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Background: There is conflicting literature on the relationship between prolonged QRS duration (QRSd) and arrhythmic events, including sudden cardiac death (SCD), in heart failure patients with or without implantable cardioverter-defibrillators (ICDs).Objective: The purpose of this study was to evaluate the prognostic significance of prolonged QRSd relative to arrhythmic outcomes in medically and ICD-treated patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II.Methods: Using a Cox proportional hazards model adjusting for ejection fraction, heart failure class, and blood urea nitrogen, we estimated the association of prolonged QRSd >/=140 ms with SCD in the medically treated arm and SCD or first appropriate ICD therapy for rapid ventricular tachycardia/fibrillation (VT/VF; cycle length Results: In the medically treated arm, prolonged QRSd was a significant independent predictor of SCD (hazard ratio 2.12; 95% confidence interval 1.20-3.76; P = .01). However, in the ICD-treated arm, prolonged QRSd did not predict SCD or rapid VT/VF (hazard ratio 0.77; 95% CI 0.47-1.24; P = .28). The difference in the prognostic effect of prolonged QRSd in these two groups was significant (P<.01). These results were not affected by varying the cycle length that defines rapid VT/VF or the duration that defines QRSd prolongation.Conclusions: In patients with prior myocardial infarction and EF

Results of randomized clinical trials are the preferred 'evidence' for establishing the benefits and safety of medical treatments. We present evidence suggesting that the conventional approach to reporting clinical trials has fundamental flaws that can result in overlooking identifiable subgroups harmed by a treatment while underestimating benefits to others. A risk-stratified approach can dramatically reduce the chances of such errors. Since professional and economic incentives reward advocating treatments for as broad a patient population as possible, we suggest that payers and regulatory bodies might need to act to motivate prompt, routine adoption of risk-stratified assessments of medical treatments' safety and benefits. [ABSTRACT FROM AUTHOR]

It has been demonstrated that patients enrolled in clinical trials frequently have a large degree of variation in their baseline risk for the outcome of interest. Thus, some have suggested that clinical trial results should routinely be stratified by outcome risk using risk models, since the summary results may otherwise be misleading. However, variation in competing risk is another dimension of risk heterogeneity that may also underlie treatment effect heterogeneity. Understanding the effects of competing risk heterogeneity may be especially important for pragmatic comparative effectiveness trials, which seek to include traditionally excluded patients, such as the elderly or complex patients with multiple comorbidities. Indeed, the observed effect of an intervention is dependent on the ratio of outcome risk to competing risk, and these risks - which may or may not be correlated - may vary considerably in patients enrolled in a trial. Further, the effects of competing risk on treatment effect heterogeneity can be amplified by even a small degree of treatment related harm. Stratification of trial results along both the competing and the outcome risk dimensions may be necessary if pragmatic comparative effectiveness trials are to provide the clinically useful information their advocates intend. [ABSTRACT FROM AUTHOR]

Introduction: While incidentally discovered covert cerebrovascular diseases (id-CCD) are associated with future stroke, it is not known if patients with id-CCD are prescribed statins., Methods: Patients age ≥50 with id-CCD on neuroimaging from 2009 to 2019 with no prior ischaemic stroke, transient ischaemic attack or dementia were identified using natural language processing in a large real-world cohort. Robust Poisson multivariable regression was used to assess statin prescription among patients without prior statins., Results: Among 2 41 050 patients, 74 975 patients (31.1%; 4.7% with covert brain infarcts (CBI); 29.0% with white matter disease (WMD)) had id-CCD. 53.5% (95% CI 53.2 to 53.9%) were not on statins within 6 months prior to the scan. Of those, 12.0% (95% CI 11.7 to 12.3%) were prescribed statins in the next 6 months compared with 9.3% (95% CI 9.1 to 9.4%) in those without CCD, a 2.7% (95% CI 2.4 to 3.1%) absolute increase in statin prescription for those with id-CCD. In adjusted analyses, the presence of id-CCD was only associated with minor increases in statin prescription (CBI or WMD (risk ratio (RR) 1.09, 95% CI 1.05 to 1.13), CBI alone (RR 1.34, 95% CI 1.21 to 1.47), WMD alone (RR 1.05, 95% CI 1.01 to 1.09), and CBI and WMD (RR 1.23, 95% CI 1.12 to 1.35))., Discussion: Identification of id-CCD is not associated with substantial changes in statin prescription in routine clinical practice., Competing Interests: No, there are no competing interests., (Copyright © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Clinical prediction models (CPMs) are tools that compute the risk of an outcome given a set of patient characteristics and are routinely used to inform patients, guide treatment decision-making, and resource allocation. Although much hope has been placed on CPMs to mitigate human biases, CPMs may potentially contribute to racial disparities in decision-making and resource allocation. While some policymakers, professional organizations, and scholars have called for eliminating race as a variable from CPMs, others raise concerns that excluding race may exacerbate healthcare disparities and this controversy remains unresolved. The Guidance for Unbiased predictive Information for healthcare Decision-making and Equity (GUIDE) provides expert guidelines for model developers and health system administrators on the transparent use of race in CPMs and mitigation of algorithmic bias across contexts developed through a 5-round, modified Delphi process from a diverse 14-person technical expert panel (TEP). Deliberations affirmed that race is a social construct and that the goals of prediction are distinct from those of causal inference, and emphasized: the importance of decisional context (e.g., shared decision-making versus healthcare rationing); the conflicting nature of different anti-discrimination principles (e.g., anticlassification versus antisubordination principles); and the importance of identifying and balancing trade-offs in achieving equity-related goals with race-aware versus race-unaware CPMs for conditions where racial identity is prognostically informative. The GUIDE, comprising 31 key items in the development and use of CPMs in healthcare, outlines foundational principles, distinguishes between bias and fairness, and offers guidance for examining subgroup invalidity and using race as a variable in CPMs. This GUIDE presents a living document that supports appraisal and reporting of bias in CPMs to support best practice in CPM development and use., (© 2024. The Author(s).)

Background and Objectives: Whether patent foramen ovale (PFO) closure benefits older patients with PFO and cryptogenic stroke is unknown because randomized controlled trials (RCTs) have predominantly enrolled patients younger than 60 years of age. Our objective was to estimate anticipated effects of PFO closure in older patients to predict the numbers needed to plan an RCT., Methods: Effectiveness estimates are derived from major observational studies (Risk of Paradoxical Embolism [RoPE] Study and Oxford Vascular Study, together referred to as the "RoPE-Ox" database) and all 6 major RCTs (Systematic, Collaborative, PFO Closure Evaluation [SCOPE] Consortium). To estimate stroke recurrence risk, observed outcomes were calculated for patients older than 60 years in the age-inclusive observational databases (n = 549). To estimate the reduction in the rate of recurrent stroke associated with PFO closure vs medical therapy based on the RoPE score and the presence of high-risk PFO features, a Cox proportional hazards regression model was developed on the RCT data in the SCOPE database (n = 3,740). These estimates were used to calculate sample sizes required for a future RCT., Results: Five-year risk of stroke recurrence using Kaplan-Meier estimates was 13.7 (95% CI 10.5-17.9) overall, 14.9% (95% CI 10.2-21.6) in those with high-risk PFO features. Predicted relative reduction in the event rate with PFO closure was 12.9% overall, 48.8% in those with a high-risk PFO feature. Using these estimates, enrolling all older patients with cryptogenic stroke and PFO would require much larger samples than those used for prior PFO closure trials, but selectively enrolling patients with high-risk PFO features would require totals of 630 patients for 90% power and 471 patients for 80% power, with an average of 5 years of follow-up., Discussion: Based on our projections, anticipated effect sizes in older patients with high-risk features make a trial in these subjects feasible. With lengthening life expectancy in almost all regions of the world, the utility of PFO closure in older adults is increasingly important to explore.

Background: The use of fidaxomicin is recommended as first line therapy for all patients with Clostridioides difficile infection (CDI). However, real-world studies have shown conflicting evidence of superiority., Methods: We conducted a retrospective single center study of patients diagnosed with CDI between 2011-2021. A primary composite outcome of clinical failure, 30-day relapse or CDI-related death was used. A multivariable cause specific Cox proportional hazards model was used to evaluate fidaxomicin compared to vancomycin in preventing the composite outcome. A separate model was fit on a subset of patients with C. difficile ribotypes adjusting for ribotype., Results: There were 598 patients included, of whom 84 received fidaxomicin. The primary outcome occurred in 8 (9.5%) in the fidaxomicin group compared to 111 (21.6%) in the vancomycin group. The adjusted multivariable model showed fidaxomicin was associated with 63% reduction in the risk of the composite outcome compared to vancomycin (HR = 0.37, 95% CI 0.17-0.80). In the 337 patients with ribotype data after adjusting for ribotype 027, the results showing superiority of fidaxomicin were maintained (HR = 0.19, 95% CI 0.05-0.77)., Conclusion: In the treatment of CDI, we showed that real-world use of fidaxomicin is associated with lower risk of a composite endpoint of treatment failure., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Older patients with Hodgkin lymphoma (HL) often have comorbid cardiovascular disease; however, the impact of pre-existing heart failure (HF) on the management and outcomes of HL is unknown., Objectives: The aim of this study was to assess the prevalence of pre-existing HF in older patients with HL and its impact on treatment and outcomes., Methods: Linked Surveillance, Epidemiology, and End Results (SEER) and Medicare data from 1999 to 2016 were used to identify patients 65 years and older with newly diagnosed HL. Pre-existing HF, comorbidities, and cancer treatment were ascertained from billing codes and cause-specific mortality from SEER. The associations between pre-existing HF and cancer treatment were estimated using multivariable logistic regression. Cause-specific Cox proportional hazards models adjusted for comorbidities and cancer treatment were used to estimate the association between pre-existing HF and cause-specific mortality., Results: Among 3,348 patients (mean age 76 ± 7 years, 48.6% women) with newly diagnosed HL, pre-existing HF was present in 437 (13.1%). Pre-existing HF was associated with a lower likelihood of using anthracycline-based chemotherapy regimens (OR: 0.42; 95% CI: 0.29-0.60) and a higher likelihood of lymphoma mortality (HR: 1.25; 95% CI: 1.06-1.46) and cardiovascular mortality (HR: 2.57; 95% CI: 1.96-3.36) in models adjusted for comorbidities. One-year lymphoma mortality cumulative incidence was 37.4% (95% CI: 35.5%-39.5%) with pre-existing HF and 26.3% (95% CI: 25.0%-27.6%) without pre-existing HF. The cardioprotective medications dexrazoxane and liposomal doxorubicin were used in only 4.2% of patients., Conclusions: Pre-existing HF in older patients with newly diagnosed HL is common and associated with higher 1-year mortality. Strategies are needed to improve lymphoma and cardiovascular outcomes in this high-risk population., Competing Interests: This study is supported by National Institute of Health grant K08HL146959 (to Dr Upshaw). The collection of cancer incidence data used in this study was supported by the California Department of Public Health pursuant to California Health and Safety Code § 103885; the Centers for Disease Control and Prevention’s National Program of Cancer Registries, under cooperative agreement 1NU58DP007156; the NCI’s SEER program under contract HHSN261201800032I awarded to the University of California-San Francisco, contract HHSN261201800015I awarded to the University of Southern California, and contract HHSN261201800009I awarded to the Public Health Institute. The ideas and opinions expressed herein are those of the authors and do not necessarily reflect the opinions of the State of California, the Department of Public Health, the NCI, and the Centers for Disease Control and Prevention or their contractors and subcontractors. The funders had no role in the design and conduct of the trial, analysis of data, or writing of the manuscript. Mr Nelson is employed by OM1 (but was employed by Tufts Medical Center while conducting the present research). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Cardiovascular disease (CVD) is the leading cause of death among people with type 2 diabetes 1-5 , most of whom are at moderate CVD risk 6 , yet there is limited evidence on the preferred choice of glucose-lowering medication for CVD risk reduction in this population. Here, we report the results of a retrospective cohort study where data for US adults with type 2 diabetes and moderate risk for CVD are used to compare the risks of experiencing a major adverse cardiovascular event with initiation of glucagon-like peptide-1 receptor agonists (GLP-1RA; n = 44,188), sodium-glucose cotransporter 2 inhibitors (SGLT2i; n = 47,094), dipeptidyl peptidase-4 inhibitors (DPP4i; n = 84,315) and sulfonylureas ( n = 210,679). Compared to DPP4i, GLP-1RA (hazard ratio (HR) 0.87; 95% confidence interval (CI) 0.82-0.93) and SGLT2i (HR 0.85; 95% CI 0.81-0.90) were associated with a lower risk of a major adverse cardiovascular event, whereas sulfonylureas were associated with a higher risk (HR 1.19; 95% CI 1.16-1.22). Thus, GLP-1RA and SGLT2i may be the preferred glucose-lowering agents for cardiovascular risk reduction in patients at moderate baseline risk for CVD. ClinicalTrials.gov registration: NCT05214573.

Background: Major adverse cardiovascular events (MACE) are a leading cause of morbidity and mortality among adults with type 2 diabetes. Currently, available MACE prediction models have important limitations, including reliance on data that may not be routinely available, narrow focus on primary prevention, limited patient populations, and longtime horizons for risk prediction., Objectives: The purpose of this study was to derive and internally validate a claims-based prediction model for 1-year risk of MACE in type 2 diabetes., Methods: Using medical and pharmacy claims for adults with type 2 diabetes enrolled in commercial, Medicare Advantage, and Medicare fee-for-service plans between 2014 and 2021, we derived and internally validated the annualized claims-based MACE estimator (ACME) model to predict the risk of MACE (nonfatal acute myocardial infarction, nonfatal stroke, and all-cause mortality). The Cox proportional hazards model was composed of 30 covariates, including patient age, sex, comorbidities, and medications., Results: The study cohort comprised 6,623,526 adults with type 2 diabetes, mean age 68.1 ± 10.6 years, 49.8% women, and 73.0% Non-Hispanic White. ACME had a concordance index of 0.74 (validation index range: 0.739-0.741). The predicted 1-year risk of the study cohort ranged from 0.4% to 99.9%, with a median risk of 3.4% (IQR: 2.3%-6.5%)., Conclusions: ACME was derived in a large usual care population, relies on routinely available data, and estimates short-term MACE risk. It can support population risk stratification at the health system and payer levels, participant identification for decentralized clinical trials of cardiovascular disease, and risk-stratified observational studies using real-world data., Competing Interests: Research reported in this work was funded through a 10.13039/100006093Patient-Centered Outcomes Research Institute (PCORI) Award (PCS-1409-24099). In the last 36 months, Dr McCoy has received support from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institute of Health (NIH), the National Institute on Aging (NIA) of the NIH, and the National Center for Advancing Translational Sciences (NCATS) for projects unrelated to this work; and serves as a consultant to Emmi (Wolters Kluwer) on developing patient education materials related to diabetes. Dr Ross currently receives research support through Yale University from Johnson and Johnson to develop methods of clinical trial data sharing, from the Medical Device Innovation Consortium as part of the National Evaluation System for Health Technology (NEST), from the Food and Drug Administration for the Yale-Mayo Clinic Center for Excellence in Regulatory Science and Innovation (CERSI) program, from the Agency for Healthcare Research and Quality, from the National Heart, Lung and Blood Institute of the NIH, and from Arnold Ventures; and he is an expert witness at the request of Relator's attorneys, the Greene Law Firm, in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen Inc; all unrelated to this work. Dr Galindo is supported in part by grants from NIDDK and received unrestricted research support (to Emory University) from Novo Nordisk, Eli Lilly, and Dexcom; and consulting fees from Sanofi, Novo Nordisk, Eli Lilly, Pfizer, Boehringer, Bayer, and Weight Watchers; all of which are unrelated to this work. Dr Umpierrez is partly supported by research grants from the Clinical and Translational Science Award program and NIDDK and has received research support (to Emory University) from AstraZeneca, Bayer, Abbott, and Dexcom, all of which are unrelated to this work. Dr Borah has received consulting fees from Boehringer-Ingelheim and Exact Sciences on projects unrelated to this work. Dr Herrin has received funding from the Centers for Medicare and Medicaid Services to develop measures of quality, from the NIH, NIA, National Cancer Institute (NCI), National Heart Lung and Blood Institute (NHLBI), National Institutes of Neurological Disorders and Stroke (NINDS), and PCORI for projects unrelated to this work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Covert cerebrovascular disease (CCD) is frequently reported on neuroimaging and associates with increased dementia and stroke risk. We aimed to determine how incidentally-discovered CCD during clinical neuroimaging in a large population associates with mortality. We screened CT and MRI reports of adults aged ≥50 in the Kaiser Permanente Southern California health system who underwent neuroimaging for a non-stroke clinical indication from 2009-2019. Natural language processing identified incidental covert brain infarcts (CBI) and/or white matter hyperintensities (WMH), grading WMH as mild/moderate/severe. Models adjusted for age, sex, ethnicity, multimorbidity, vascular risks, depression, exercise, and imaging modality. Of n=241,028, the mean age was 64.9 (SD=10.4); mean follow-up 4.46 years; 178,554 (74.1%) had CT; 62,474 (25.9%) had MRI; 11,328 (4.7%) had CBI; and 69,927 (29.0%) had WMH. The mortality rate per 1,000 person-years with CBI was 59.0 (95%CI 57.0-61.1); with WMH=46.5 (45.7-47.2); with neither=17.4 (17.1-17.7). In adjusted models, mortality risk associated with CBI was modified by age, e.g. HR 1.34 [1.21-1.48] at age 56.1 years vs HR 1.22 [1.17-1.28] at age 72 years. Mortality associated with WMH was modified by both age and imaging modality e.g., WMH on MRI at age 56.1 HR = 1.26 [1.18-1.35]; WMH on MRI at age 72 HR 1.15 [1.09-1.21]; WMH on CT at age 56.1 HR 1.41 [1.33-1.50]; WMH on CT at age 72 HR 1.28 [1.24-1.32], vs. patients without CBI or without WMH, respectively. Increasing WMH severity associated with higher mortality, e.g. mild WMH on MRI had adjusted HR=1.13 [1.06-1.20] while severe WMH on CT had HR=1.45 [1.33-1.59]. Incidentally-detected CBI and WMH on population-based clinical neuroimaging can predict higher mortality rates. We need treatments and healthcare planning for individuals with CCD.

Background: Covert cerebrovascular disease (CCD) includes white matter disease (WMD) and covert brain infarction (CBI). Incidentally discovered CCD is associated with an increased risk of subsequent symptomatic stroke. However, it is unknown whether the severity of WMD or the location of CBI predicts risk., Objectives: The objective of this study was to examine the association of incidentally discovered WMD severity and CBI location with a risk of subsequent symptomatic stroke., Method: This retrospective cohort study includes patients ≥50 years old from the Kaiser Permanente Southern California health system who received neuroimaging for a nonstroke indication between 2009 and 2019. Incidental CBI and WMD were identified via natural language processing of the neuroimage report, and WMD severity was classified into grades., Results: 261,960 patients received neuroimaging, 78,555 (30.0%) were identified to have incidental WMD, and 12,857 were identified (4.9%) to have incidental CBI. Increasing WMD severity is associated with the increased incidence rate of future stroke. However, the stroke incidence rate in CT-identified WMD is higher at each level of severity compared to rates in MRI-identified WMD. Patients with mild WMD via CT have a stroke incidence rate of 24.9 per 1,000 person-years, similar to that of patients with severe WMD via MRI. Among incidentally discovered CBI patients with a determined CBI location, 97.9% have subcortical infarcts rather than cortical infarcts. CBI confers a similar risk of future stroke, whether cortical or subcortical, or whether MRI detected or CT detected., Conclusions: Increasing severity of incidental WMD is associated with an increased risk of future symptomatic stroke, dependent on the imaging modality. Subcortical and cortical CBI conferred similar risks., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: Covert brain infarction (CBI) is highly prevalent and linked with stroke risk factors, increased mortality, and morbidity. Evidence to guide management is sparse. We sought to gain information on current practice and attitudes toward CBI and to compare differences in management according to CBI phenotype., Methods: We conducted a web-based, structured, international survey from November 2021 to February 2022 among neurologists and neuroradiologists. The survey captured respondents' baseline characteristics, general approach toward CBI and included two case scenarios designed to evaluate management decisions taken upon incidental detection of an embolic-phenotype and a small-vessel-disease phenotype., Results: Of 627 respondents (38% vascular neurologists, 24% general neurologists, and 26% neuroradiologists), 362 (58%) had a partial, and 305 (49%) a complete response. Most respondents were university hospital senior faculty members experienced in stroke, mostly from Europe and Asia. Only 66 (18%) of respondents had established institutional written protocols to manage CBI. The majority indicated that they were uncertain regarding useful investigations and further management of CBI patients (median 67 on a slider 0-100, 95% CI 35-81). Almost all respondents (97%) indicated that they would assess vascular risk factors. Although most would investigate and treat similarly to ischemic stroke for both phenotypes, including initiating antithrombotic treatment, there was considerable diagnostic and therapeutic heterogeneity. Less than half of respondents (42%) would assess cognitive function or depression., Conclusions: There is a high degree of uncertainty and heterogeneity regarding management of two common types of CBI, even among experienced stroke physicians. Respondents were more proactive regarding the diagnostic and therapeutic management than the minimum recommended by current expert opinions. More data are required to guide management of CBI; meantime, more consistent approaches to identification and consistent application of current knowledge, that also consider cognition and mood, would be promising first steps to improve consistency of care., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Invasive infection remains a dangerous complication of heart transplantation (HT). No objectively defined set of clinical risk factors has been established to reliably predict infection in HT. The aim of this study was to develop a clinical prediction model for use at 1 mo post-HT to predict serious infection by 1 y., Methods: A retrospective cohort study of HT recipients (2000-2018) was performed. The composite endpoint included cytomegalovirus (CMV), herpes simplex or varicella zoster virus infection, blood stream infection, invasive fungal, or nocardial infection occurring 1 mo to 1 y post-HT. A least absolute shrinkage and selection operator regression model was constructed using 10 candidate variables. A concordance statistic, calibration curve, and mean calibration error were calculated. A scoring system was derived for ease of clinical application., Results: Three hundred seventy-five patients were analyzed; 93 patients experienced an outcome event. All variables remained in the final model: aged 55 y or above, history of diabetes, need for renal replacement therapy in first month, CMV risk derived from donor and recipient serology, use of induction and/or early lymphodepleting therapy in the first month, use of trimethoprim-sulfamethoxazole prophylaxis at 1 mo, lymphocyte count under 0.75 × 10 3 cells/µL at 1 mo, and inpatient status at 1 mo. Good discrimination (C-index 0.80) and calibration (mean absolute calibration error 3.6%) were demonstrated., Conclusion: This model synthesizes multiple highly relevant clinical parameters, available at 1 mo post-HT, into a unified, objective, and clinically useful prediction tool for occurrence of serious infection by 1 y post-HT., Competing Interests: D.R.S. and J.K.C. have grants to Tufts Medical Center from Merck and Kamada. D.R.S. is a consultant to Merck, Kamada, and Moderna. J.K.C. is also a consultant to Moderna. The other authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Introduction: Integrated care is effective in reducing all-cause mortality in patients with atrial fibrillation (AF) in primary care, though time and resource intensive. The aim of the current study was to assess whether integrated care should be directed at all AF patients equally., Methods: The ALL-IN trial (n = 1,240 patients, median age 77 years) was a cluster-randomized trial in which primary care practices were randomized to provide integrated care or usual care to AF patients aged 65 years and older. Integrated care comprised of (i) anticoagulation monitoring, (ii) quarterly checkups and (iii) easy-access consultation with cardiologists. For the current analysis, cox proportional hazard analysis with all clinical variables from the CHA2DS2-VASc score was used to predict all-cause mortality in the ALL-IN trial. Subsequently, the hazard ratio and absolute risk reduction were plotted as a function of this predicted mortality risk to explore treatment heterogeneity., Results: Under usual care, after a median of 2 years follow-up the absolute risk of all-cause mortality in the highest-risk quarter was 31.0%, compared to 4.6% in the lowest-risk quarter. On the relative scale, there was no evidence of treatment heterogeneity (p for interaction = 0.90). However, there was substantial treatment heterogeneity on the absolute scale: risk reduction in the lowest risk- quarter of risk 3.3% (95% CI -0.4% - 7.0) compared to 12.0% (95% CI 2.7% - 22.0) in the highest risk quarter., Conclusion: While the relative degree of benefit from integrated AF care is similar in all patients, patients with a high all-cause mortality risk have a greater benefit on an absolute scale and should therefore be prioritized when implementing integrated care., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: G.J. Geersing, F.H. Rutten, and M.E.W. Hemels report unrestricted institutional grants for performing research in the field of atrial fibrillation from Boehringer-Ingelheim, Bayer Healthcare, BMS Pfizer and Daiichi Sankyo. I.C. van Gelder reports consultancy fees from Boston, BMS and Bayer to the institution, unrestricted research grants from the Netherlands Cardiovascular Research Initiative, unrestricted research grant from the European Union’s Horizon 2020 research and innovation programme under grant agreement: EHRA-PATHS (945260). M. Rienstra reports Consultancy fees from Bayer, Microport, InCarda Therapeutics to the institution, an unrestricted research grant from ZonMW and the Dutch Heart Foundation; DECISION project 848090001, unrestricted research grants from the Netherlands Cardiovascular Research Initiative: an initiative with support of the Dutch Heart Foundation; RACE V (CVON 2014–9), RED-CVD (CVON2017-11), an unrestricted research grant from Top Sector Life Sciences & Health to the Dutch Heart Foundation (PPP Allowance; CVON-AI (2018B017)), and an unrestricted research grant from the European Union’s Horizon 2020 research and innovation programme under grant agreement; EHRA-PATHS (945260). S. van Doorn reports an unrestricted institutional grant for performing research in the field of stroke diagnosis from Stoffels-Hornstra. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Trinks-Roerdink et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Multiple sclerosis (MS) is heterogeneous with respect to outcomes, and evaluating possible heterogeneity of treatment effect (HTE) is of high interest. HTE is non-random variation in the magnitude of a treatment effect on a clinical outcome across levels of a covariate (i.e. a patient attribute or set of attributes). Multiple statistical techniques can evaluate HTE. The simplest but most bias-prone is conventional one variable-at-a-time subgroup analysis. Recently, multivariable predictive approaches have been promoted to provide more patient-centered results, by accounting for multiple relevant attributes simultaneously. We review approaches used to estimate HTE in clinical trials of MS.