Humayun, Zainab

Abstract: Cardiovascular disease (CVD) remains the leading cause of death worldwide. While advances in treatment have improved outcomes, the greatest gains in public health will come from primary prevention. Risk stratification is the foundation of CVD prevention. Traditional tools, such as pooled cohort equations (PCEs) and SCORE2, do not capture non-traditional risk factors and individual variability, driving efforts to refine existing approaches. We critically discuss emerging risk determinants for primary CVD prevention. Coronary artery calcium scoring can reclassify CVD risk but has limitations related to cost, access, and unvalidated improvements in clinical endpoints. Biomarkers such as apolipoprotein B and lipoprotein(a) may identify residual risk beyond LDL-C, particularly in patients with lipid discordance, but remain underused due to uncertain thresholds and the lack of prospective triallevel outcome data. Trials of colchicine in primary prevention have yielded mixed results, making the role of targeting inflammation unclear in CVD prevention. Polygenic risk scores can stratify genetic risk but face challenges in sensitivity, specificity, and generalizability. Multiomics approaches, while offering the promise of deeper phenotyping, lack established clinical applications and consensus on when their use is appropriate. Artificial intelligence may allow better prediction across cohorts but requires broader validation. Clonal hematopoiesis of indeterminate potential, a marker of inflammation and age-related CVD risk, lacks evidence supporting routine screening or intervention in younger, asymptomatic individuals. The proliferation of new risk stratification tools poses a key challenge: determining when additional data meaningfully alter clinical decisions. Until robust outcome-based evidence emerges, risk enhancers should guide, but not dictate, therapy in selected patients.

Complete revascularization improves outcomes in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel coronary artery disease (MVD); however, the optimal timing of noninfarct-related artery intervention during the index procedure, immediate revascularization (IR) versus a staged approach (SR), remains uncertain. We conducted a systematic review and meta-analysis of randomized controlled trials comparing SR and IR in patients with STEMI and MVD. The primary outcome was major adverse cardiovascular events. Secondary outcomes included all-cause and cardiovascular mortality, recurrent myocardial infarction, unplanned ischemia-driven revascularization, stent thrombosis, stroke, major bleeding, acute kidney injury, and heart failure hospitalization. Random-effects models with Hartung–Knapp adjustment were used. Trial sequential analysis assessed evidence conclusiveness, and the certainty of evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation. Eight randomized trials, including 5077 patients (2556 SR; 2521 IR), were analyzed. No significant differences were observed between SR and IR for major adverse cardiovascular events [odds ratios (ORs), 1.07; 95% confidence intervals (CI), 0.76–1.49], recurrent myocardial infarction (OR, 1.30; 95% CI, 0.80–2.14), cardiovascular mortality (OR, 0.76; 95% CI, 0.51–1.13), or all-cause mortality (OR, 0.75; 95% CI, 0.54–1.06). Rates of stent thrombosis, stroke, unplanned ischemia-driven revascularization, major bleeding, acute kidney injury, and heart failure hospitalization were also comparable. Trial sequential analysis indicated insufficient information size to draw definitive conclusions, and the certainty of evidence ranged from very low to low. In patients with STEMI and MVD, staged and immediate complete revascularization provide comparable ischemic, safety, and mortality outcomes. Current evidence supports clinical equipoise, and revascularization timing should be individualized pending results from adequately powered trials.

ABSTRACT Background Factor XI/XIa inhibitors are emerging anticoagulants with potential to reduce bleeding complications in atrial fibrillation (AF) patients. This meta‐analysis evaluated their efficacy and safety compared to direct oral anticoagulants (DOACs) and explored dose optimization. Methods A systematic search of PubMed, Cochrane, and Embase was conducted through March 2025 following PRISMA guidelines. Randomized controlled trials (RCTs) comparing Factor XI/XIa inhibitors with DOACs in AF patients were included. Outcomes assessed were major bleeding, stroke, systemic embolism, all‐cause and cardiovascular mortality and serious adverse events. Risk ratios (RR) with 95% confidence intervals (CI) were pooled using a Mantel‐Haenszel random‐effects model. Heterogeneity was evaluated with the I² statistic, and evidence certainty assessed by the GRADE approach. Trial Sequential Analysis (TSA) was performed. Results Three RCTs including 16,772 patients (mean age 73 years, CHA₂DS₂‐VASc 3.9–5) were analyzed. Factor XI/XIa inhibitors significantly reduced major bleeding (RR: 0.41, 95% CI: 0.36–0.46, I² = 0%) compared to DOACs. However, stroke risk was increased (RR: 3.42, 95% CI: 2.62–4.46), particularly with asundexian 50 mg (RR: 4.02). No significant differences were observed in all‐cause mortality (RR: 0.82) or cardiovascular death (RR: 1.05). Systemic embolism risk was higher (RR: 4.26), while serious adverse events were comparable (RR: 0.95). TSA indicated encouraging safety outcomes but highlighted the need for further large‐scale studies. Conclusion Factor XI/XIa inhibitors lower major bleeding risk in AF patients but increase stroke and systemic embolism rates without impacting mortality.