Five-year Risk Research Articles

Assessing one-year risk of heart failure following first time myocardial infarction and subsequent five-year mortality risk: a nationwide study of 34,401 patients

Abstract Introduction A comprehensive understanding of the post-myocardial infarction (MI) trajectory leading to heart failure (HF) and its profound impact on long-term mortality is imperative for effective secondary prevention and risk assessment. Methods We conducted a registry-based nationwide cohort study of all Danish patients with a first MI during 2014 to 2020. Excluding patients with prior HF, individuals were followed for one year post-MI, assessing HF incidence through hospital admissions and visits to elective HF ambulatory clinics. Among those who survived one year, long-term mortality 1-6 years post-index MI was assessed using landmark analysis and Cox proportional hazards models adjusting for age, gender and comorbidities and hazard. Patients were categorized into three groups: not HF, referred for elective HF outpatient follow-up, and acute admission for HF. Results Among 34,301 individuals with a first MI and surviving the first year (median age 67.5, and 66.9 % male), 3.3 % were admitted acute for HF while 11.2 % had an elective HF outpatient follow-up within one year of the MI event (see Figure 1a). We observed a significant association between acute HF admissions post-MI and increased five-year mortality risk (hazard ratio [HR] 1.63, 95% confidence interval [CI] 1.40-1.90, p-value <0.001, see Figure 1b) (absolute 5-year risk: 18.4 %). In contrast, the five-year mortality risk for patients with elective outpatient HF follow-up was comparable to that of individuals without HF (HR 1.06 [0.94-1.19], p-value 0.34) (absolute 5-year risk: 9.6 vs 8.5 %). Conclusion Our findings suggest that acute admission for HF after a first time MI occur in 3.3 % of the patients with a subsequent significantly increased mortality risk compared to patients that do not develop clinical HF. Admission for HF in patients with a first time MI should be considered as a relatively rare but fatal complication.

Temporal trends in clinical outcomes in heart failure patients with and without atrial fibrillation: a nationwide study from 1997-2018

Abstract Background Given the many advances in treating heart failure (HF) and atrial fibrillation (AF) separately over the past decades, it remains unclear how the prognosis of patients diagnosed with both conditions has changed over time. Purpose We aimed to investigate the temporal trends in all-cause mortality, HF hospitalisation, and stroke from 1997 to 2018 in patients diagnosed with both HF and AF. Methods From Danish nationwide registries, we identified 152,059 patients with a first-time HF-diagnosis from 1997 to 2018. Patients were categorised into groups based on their AF status: prevalent AF (n=34,734), new-onset AF (n=12,691), and absence of AF (n=104,634). Patients were further subdivided into four year groups (1997-2001, 2002-2006, 2007-2012, 2013-2018), based on the year of HF onset. The primary outcome of interest was the absolute five-year risk of all-cause mortality, and key secondary outcomes were HF hospitalisation and stroke, investigated using the Aalen-Johansen estimator, accounting for competing risk of death. Results Between 1997 and 2018 the proportion of patients with new-onset HF and prevalent AF increased from 17.0% (n = 6,372) to 27.7% (n = 11,569), while those with concurrent new-onset AF increased from 7.7% (n = 2,884) to 8.1% (n = 3401). Contrary, the proportion of patients decreased among those with no AF from 75.3% (n = 28,235) to 64.2% (n = 26,850). The five-year risk of all-cause mortality decreased from 69.1% (95% CI): 67.9%-70.2%) to 51.3% (49.9%-52.7%), 62.3% (60.5%-64.4%) to 43.0% (40.5%-45.5%), and 61.9% (61.3%-62.4%) to 36.7% (35.9%-37.6%) for the prevalent AF, new-onset AF, and no AF group, respectively (Figure 1). The five-year risk of HF hospitalisation went from 33.3% (32.1%-34.4%) to 30.3% (29.2%-31.4%) in the prevalent AF group, from 25.8% (24.2%-27.4%) to 29.6% (27.7%-31.5%) in the new-onset AF group, and from 28.4% (27.8%-28.9%) to 28.0% (27.2%-28.6%) in the no AF group. The five-year risk of stroke decreased from 8.5% (7.8%-9.1%) to 5.0% (4.4%-5.5%) in the prevalent AF group, 8.2% (7.2%-9.2%) to 4.6% (3.7%-5.5%) in the new-onset AF group, and 6.3% (6.1%-6.6%) to 4.9% (4.6%-5.3%) in the no AF group (Figure 2). Simultaneously, the proportion of patients prescribed anticoagulant therapy within 90 days after HF onset increased from 42.7% to 93.1% in patients with prevalent AF and 41.9% to 92.5% in patients with new-onset AF. Conclusion From 1997 to 2018, we observed an increase in patients with HF and coexisting AF. The five-year risk of mortality and stroke decreased across all patient groups regardless of AF-status. Additionally, prescriptions of anticoagulation therapy increased, and stroke risk in patients with HF and AF was reduced to similar levels as patients with HF without AF at the end of the study period.Figure 1 - Mortality in HF patientsFigure 2 - Stroke risk in HF patients

Temporal trends in treatment patterns, morbidity, and mortality in patients with new-onset heart failure compared to heart failure survivors: a nationwide 23-year perspective

Abstract Background New therapy options have improved the prognosis of heart failure (HF) over recent decades. However, temporal trends in the prognosis and treatment disparities between patients with new-onset HF and HF survivors remain unexplored. Purpose To investigate temporal trends in HF treatment patterns, worsening HF and all-cause mortality, in new-onset HF patients compared to HF survivors. Methods We defined two separate cohorts of patients with HF, using the Danish nationwide registers. One cohort comprised all patients with new-onset HF each year from 1996 to 2018, included at the date of HF diagnosis (new-onset HF patients). The second cohort comprised patients with HF who have survived at least three years since being diagnosed with HF, included on January 1st of each year from 1996 to 2018 (HF survivors). Patients were allowed to contribute in both cohorts. The proportion of patients in guideline recommended therapy and the absolute five-year risk of worsening HF and all-cause mortality were assessed in the two cohorts separately, accounting for competing risks where relevant. Results From 1996 to 2018, the proportion of HF survivors tripled, while the number of yearly new-onset HF patients remained constant (figure 1). The proportion of new-onset HF patients who redeemed a prescription of BB increased from 17.1% in 1996 to 78.2% in 2018, while it increased from 15.9% to 69.4% in HF survivors during the same period. The proportion of patients in ACEi/ARB therapy increased from 49.1% to 81.5% in the new-onset HF patients, while it increased from 37.8% to 69.0% in HF survivors. The proportion of patients in MRA therapy increased from 14.4 to 33.0% in those with new-onset HF, and from 19.1% to 24.8% in HF survivors. The absolute risk (AR)[±95CI] for all-cause mortality decreased from 68.4% [67.9-68.9] in the first year group (1996-2000) to 45.7% [45.0-46.3] in the latest year group (2013-2018) for new-onset HF patients, while it decreased from 58.4% [58.2-58.9] to 39.7% [39.4-40.0] for the HF survivors. Additionally, the AR for worsening HF went from 27.4% [26.9-27.8] in the first year group to 27.8% [27.3-28.2] in the latest year group for the new-onset HF patients, whereas it for the HF survivors decreased from 19.6% [19.3-20.0] to 16.7% [16.4-19.9]. Conclusions Over a 23-year period, the annual number of patients with incident HF has remained constant while the number of HF survivors has increased by 304%. Although HF survivors show a lower prescription redemption prevalence for essential HF medications compared to incident HF patients, they exhibit significantly lower risk of all-cause mortality and worsening HF.Figure 1:OverviewFigure 2:Prescription redememption rates

Dementia in patients with early cardiovascular complications following ischaemic stroke: A neglected complication of the stroke-heart syndrome

Abstract Background Early cardiovascular complications may occur in 20-30% of patients following following ischaemic stroke (stroke-heart-syndrome, SHS). The risk of dementia in patients with SHS remains unexplored. We aimed to quantify the risk of incident dementia in patients with SHS. Methods We conducted a retrospective analysis using a global federated health care network (TriNetX). We included patients who were discharged alive post-ischaemic stroke from 2000 to 2022. These individuals were classified into two cohorts based on the incidence of cardiovascular complications within 30 days post-stroke (acute heart failure [HF], acute myocardial infarction [AMI], ventricular fibrillation or flutter [VFF], or Takotsubo disease [TTS]), ie. those with SHS (Group 1) and those with stroke-only (without SHS; Group 2). The primary outcome was the five-year risk of dementia (vascular dementia [F01], dementia in other disease [F02], unspecified dementia [F03], Alzheimer’s disease [G30]). Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox regression analysis after 1:1 propensity score matching (PSM). Results We identified 70,113 patients with SHS (age 67.3±14.0; 42.2% females) and 1,092,540 patients with stroke-only (age 65.2±14.9, 48.1% females). Prior to PSM, patients with SHS were generally older and had a higher prevalence of cardiovascular treatments compared to those without SHS. Following PSM, 70,111 well-balanced patients were considered in each group, however, patients with SHS had a higher risk of dementia compared to patients with stroke-only (HR 1.25, 95%CI 1.20-1.30). Among the SHS complications, the highest dementia risks were associated with acute HF (HR 1.28, 95%CI 1.21-1.36) and AMI (HR 1.24, 95%CI 1.17-1.30), with no significant associations were found for TTS, and VFF. The increased risk of dementia in patients with SHS compared to patients with stroke-only was independent of oral anticoagulant (OAC) use, sex, and age (> or < 75 years) [Figure 1]. Conclusion Stroke-heart syndrome is associated with increased risk of dementia. Innovative strategies to identify and to prevent SHS complications would improve long-term prognosis in patients with recent stroke.

Patterns of intrinsic capacity trajectory and onset of activities of daily living disability among community-dwelling older adults.

Global population ageing has brought about new challenges for elderly care. Exploring intrinsic capacity (IC) over time, which is designed as a composite measure of an individual's physical and mental capabilities, is essential for promoting healthy ageing and preventing dependency, such as that emerging from disability in activities of daily living (ADL). We aimed to identify and examine the differences between classes of IC trajectory and onset of ADL disability. We conducted an observational study using data from three waves (2011-15) of the China Health and Retirement Longitudinal Study, comprising 2609 participants with 6034 observations. IC was measured by five domains, including locomotion, cognition, psychological, sensory capacities, and vitality. We used joint latent class modelling to identify distinct classes with similar patterns of IC trajectory and onset of ADL disability, as well as to explore the variation in IC trajectory and predict five-year risks of ADL disability considering the heterogeneity in the elderly population. The average baseline IC score was 7.15 (range: 0-15). We observed that IC scores slowly decreased with age, with 17.25% of participants developing ADL disability. We identified three classes of IC, which could be described as moderate health (class 1: n = 1634, 62.63%), at-risk (class 2: n = 716, 27.44%; had the highest risk of ADL disability), and optimal health (class 3: n = 259, 9.93%; had the lowest baseline risk of ADL disability). The probability of being in the moderate health class was decreased the most by emotional problems (odds ratio (OR) = 0.219; P < 0.001). Having a self-rated poor standard of living substantially reduced the chances of moderate (OR = 0.308; P = 0.001) and optimal health (OR = 0.110; P < 0.001). Observing IC trajectories and the onset of ADL disability can stratify the elderly into heterogeneous groups, as well as provide data for implementing person-centred care plans to reverse the trend and delay the adverse outcomes in clinical practice.

The Possible Role of PM2.5 Chronic Exposure on 5-Year Survival in Patients with Left Ventricular Dysfunction Following Coronary Artery Bypass Grafting.

The survival benefit of surgical revascularization in multivessel coronary artery disease is well understood, though it can be modified by left ventricular dysfunction. Chronic exposure to air pollutants has gained more attention recently as a possible non-traditional morbidity and mortality cardiovascular risk factor. This study identified possible 5-year mortality risk factors related to postoperative left ventricular performance, including air pollutants. There were 283 patients (244 (86%) males) with a median age of 65 (60-70) years enrolled in the retrospective analysis. All patients were referred for off-pump coronary artery revascularization due to chronic coronary syndrome that presented as a multivessel coronary artery disease. They were divided into three groups depending on the postoperative course of left ventricular fraction (LVEF 50% or more (169 patients), LVEF between 41 and 49% (61 patients), and LVEF 40% or less (53 patients)). The overall survival rate was 84% (237 patients) in a median follow-up time of 5.3 (4.8-6.1) years. The median (Q1-Q3) chronic air pollution exposures for the analyzed group were 19.3 (16.9-22.4) μg/m3 for fine particles such as PM2.5, 25.8 (22.5-29.4) μg/m3 for coarse particles such as PM10, and 12.2 (9.7-14.9) μg/m3 for nitric dioxide (NO2). The mortality in the first group (LVEF at least 50%) was 23 (13.6%), in the second group (LVEF 41-49%) was 9 (15%), and in the third group (LVEF 40% or less) was 14 (26%). The multivariable regression analysis for the five-year mortality risk in the first group revealed the predictive value of dyslipidemia (HR: 3.254, 95% CI: 1.008-10.511, p = 0.049). The multivariable regression analysis for five-year mortality risk in the second group revealed the predictive value of dyslipidemia (HR: 3.391, 95% CI: 1.001-11.874, p = 0.050) and PM2.5 (HR: 1.327, 95% CI: 1.085-1.625, p = 0.006). In the third group (severely decreased LVEF), chronic PM2.5 exposure was found to be significant (HR: 1.518, 95% CI: 1.50-2.195, p = 0.026) for 5-year mortality prediction. Traditional risk factors, such as dyslipidemia, are pivotal in the 5-year mortality risk following surgical revascularization. Chronic exposure to ambient air pollutants such as PM2.5 may be an additional risk factor in patients with left ventricular dysfunction.

The long-term impact of increased red blood cell distribution width detected during hospitalization for heart failure.

Aim: We determined the long-term role of increased RDW (red blood cell distribution width) detected during cardiac decompensation.Methods: We followed 3697 patients [mean age 71.4years (±SD 10.1), 59.1% males] hospitalized for acute heart failure (HF) and assessed the five-year all-cause mortality risk associated with tertiles of RDW.Results: Patients with RDW in the top tertile showed roughly twofold higher 5-year mortality risk than those in the bottom tertile. The association remained significant not only after adjustments for potential covariates but even if we excluded patients who deceased during the first year of follow-up [HRR 1.76 (95% CIs:1.42-2.18), p<0.0001].Conclusion: The high degree of anisocytosis represents an independent predictor of poor prognosis in HF patients, even long-term after an acute manifestation.

Temporal trends in infection-related hospitalizations among patients with heart failure: A Danish nationwide study from 1997 to 2017

BackgroundDespite improved survival, hospitalization is still common among patients with heart failure (HF). ObjectiveThis study aimed to examine temporal trends in infection-related hospitalization among HF patients and compare it to temporal trends in the risk of HF hospitalization and death. MethodsUsing Danish nationwide registers, we included all patients aged 18-100 years, with HF diagnosed between 1st January 1997 and 31st December 2017, resulting in a total population of 147.737 patients. The outcomes of interest were primarily infection-related hospitalization and HF hospitalization and secondarily all-cause mortality. The Aalen Johansen's estimator was used to estimate five-year absolute risks for the primary outcomes. Additionally, cox analysis was used for adjusted analyses. ResultsThe population had a median age of 74 [64, 82] years and 57.6 % were males. Patients with HF had a higher risk of infection over time 16.4 % (95% CI 16.0–16.8) in 1997–2001 vs. 24.5% (95% CI 24.0–24.9) in 2012–2017. In contrast, they had a lower risk of HF hospitalization 26.5% (95% CI 26.1–27.0) in 1997–2001 vs. 23.2% (95% CI 22.8–23.7) in 2012–2017. The risk of infection stratified by infection type showed similar trends for all infection types and marked the risk of pneumonia infection as the most significant in all subintervals. ConclusionIn the period from 1997 to 2017, we observed patients with HF had an increased risk of infection-related hospitalization, driven by pneumonia infections. In contrast, the risk of HF hospitalization decreased over time.

Temporal trends in mortality, heart failure hospitalisation, and stroke in heart failure patients with and without atrial fibrillation: a nationwide study from 1997-2018 on 152,059 patients.

We aimed to investigate temporal trends in all-cause mortality, heart failure (HF) hospitalisation, and stroke from 1997 to 2018 in patients diagnosed with both HF and atrial fibrillation (AF). From Danish nationwide registers, we identified 152059 patients with new-onset HF between 1997 and 2018. Patients were grouped according to year of new-onset HF and AF-status: Prevalent AF (n=34734), New-onset AF (n=12691), and No AF (n=104634). Median age decreased from 76 to 73 years between 1997 and 2018. The proportion of patients with prevalent or new-onset AF increased from 24.7% (n=9256) to 35.8% (n=14970). Five-year risk of all-cause mortality went from 69.1% (CI: 67.9%-70.2%) to 51.3% (CI: 49.9%-52.7%), 62.3% (CI: 60.5%-64.4%) to 43.0% (CI: 40.5%-45.5%), and 61.9% (CI: 61.3%-62.4%) to 36.7% (CI: 35.9%-37.6%) for the Prevalent AF, New-onset AF and No AF-group, respectively. Minimal changes were observed in the risk of HF-hospitalisation. Five-year stroke risk decreased from 8.5% (CI: 7.8%-9.1%) to 5.0% (CI: 4.4%-5.5%) for the prevalent AF group, 8.2% (CI: 7.2%-9.2%) to 4.6% (CI: 3.7%-5.5%) for new-onset AF, and 6.3% (CI: 6.1%-6.6%) to 4.9% (CI: 4.6%-5.3%) for the No AF group. Simultaneously, anticoagulant therapy increased for patients with prevalent (from 42.7% to 93.1%) and new-onset AF (from 41.9% to 92.5%). From 1997 to 2018, we observed an increase in patients with HF and co-existing AF. Mortality decreased for all patients, regardless of AF-status. Anticoagulation therapy increased, and stroke risk for patients with AF was reduced to a similar level as patients without AF in 2013-2018.

Additive interaction of disability with chronic conditions on mortality risk in middle-aged and older adults in Spain

BackgroundDisability and chronic diseases are prevalent conditions associated with mortality, but little information is available on their potential synergistic effects. ObjectiveThis study aimed to describe additive interactions between disability and chronic diseases on mortality risk in middle-aged and older adults. MethodsA representative cohort of 22,800 community-dwelling Spanish people aged 50 years or older were interviewed for disability with the Global Activity Limitation Indicator and specific chronic diseases in the 2011–12 and 2014 National Health Surveys and subsequently followed up for mortality. Five-year all-cause mortality risks were standardized in each disability-by-comorbidity category through inverse probability weighting. We computed interaction contrasts as the departure of the standardized risk difference for people with both conditions from the sum of the standardized risk differences for those with any single condition. ResultsThe baseline prevalence of disability was 35.1 % (95 % confidence interval [CI] 34.4 %, 35.9 %). There was compelling evidence of synergistic effects of disability with chronic liver disease, heart diseases other than myocardial infarction, cancer, and cerebrovascular disease, with large positive interaction contrasts (95 % CIs) of 106.7 (−16.4, 229.9), 45.7 (6.9, 84.5), 45.1 (−15.0, 105.2), and 42.9 (−41.0, 126.9) excess deaths per 1000 persons. Less clear synergistic responses were observed for other comorbidities. We found some evidence of antagonism for osteoporosis, with a negative interaction contrast of −18.0 (95 % CI −82.2, 46.2) deaths per 1000 persons. ConclusionGiven the high mortality risk in people with disability, the study of its synergistic effects with target comorbidities can provide relevant information regarding preventive measures.

The Use of a Tailored Decision Aid to Improve Understanding of Lung Cancer Screening in People With HIV

People with HIV are at increased risk for lung cancer and multimorbidity, complicating the balance of risks and benefits of lung cancer screening. We previously adapted Decision Precision (screenlc.com) to guide shared decision-making for lung cancer screening in people with HIV. Does an HIV-adapted and personally tailored decision aid improve shared decision-making regarding lung cancer screening in people with HIV as measured by knowledge, decisional conflict, and acceptability? This was a single-arm pilot trial of the decision aid in 40 participants with HIV eligible for lung cancer screening. The decision aid included personalized screening recommendations and HIV-specific, five-year risk estimates of lung cancer and all-cause mortality. Participants reviewed the decision aid at shared decision-making visits and completed pre- and post-visit surveys with measures of knowledge about lung cancer screening, acceptability, and decisional conflict. The 40 enrolled participants were a median 62 years old and 60% were currently smoking with median five-year risks of lung cancer and all-cause mortality of 2.0% (IQR 1.4-3.3%) and 4.1% (IQR 3.3-7.9%). Personalized recommendations included "Encourage Screening" for 53% of participants and "Preference Sensitive" recommendations for the remainder. Participants showed improvement in two validated knowledge measures with relative improvement of 60% (p<0.001) on the LCS-12 and 27% (p<0.001) on the LKS-7, with significant improvement on questions regarding false-positive and false-negative findings, incidental findings, lung cancer-specific mortality benefit, and the possible harms of screening. Participants reported low scores on the decisional conflict scale (median score 0, IQR 0-5) and high acceptability. Ninety percent ultimately underwent screening within one month of the visit. This HIV-adapted and personally tailored decision aid improved participants' knowledge of risks, benefits, and characteristics of screening with low decisional conflict and high acceptability. This decision aid can enable high-quality shared decision-making in this high-risk population.

Sex differences in hemoglobin levels and five-year refracture risk in patients with osteoporotic fractures: a retrospective cohort analysis.

Hematopoiesis and bone health have a reciprocal influence on each other. Nevertheless, there is a scarcity of in-depth research on the association between Hb levels and the occurrence of fractures. The present research aimed to investigate the correlation between Hb levels and the rate of refracture within 5years among individuals with OPFs. A retrospective cohort analysis was undertaken between 2017 and 2022. The study included 1906 individuals who were inhabitants of Kunshan and were over 60years old. These individuals had experienced an OPF between January 1, 2017, and July 27, 2022, resulting in their hospitalization. Cox proportional hazard regression models were used to evaluate the risk of refracture within 5years based on the Hb levels acquired during the admission examination, with consideration for sex differences. A nonlinear relationship was identified using smoothed curve fitting and threshold analysis. Kaplan-Meier curves were used to compare refracture rates between patients with low and high Hb levels. Elderly female patients with OPFs and lower Hb levels exhibited a significantly higher risk of a 5-year refracture. Conversely, no significant associations were observed between the two variables in male patients. A nonlinear correlation was found between Hb levels and the probability of refracture in females, with a turning point identified at 10.7g/dL of Hb levels. A strong negative association was observed with the five-year refracture rate when Hb levels fell below 10.7g/dL (hazard ratio (HR) = 0.63; 95% confidence interval (CI) 0.48 to 0.83; P-value = 0.0008). This finding suggests that for every 1g/dL increase in Hb below 10.7g/dL, the risk of refracture reduced by 37%. However, no statistically significant association was observed when Hb levels were above 10.7g/dL. The findings demonstrated a significant negative correlation between Hb levels and the likelihood of refracture in elderly female patients with OPFs and suggested that elderly females with recent OPFs and Hb levels below 10.7g/dL may be at a higher risk of refracture. Additionally, the Hb levels can serve as an indicator of bone fragility in elderly female patients with OPFs. These findings highlight the importance of monitoring Hb levels as apart of comprehensive management strategies to both assess skeletal health and prevent refractures in this population.

Association between tissue loss type and amputation risk among Medicare patients with concomitant diabetes and peripheral arterial disease

ObjectivePrior studies have described risk factors associated with amputation in patients with concomitant diabetes and peripheral arterial disease (DM/PAD). However, the association between the severity and extent of tissue loss type and amputation risk remains less well-described. We aimed to quantify the role of different tissue loss types in amputation risk among patients with DM/PAD, in the context of demographic, preventive, and socioeconomic factors. MethodsApplying International Classification of Diseases (ICD)-9 and ICD-10 codes to Medicare claims data (2007-2019), we identified all patients with continuous fee-for-service Medicare coverage diagnosed with DM/PAD. Eight tissue loss categories were established using ICD-9 and ICD-10 diagnosis codes, ranging from lymphadenitis (least severe) to gangrene (most severe). We created a Cox proportional hazards model to quantify associations between tissue loss type and 1- and 5-year amputation risk, adjusting for age, race/ethnicity, sex, rurality, income, comorbidities, and preventive factors. Regional variation in DM/PAD rates and risk-adjusted amputation rates was examined at the hospital referral region level. ResultsWe identified 12,257,174 patients with DM/PAD (48% male, 76% White, 10% prior myocardial infarction, 30% chronic kidney disease). Although 2.2 million patients (18%) had some form of tissue loss, 10.0 million patients (82%) did not. The 1-year crude amputation rate (major and minor) was 6.4% in patients with tissue loss, and 0.4% in patients without tissue loss. Among patients with tissue loss, the 1-year any amputation rate varied from 0.89% for patients with lymphadenitis to 26% for patients with gangrene. The 1-year amputation risk varied from two-fold for patients with lymphadenitis (adjusted hazard ratio, 1.96; 95% confidence interval, 1.43-2.69) to 29-fold for patients with gangrene (adjusted hazard ratio, 28.7; 95% confidence interval, 28.1-29.3), compared with patients without tissue loss. No other demographic variable including age, sex, race, or region incurred a hazard ratio for 1- or 5-year amputation risk higher than the least severe tissue loss category. Results were similar across minor and major amputation, and 1- and 5-year amputation outcomes. At a regional level, higher DM/PAD rates were inversely correlated with risk-adjusted 5-year amputation rates (R2 = 0.43). ConclusionsAmong 12 million patients with DM/PAD, the most significant predictor of amputation was the presence and extent of tissue loss, with an association greater in effect size than any other factor studied. Tissue loss could be used in awareness campaigns as a simple marker of high-risk patients. Patients with any type of tissue loss require expedited wound care, revascularization as appropriate, and infection management to avoid amputation. Establishing systems of care to provide these interventions in regions with high amputation rates may prove beneficial for these populations.

Cardiovascular risk in anti-VEGF treatment of neovascular age-related macular degeneration

ObjectiveAssess 5-year all-cause mortality (ACM), hemorrhagic stroke, ischemic stroke, and myocardial infarction (MI) risks in nAMD patients receiving anti-VEGF injections compared with controls. DesignPopulation-based retrospective cohort study using a U.S. federated health research network, containing de-identified data of 96 million patients from 1/1/2003 to 3/6/2023. ParticipantsnAMD Patients with anti-VEGF injections. Controls included nAMD patients without anti-VEGF injections, non-exudative AMD patients, and patients without AMD. MethodsPatients were identified using nAMD ICD-10 and anti-VEGF CPT codes and matched for age, sex, and comorbidities. Five-year relative risk of ACM (RR1), hemorrhagic stroke (RR2), ischemic stroke (RR3), and MI (RR4) in nAMD patients receiving anti-VEGF injections were calculated. ResultsA total of 27,609 nAMD patients (mean diagnosis age [SD], [78.2 (10.3)]) received anti-VEGF injections; 769 nAMD patients without injections (75.8 [12.2]), 27,599 non-exudative AMD patients (78.2 [10.3]), and 21,902 no-AMD patients (76.1 [10.5]) were identified. After matching, nAMD patients receiving injections did not show increased risk versus nAMD patients without injections (RR1, 0.66; 95% CI [0.53, 0.82]), (RR2, 1.00 [0.42, 2.38]), (RR3, 1.70 [0.92,3.13]), (RR4, 0.63 [0.33, 1.18]). No increased risk was found compared to non-exudative AMD patients (RR1, 0.99 [0.95, 1.03]), (RR2, 0.94 [0.83,1.07]), (RR3, 1.04 [0.96, 1.12]), (RR4, 0.99 [0.91, 1.08]). Increased risk for ACM was observed versus no-AMD patients (RR1, 1.21 [1.15, 1.27]), but no other differences were found (RR2, 0.81 [0.70, 0.93]), (RR3, 1.00 [0.92, 1.09]), (RR4, 0.986 [0.90, 1.09]). ConclusionAnti-VEGF injections were not associated with major cardiovascular events in nAMD patients over 5 years.

Patent Foramen Ovale Closure in Older Patients With Stroke: Patient Selection for Trial Feasibility.

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. 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. 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. 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.

Breast conserving surgery with intraoperative electron beam radiation therapy for low-risk breast cancer: Five-year follow-up of 306 patients.

Recent studies have reported a higher than expected risk of ipsilateral breast tumor recurrence (IBTR) after breast conserving surgery (BCS) and a single dose of electron beam intra-operative radiotherapy (IORT). This finding was the rationale to perform a retrospective single center cohort study evaluating the oncologic results of consecutive patients treated with BCS and IORT. Women were eligible if they had clinical low-risk (N0, ≤2 cm unifocal, Bloom and Richardson grade 1-2), estrogen receptor-positive and human-epidermal-growth-factor-receptor-2-negative breast cancer. Prior to BCS, pN0 status was determined by sentinel lymph node biopsy. Data on oncologic follow-up were analyzed. Between 2012 and 2019, 306 consecutive patients were treated and analyzed, with a median age of 67 (50-86) years at diagnosis. Median follow-up was 60 (8-120) months. Five-year cumulative risk of IBTR was 13.4% (95% confidence interval [CI] 9.4-17.4). True in field recurrence was present in 3.9% of the patients. In 4.6% of the patients, the IBRT was classified as a local recurrence due to seeding of tumor cells in the cutis or subcutis most likely related to percutaneous biopsy. In 2.9% of the patients, the IBRT was a new outfield primary tumor. Three patients had a regional lymph node recurrence and two had distant metastases as first event. One breast cancer-related death was observed. Estimated 5-year overall survival was 89.8% (95% CI 86.0-93.6). In conclusion, although some of IBTR cases could have been prevented by adaptations in biopsy techniques and patient selection, BCS followed by IORT was associated with a substantial risk of IBTR.

Abstract PS10-09: Development of an absolute risk prediction model for premenopausal breast cancer in an international consortium

Abstract Risk prediction models that have been developed for overall breast cancer risk are based on a limited number of premenopausal cases in individual cohorts. As some risk factors differ in their associations with pre- versus postmenopausal breast cancer, a distinct risk prediction model is needed for premenopausal breast cancer. We developed a risk prediction model for premenopausal breast cancer using 779,601 participants and 9,665 incident cases from 18 prospective studies within the Premenopausal Breast Cancer Collaborative Group (PBCCG), across North America (N=9), Europe (N=6), Australia (N=1), and Asia (N=2). Data were split, within each cohort, into training (2/3) and testing (1/3) datasets. Individual risk was assessed in five-year intervals, using variables reported at the start of the time interval. Cox proportional hazards regression was used to model risk factors in a backwards-selection method, stratified by cohort: age at menarche, age at first birth, parity, breastfeeding (months), height (cm), BMI (kg/m2), BMI at age 18, recent weight change (kg), alcohol consumption (drinks/week), first-degree family history of breast cancer, and personal history of benign breast disease. To enable the use of information from all cohorts despite differences in missing variables by design, cohorts were grouped by available variables and risk models were fit for each group. In cohorts with incomplete data, model coefficients were adjusted based on the correlation of covariates with the missing variables in the complete case dataset. Coefficients were meta-analyzed with inverse variance weighting to obtain final coefficients. Discrimination was evaluated in the testing dataset by calculation of the c-index. Work is ongoing to calibrate the model based on five-year absolute risk using GLOBOCAN continent- and age-specific incidence rates to represent baseline risk. The final model included age at menarche, parity, height, BMI, BMI at age 18, first-degree family history of breast cancer, and history of benign breast disease. Young adulthood BMI and BMI (at start of the 5-year risk interval) were associated with a decreased risk (Hazard Ratio (HR) (95% confidence interval (CI)) per 5 kg/m2 = 0.87 (0.81-0.93) and 0.90 (0.86-0.95), respectively) as was parity (HR (95% CI) = 0.92 (0.90-0.94)). Height was associated with increased risk (HR (95% CI) per 10 cm = 1.14 (1.07-1.21)), while history of benign breast disease and family history were associated with larger increases in risk (HR (95% CI) = 1.64 (1.30-2.06) and 1.76 (1.63-1.90), respectively). Model discrimination was higher than that reported for women under 50 years in existing breast cancer risk prediction models considering clinical factors (AUC (95% CI) = 0.61 (0.59-0.62)). Calibration of absolute 5-year risk is ongoing. Several factors driving risk prediction of postmenopausal breast cancer have similar influence on risk of premenopausal breast cancer, while family history has a stronger influence on premenopausal breast cancer risk. Our model demonstrates acceptable discrimination and will enable individual 5-year absolute risk prediction for premenopausal breast cancer. Citation Format: Kristen Brantley, Michael Jones, Minouk Schoemaker, Hazel Nichols, Anthony Swerdlow, Robert MacInnis, Roger Milne, Tess Clenenden, Yu Chen, Xiao-Ou Shu, Wei Zheng, Woon-Puay Koh, Jian-Min Yuan, Cari Kitahara, Martha Linet, Dale Sandler, Bernard A Rosner, Peter Kraft, A. Heather Eliassen. Development of an absolute risk prediction model for premenopausal breast cancer in an international consortium [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS10-09.

Morbidity and mortality risks associated with valproate withdrawal in young adults with epilepsy.

Valproate is the most effective treatment for idiopathic generalized epilepsy. Current guidance precludes its use in females of childbearing potential, unless other treatments are ineffective or not tolerated, because of high teratogenicity. This risk was recently extended to males. New guidance will limit use both in males and females aged <55 years, resulting in withdrawal of valproate from males already taking it, as occurs for females. Whether there are risks of personal harm (including injury or death) associated with valproate withdrawal has not yet been quantified for males or females ON valproate, meaning clinicians cannot reliably counsel either sex when discussing valproate withdrawal with them, despite that this concern may be at the forefront of patients' and clinicians' minds. We assessed whether there are any morbidity or mortality risks associated with valproate withdrawal in young males and females. We performed a retrospective cohort study of internationally derived electronic health data within the TriNetX Global Collaborative Network. Included were males and females aged 16-54 years with ≥1 epilepsy disease or symptom code between 1 December 2017 and 1 December 2018, and ≥2 valproate prescriptions over the preceding 2 years (1 January 2015-30 November 2017). Five-year propensity-matched risks of mortality and a range of morbidity outcomes were compared between those remaining ON versus withdrawn from valproate during the 1 December 2017-1 December 2018 recruitment period, regardless of whether switched to another antiseizure medication. Survival analysis was undertaken using Cox-proportional hazard models, generating hazard ratios (HRs) with 95% confidence intervals (CIs). In total, 8991 males and 5243 females taking valproate were recruited. Twenty-eight per cent of males and 36% of females were subsequently withdrawn from valproate. Valproate withdrawal was associated with significantly increased risks of emergency department attendance [HRs overall: 1.236 (CI 1.159-1.319), males: 1.181 (CI 1.083-1.288), females: 1.242 (CI 1.125-1.371)], hospital admission [HRs overall: 1.160 (CI 1.081-1.246), males: 1.132 (CI 1.027-1.249), females: 1.147 (CI 1.033-1.274)], falls [HRs overall: 1.179 (CI 1.041-1.336), males: 1.298 (CI 1.090-1.546)], injuries [HRs overall: 1.095 (CI 1.021-1.174), males: 1.129 (CI 1.029-1.239)], burns [HRs overall: 1.592 (CI 1.084-2.337)] and new-onset depression [HRs overall 1.323 (CI 1.119-1.565), females: 1.359 (CI 1.074-1.720)]. The risk of these outcomes occurring was 1%-7% higher in those withdrawn from valproate than in those remaining ON valproate. Overall, valproate withdrawal was not associated with increased mortality. These results may help patients and clinicians have a more informed discussion about personal safety when considering valproate withdrawal.

Temporal trends in mortality in patients with systemic lupus erythematosus: a Danish population-based matched cohort study.

Excess mortality has been demonstrated in patients with SLE compared with the general population. We aimed to investigate the 5-year and 10-year all-cause mortality in patients with SLE compared with the general population in recent decades. This was a Danish nationwide population-based exposure-matched cohort study. Incident cases of SLE diagnosed between 1996 and 2015 were identified using administrative health registries and followed until 2020, allowing for 5 and 10 years of follow-up. Patients with SLE were matched 1:5 on age and sex with individuals from the Danish general population. Time-to-event analyses were performed using the pseudo-observation approach. In total, 1351 incident cases of SLE and 6755 matched controls were identified. The crude risk difference (RD) for 5-year mortality decreased over the study period, from 10.3% (95% CI 6.5-14.1%) to 4.6% (95% CI 1.4-7.8%) for patients with SLE compared with controls. The relative risk (RR) for 5-year mortality decreased similarly in the same period. Adjustment for comorbidities revealed lower RD and RR for mortality in patients with SLE compared with controls, but the decreasing trend remained. The crude and adjusted RD and RR for 10-year mortality did not change over the calendar period. The 10-year RR was highest in young patients with SLE (<50 years of age). The 5-year mortality risk decreased over time for both patients with SLE and matched controls. However, excess 5-year mortality for patients with SLE in the most recent calendar period and excess mortality late in their disease course remained. Continued focus on preventing disease progression and comorbidity is required.

Predicting post-stroke cognitive impairment using electronic health record data.

Secondary prevention interventions to reduce post-stroke cognitive impairment (PSCI) can be aided by the early identification of high-risk individuals who would benefit from risk factor modification. To develop and evaluate a predictive model to identify patients at increased risk of PSCI over 5 years using data easily accessible from electronic health records. Cohort study that included primary care patients from two academic medical centers. Patients were aged 45 years or older, without prior stroke or prevalent cognitive impairment, with primary care visits and an incident ischemic stroke between 2003 and 2016 (development/internal validation cohort) or 2010 and 2022 (external validation cohort). Predictors of PSCI were ascertained from the electronic health record. The outcome was incident dementia/cognitive impairment within 5 years and beginning 3 months following stroke, ascertained using International Classification of Diseases, Ninth/Tenth Revision (ICD-9/10) codes. For model variable selection, we considered potential predictors of PSCI and constructed 400 bootstrap samples with two-thirds of the model derivation sample. We ran 10-fold cross-validated Cox proportional hazards models using a least absolute shrinkage and selection operator (LASSO) penalty. Variables selected in >25% of samples were included. The analysis included 332 incident diagnoses of PSCI in the development cohort (n = 3741), and 161 and 128 incident diagnoses in the internal (n = 1925) and external (n = 2237) validation cohorts, respectively. The C-statistic for predicting PSCI was 0.731 (95% confidence interval (CI): 0.694-0.768) in the internal validation cohort, and 0.724 (95% CI: 0.681-0.766) in the external validation cohort. A risk score based on the beta coefficients of predictors from the development cohort stratified patients into low (0-7 points), intermediate (8-11 points), and high (12-23 points) risk groups. The hazard ratios (HRs) for incident PSCI were significantly different by risk categories in internal (high, HR: 6.2, 95% CI: 4.1-9.3; Intermediate, HR: 2.7, 95% CI: 1.8-4.1) and external (high, HR: 6.1, 95% CI: 3.9-9.6; Intermediate, HR: 2.8, 95% CI: 1.9-4.3) validation cohorts. Five-year risk of PSCI can be accurately predicted using routinely collected data. Model output can be used to risk stratify and identify individuals at increased risk for PSCI for preventive efforts. Mass General Brigham data contain protected health information and cannot be shared publicly. The data processing scripts used to perform analyses will be made available to interested researchers upon reasonable request to the corresponding author.