Figure 1: Cumulative incidence of lymphoma mortality (blue), cardiovascular mortality (red) and all-cause mortality (black). Dashed line represents patients with heart failure at the time of lymphoma diagnosis and solid lines patients without heart failure Background: Anthracycline-containing regimens are recommended as first-line treatment for Hodgkin lymphoma (HL); however, the management and outcomes of patients with cardiomyopathy or heart failure (HF) at the time of lymphoma diagnosis is not known. Methods: US Surveillance, Epidemiology, and End Results (SEER)-Medicare data from 1999–2016 were used to identify newly diagnosed HL in patients 66 years and older with one year of Medicare A and B prior to lymphoma diagnosis. Prevalent HF and comorbidities in the year prior to lymphoma diagnosis were identified using International Classification of Diseases codes. Cancer treatment, including doxorubicin and cardioprotective medications (i.e., liposomal doxorubicin and dexrazoxane) were assessed using Healthcare Common Procedure Coding Systems codes. Cause of death was defined using the SEER Cause of Death Recodes. The association between prevalent HF and cancer treatment was estimated using logistic regression with adjustment for comorbidities, social determinants of health and hospital level variables. The association between prevalent HF and cause specific mortality was evaluated using competing risk Cox proportional hazards models with sequential adjustment for comorbidities and cancer treatment. Results: Among 3,348 individuals with newly diagnosed HL, prevalent HF was present in 13.1%. Patients with prevalent HF were less likely to be treated with an anthracycline in the first year after diagnosis (OR 0.42, 95% CI 0.29, 0.60). Among patients with HF who received an anthracycline, dexrazoxane or liposomal doxorubicin was used in only 4.5%. For those with prevalent HF, 1-year lymphoma mortality was 37.4% (95% CI 35.5, 39.5%) [Fig]. In multivariable models adjusting for clinical covariates, prevalent HF was associated with higher lymphoma mortality (HR 1.21, 95% CI 1.03, 1.41); however, the effect of prevalent HF on lymphoma mortality was no longer significant when adding cancer treatment variables to the model (HR 1.05, 95% CI 0.71, 1.56) [Fig]. Prevalent HF was also associated with cardiovascular mortality in fully adjusted models (HR 1.77, 95% CI 1.34, 2.32). Conclusion: HF is common in older patients with HL and is associated with less anthracycline use and higher lymphoma mortality. Dexrazoxane and liposomal doxorubicin are used infrequently. Future randomized trials are needed to determine strategies to decrease lymphoma and cardiac mortality in this high-risk population.
Incidentally discovered silent brain infarcts (id-SBIs) are an understudied condition with probable clinical significance, but it is not known how patients respond to or prioritize this condition. We sought to assess reporting of id-SBIs and how patients approach their diagnosis.Patients with id-SBIs were identified from sequential scans between 12/2015-5/2016, were referred by treating clinicians, or self-referred for the study. This study used qualitative semi-structured interviews. Purposeful sampling was used to achieve diversity in acuity, setting, and recruitment strategy. Interviews were audio-recorded and transcribed. A constant comparative method was used to develop a coding schema, find consensus, and iteratively explore emergent themes until thematic saturation was achieved.Only 10 of 102 patients prospectively identified by neuroimaging were informed of the imaging findings. Twelve participants in total were interviewed. Among the study participants, the primary themes were cognitive, emotional, and behavioral responses to diagnostic, prognostic, and therapeutic uncertainty regarding id-SBIs. Clinicians described id-SBIs to participants as an ambiguous condition. Participants feared potential consequences of id-SBIs, including symptomatic stroke, dementia, and disability. Participants attempted to reduce uncertainty with strategies including equating id-SBIs with symptomatic stroke, self-education about stroke, and seeking second opinions.Participants considered id-SBIs to be a serious medical condition. Ambiguous counseling by clinicians on id-SBIs provoked or failed to attenuate fear, leading to participants adopting strategies aimed at reducing uncertainty.
Major adverse cardiovascular events (MACE) are a major cause of morbidity and mortality among adults with type 2 diabetes. Currently available risk prediction models estimate long-term risk (typically 10-year) and require clinical data not routinely available in real-world data sources, which limit their use on population level. Using de-identified claims data from OptumLabs® Data Warehouse for enrollees in private and Medicare Advantage health plans linked to 100% sample of Medicare fee-for-service beneficiaries between 2014 and 2021, we derived ACME to estimate annualized risk of non-fatal myocardial infarction, non-fatal stroke, or all-cause mortality in patients with type 2 diabetes aged ≥21 years (N=6,623,526). The Cox proportional hazards model, combined with an estimate of the baseline hazard using the Nelson-Aalen estimator to allow conditional survival predictions, included 28 covariates available in claims (age, sex, cardiovascular comorbidities, and cardiovascular medications). The study population had mean age 68.1 (SD, 10.6) years, 49.8% were women, and 73.0% were non-Hispanic White. ACME’s concordance index was 0.74 (se = 0.0002) and it performed comparably in all racial and ethnic groups. Strongest predictors of MACE were acute myocardial infarction and stroke within the past 3 months, heart failure hospitalization within the past year, and end-stage kidney disease. Overall, 4.2% of patients were predicted to have low (<1%) annualized MACE risk, 62.8% were predicted to have moderate (≥1 to <5%) annualized risk, and 33.0% were predicted to have high (≥5%) annualized risk. Other thresholds can be chosen for individualized applications. ACME can support population risk stratification and health management efforts at the health system and payer levels, participant identification for decentralized pragmatic clinical trials of cardiovascular disease and its prevention, and risk-stratified observational studies using real-world data. Disclosure R.G.Mccoy: Consultant; Emmi. G.Umpierrez: Research Support; Abbott, Dexcom, Inc., Baxter. R.J.Galindo: Consultant; Novo Nordisk, Eli Lilly and Company, Sanofi, Pfizer Inc., Bayer Inc., WW (Weight Watchers), Research Support; Novo Nordisk, Eli Lilly and Company, Dexcom, Inc. J.Brito: None. M.Mickelson: None. E.Polley: None. K.Swarna: None. Y.Deng: None. J.Herrin: Consultant; Johnson & Johnson Medical Devices Companies. J.Ross: Research Support; Johnson & Johnson. D.M.Kent: Research Support; W.L. Gore. B.Borah: Consultant; Boehringer Ingelheim Inc., Exact Sciences. W.Crown: Consultant; Janssen Scientific Affairs, LLC, UnitedHealth Group, Viatris Inc. V.M.Montori: None. Funding Patient-Centered Outcomes Research Institute (DB-2020C2-20306)
If clinical trials were sporting contests, then it would be fair to say that low-dose aspirin plus extended-release dipyridamole (Aggrenox) was the clear favorite against clopidogrel going into the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial (ClinicalTrials.gov number, NCT00153062). The trial, reported on in this issue of the Journal by Sacco et al.,1 tested these two antiplatelet agents for secondary stroke prevention in their first head-to-head contest.In two previous large randomized clinical trials enrolling patients after stroke (the European Stroke Prevention Study 2 [ESPS2]2 and the European/Australasian Stroke Prevention in Reversible Ischemia Trial3 [ESPRIT, NCT00161070]), low-dose aspirin . . .
Although often conflated, determining the best treatment for an individual (the task of a doctor) is fundamentally different from determining the average effect of treatment in a population (the purpose of a trial). In this paper, we review concepts of heterogeneity of treatment effects (HTE) essential in providing the evidence base for precision medicine and patient-centred care, and explore some inherent limitations of using group data (e.g. from a randomized trial) to guide treatment decisions for individuals. We distinguish between person-level HTE (i.e. that individuals experience different effects from a treatment) and group-level HTE (i.e. that subgroups have different average treatment effects), and discuss the reference class problem, engendered by the large number of potentially informative subgroupings of a study population (each of which may lead to applying a different estimated effect to the same patient), and the scale dependence of group-level HTE. We also review the limitations of conventional 'one-variable-at-a-time' subgroup analyses and discuss the potential benefits of using more comprehensive subgrouping schemes that incorporate information on multiple variables, such as those based on predicted outcome risk. Understanding the conceptual underpinnings of HTE is critical for understanding how studies can be designed, analysed, and interpreted to better inform individualized clinical decisions.
Importance Anthracycline-containing regimens are highly effective for diffuse large B-cell lymphoma (DLBCL); however, patients with preexisting heart failure (HF) may be less likely to receive anthracyclines and may be at higher risk of lymphoma mortality. Objective To assess the prevalence of preexisting HF in older patients with DLBCL and its association with treatment patterns and outcomes. Design, Setting, and Participants This longitudinal cohort study used data from the Surveillance, Epidemiology, and End Results (SEER)–Medicare registry from 1999 to 2016. The SEER registry is a system of population-based cancer registries, capturing more than 25% of the US population. Linkage to Medicare offers additional information from billing claims. This study included individuals 65 years and older with newly diagnosed DLBCL from 2000 to 2015 with Medicare Part A or B continuously in the year prior to lymphoma diagnosis. Data were analyzed from September 2020 to December 2022. Exposures Preexisting HF in the year prior to DLBCL diagnosis ascertained from billing codes required one of the following: (1) 1 primary inpatient discharge diagnosis, (2) 2 outpatient diagnoses, (3) 3 secondary inpatient discharge diagnoses, (4) 3 emergency department diagnoses, or (5) 2 secondary inpatient discharge diagnoses plus 1 outpatient diagnosis. Main Outcomes and Measures The primary outcome was anthracycline-based treatment. The secondary outcomes were (1) cardioprotective medications and (2) cause-specific mortality. The associations between preexisting HF and cancer treatment were estimated using multivariable logistic regression. The associations between preexisting HF and cause-specific mortality were evaluated using cause-specific Cox proportional hazards models with adjustment for comorbidities and cancer treatment. Results Of 30 728 included patients with DLBCL, 15 474 (50.4%) were female, and the mean (SD) age was 77.8 (7.2) years. Preexisting HF at lymphoma diagnosis was present in 4266 patients (13.9%). Patients with preexisting HF were less likely to be treated with an anthracycline (odds ratio, 0.55; 95% CI, 0.49-0.61). Among patients with preexisting HF who received an anthracycline, dexrazoxane or liposomal doxorubicin were used in 78 of 1119 patients (7.0%). One-year lymphoma mortality was 41.8% (95% CI, 40.5-43.2) with preexisting HF and 29.6% (95% CI, 29.0%-30.1%) without preexisting HF. Preexisting HF was associated with higher lymphoma mortality in models adjusting for baseline and time-varying treatment factors (hazard ratio, 1.24; 95% CI, 1.18-1.31). Conclusions and Relevance In this study, preexisting HF in patients with newly diagnosed DLBCL was common and was associated with lower use of anthracyclines and lower use of any chemotherapy. Trials are needed for this high-risk population.
