Episode 391: 402. Functional disability after clinically significant extracranial bleeding: a secondary analysis of ASPREE

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https://www.jthjournal.org/article/S1538-7836(25)00109-6/fulltextAntithrombotic agents, like aspirin and anticoagulants, are essential for treating many cardiovascular conditions. However, a common side effect is bleeding, with extracranial bleeding—bleeding outside the brain and spinal cord—being quite prevalent. This study, a secondary analysis of the Aspirin in Reducing Events in the Elderly, or ASPREE trial, aimed to explore how clinically significant extracranial bleeding affects the development of functional disability in otherwise healthy older adults.What did the researchers find?Summary of Findings: Incidence of Bleeding: Out of nearly 19,000 participants, about 2.9%, or 547 individuals, experienced clinically significant extracranial bleeding. Functional Independence Impact: Those who experienced such bleeding had a more than two-fold increase in the risk of developing dependence on activities of daily living, or ADLs. Specifically, the hazard ratio for ADL dependence was 2.46, indicating a significant association. Types of Bleeding: Both gastrointestinal (GI) bleeding and other non-GI extracranial bleeding showed similar risks, with hazard ratios of 2.29 and 2.68 respectively. Importantly, these associations held true whether participants were on aspirin or a placebo. Strengths of the Study: Large Sample Size: With nearly 19,000 participants, the study provides robust data. Rigorous Data Collection: Bleeding events were meticulously documented and adjudicated by medical professionals. Comprehensive Analysis: The detailed follow-up and frequent assessments allowed for thorough monitoring of participants' health outcomes over several years. Weaknesses of the Study: Granular Data Absence: Specific details about hospitalization, such as length of stay or the number of transfusions, were not available. Data Collection Frequency: Bleeding events were assessed continuously, whereas ADL dependence was assessed biannually. This discrepancy could lead to challenges in pinpointing the exact onset of functional dependence relative to bleeding events.

https://www.nejm.org/doi/full/10.1056/NEJMoa2405182?query=recirc_Semantic  Key Takeaways Extended Predictive Value of Biomarkers: High-sensitivity C-reactive protein (CRP), LDL cholesterol, and lipoprotein(a) levels were found to be predictive of cardiovascular events over a 30-year period. These markers contribute independently to long-term cardiovascular risk beyond traditional 10-year risk estimates. Study Design and Population: The study enrolled 27,939 initially healthy U.S. women who were followed for 30 years. The primary endpoint was the occurrence of a first major adverse cardiovascular event, including myocardial infarction, coronary revascularization, stroke, or death from cardiovascular causes. Predictive Strength of Biomarkers: Among the biomarkers, high-sensitivity CRP showed the strongest association with future cardiovascular events (hazard ratio for top quintile: 1.70). LDL cholesterol and lipoprotein(a) also significantly predicted risk, albeit to a slightly lower degree (hazard ratios: 1.36 and 1.33, respectively).  NOT STATIN WITH CRP Implications for Clinical Practice: Combining all three biomarkers may offer the best method for identifying high-risk individuals who might benefit from early intervention.   YOU HAVE TO PROSPECTIVELY VALIDATE THIS The study supports extending cardiovascular prevention strategies beyond traditional risk assessments. Lifestyle and pharmacologic interventions should target multiple pathways, including lipid levels and inflammation. Key Limitations Study Population: The study cohort predominantly consisted of female health professionals who are mostly White (94%), which may limit generalizability. The results may not extend to males or more diverse populations without further studies. Absence of Repeated Measures: Biomarkers were measured only at baseline without repeated measures over time. This limits the ability to observe changes in biomarker levels and their association with risk over time. Statin Use Data: Increasing use of statins over the study period was not thoroughly considered in initial analyses, and detailed data on adherence and duration are lacking. Sensitivity analyses attempted to account for this by censoring data at the time of first statin prescription, but residual confounding may be present. Concerns with Study Design Cohort Composition: The study's focus on health professionals might have led to better access to healthcare and healthier lifestyle choices, potentially skewing outcomes. Non-White participants were underrepresented, raising concerns about the applicability of findings to more diverse groups. Single Time Point Measurement:Only baseline biomarker levels were used for long-term prediction, which may not account for variability and changes in risk factors over time.