain what has happened to general practice contacts for acute physical and mental health outcomes during the pandemic. METHODS: Using de-identified electronic health records from the Clinical Research Practice Datalink (CPRD) Aurum (covering 13% of the UK population), between 2017 and 2020, we calculated weekly primary care contacts for selected acute physical and mental health conditions: anxiety, depression, self-harm (fatal and non-fatal), severe mental illness, eating disorder, obsessive-compulsive disorder, acute alcohol-related events, asthma exacerbation, chronic obstructive pulmonary disease exacerbation, acute cardiovascular events (cerebrovascular accident, heart failure, myocardial infarction, transient ischaemic attacks, unstable angina, and venous thromboembolism), and diabetic emergency. Primary care contacts included remote and face-to-face consultations, diagnoses from hospital discharge letters, and secondary care referrals, and conditions were identified through primary care records for diagnoses, symptoms, and prescribing. Our overall study population included individuals aged 11 years or older who had at least 1 year of registration with practices contributing to CPRD Aurum in the specified period, but denominator populations varied depending on the condition being analysed. We used an interrupted time-series analysis to formally quantify changes in conditions after the introduction of population-wide restrictions (defined as March 29, 2020) compared with the period before their introduction (defined as Jan 1, 2017 to March 7, 2020), with data excluded for an adjustment-to-restrictions period (March 8-28). FINDINGS: The overall population included 9 863 903 individuals on Jan 1, 2017, and increased to 10 226 939 by Jan 1, 2020. Primary care contacts for almost all conditions dropped considerably after the introduction of population-wide restrictions. The largest reductions were observed for contacts for diabetic emergencies (odds ratio 0·35 [95% CI 0·25-0·50]), depression (0·53 [0·52-0·53]), and self-harm (0·56 [0·54-0·58]). In the interrupted time-series analysis, with the exception of acute alcohol-related events (0·98 [0·89-1·10]), there was evidence of a reduction in contacts for all conditions (anxiety 0·67 [0·66-0·67], eating disorders 0·62 [0·59-0·66], obsessive-compulsive disorder [0·69 [0·64-0·74]], self-harm 0·56 [0·54-0·58], severe mental illness 0·80 [0·78-0·83], stroke 0·59 [0·56-0·62], transient ischaemic attack 0·63 [0·58-0·67], heart failure 0·62 [0·60-0·64], myocardial infarction 0·72 [0·68-0·77], unstable angina 0·72 [0·60-0·87], venous thromboembolism 0·94 [0·90-0·99], and asthma exacerbation 0·88 [0·86-0·90]). By July, 2020, except for unstable angina and acute alcohol-related events, contacts for all conditions had not recovered to pre-lockdown levels. INTERPRETATION: There were substantial reductions in primary care contacts for acute physical and mental conditions following the introduction of restrictions, with limited recovery by July, 2020. Further research is needed to ascertain whether these reductions reflect changes in disease frequency or missed opportunities for care. Maintaining health-care access should be a key priority in future public health planning, including further restrictions. The conditions we studied are sufficiently severe that any unmet need will have substantial ramifications for the people with the conditions as well as health-care provision. FUNDING: Wellcome Trust Senior Fellowship, Health Data Research UK.