Abstract: Apolipoprotein B (apoB) provides an integrated measure of atherogenic risk. Whether apoB levels and apoB lowering hold incremental predictive information on residual risk after acute coronary syndrome beyond that provided by low-density lipoprotein cholesterol is uncertain. Methods: The ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) compared the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome and elevated atherogenic lipoproteins despite optimized statin therapy. Primary outcome was major adverse cardiovascular events (MACE; coronary heart disease death, nonfatal myocardial infarction, fatal/nonfatal ischemic stroke, hospitalization for unstable angina). Associations between baseline apoB or apoB at 4 months and MACE were assessed in adjusted Cox proportional hazards and propensity score–matched models. Results: Median follow-up was 2.8 years. In proportional hazards analysis in the placebo group, MACE incidence increased across increasing baseline apoB strata (3.2 [95% CI, 2.9–3.6], 4.0 [95% CI, 3.6–4.5] , and 5.5 [95% CI, 5.0–6.1] events per 100 patient-years in strata 〈 75, 75– 〈 90, ≥90 mg/dL, respectively; P trend 〈 0.0001) and after adjustment for low-density lipoprotein cholesterol ( P trend =0.035). Higher baseline apoB stratum was associated with greater relative ( P trend 〈 0.0001) and absolute reduction in MACE with alirocumab versus placebo. In the alirocumab group, the incidence of MACE after month 4 decreased monotonically across decreasing achieved apoB strata (4.26 [95% CI, 3.78–4.79], 3.09 [95% CI, 2.69–3.54] , and 2.41 [95% CI, 2.11–2.76] events per 100 patient-years in strata ≥50, 〉 35– 〈 50, and ≤35 mg/dL, respectively). Compared with propensity score–matched patients from the placebo group, treatment hazard ratios for alirocumab also decreased monotonically across achieved apoB strata. Achieved apoB was predictive of MACE after adjustment for achieved low-density lipoprotein cholesterol or non–high-density lipoprotein cholesterol but not vice versa. Conclusions: In patients with recent acute coronary syndrome and elevated atherogenic lipoproteins, MACE increased across baseline apoB strata. Alirocumab reduced MACE across all strata of baseline apoB, with larger absolute reductions in patients with higher baseline levels. Lower achieved apoB was associated with lower risk of MACE, even after accounting for achieved low-density lipoprotein cholesterol or non–high-density lipoprotein cholesterol, indicating that apoB provides incremental information. Achievement of apoB levels as low as ≤35 mg/dL may reduce lipoprotein-attributable residual risk after acute coronary syndrome. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01663402.

Abstract: Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus. Methods: CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-analysis. Results: In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo; hazard ratio [HR], 0.77 [95% CI, 0.55–1.08] ). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61–1.28]; n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19–1.32] ; n=18), and undetermined (HR, 0.54 [95% CI, 0.20–1.46]; n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53–1.10] ; n=115). The overall effects in the 4 CVOTs combined were: total stroke (HR pooled , 0.96 [95% CI, 0.82–1.12]), ischemic stroke (HR pooled , 1.01 [95% CI, 0.89–1.14]), hemorrhagic stroke (HR pooled , 0.50 [95% CI, 0.30–0.83]), undetermined stroke (HR pooled , 0.86 [95% CI, 0.49–1.51]), and AF/AFL (HR pooled , 0.81 [95% CI, 0.71–0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate ( P =0.01), with protection in the lowest estimated glomerular filtration rate ( 〈 45 mL/min/1.73 m 2 ]) subgroup (HR pooled , 0.50 [95% CI, 0.31–0.79]). Conclusions: Although we found no clear effect of SGLT2i on total stroke in CREDENCE or across trials combined, there was some evidence of benefit in preventing hemorrhagic stroke and AF/AFL, as well as total stroke for those with lowest estimated glomerular filtration rate. Future research should focus on confirming these data and exploring potential mechanisms. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02065791.

Abstract: To investigate the frequency, nature, and severity of intraoperative adverse near miss events within advanced laparoscopic surgery and report any associated clinical impact. Background: Despite implementation of surgical safety initiatives, the intraoperative period is poorly documented with evidence of underreporting. Near miss analyses are undertaken in high-risk industries but not in surgical practice. Methods: Case video and data from 2 laparoscopic total mesorectal excision randomized controlled trials were analyzed (ALaCaRT ACTRN12609000663257, 2D3D ISRCTN59485808). Intraoperative adverse events were identified and categorized using the observational clinical human reliability analysis technique. The EAES classification was applied by 2 blinded assessors. EAES grade 1 events (nonconsequential error, no damage, or need for correction) were considered near misses. Associated clinical impact was assessed with early morbidity and histopathology outcomes. Results: One hundred seventy-five cases contained 1113 error events. Six hundred ninety-eight (62.7%) were near misses (median 3, IQR 2–5, range 0–15) with excellent inter-rater and test–retest reliability (κ=0.86, 95% CI 0.83–0.89, P 〈 0.001 and κ=0.88, 95% CI 0.85–0.9, P 〈 0.001 respectively). Significantly more near misses were seen in patients who developed early complications (4 (3–6) vs. 3 (2–4), P 〈 0.001). Higher numbers of near misses were seen in patients with more numerous ( P = 0.002) and more serious early complications ( P = 0.003). Cases containing major intraoperative adverse events contained significantly more near misses (5 (3–7) vs. 3 (2–5), P 〈 0.001) with a major event observed for every 19.4 near misses. Conclusion: Intraoperative adverse events and near misses can be reliably and objectively captured in advanced laparoscopic surgery. Near misses are commonplace and closely associated with morbidity outcomes.

Abstract: Laparoscopic total mesorectal excision is a challenging procedure requiring high-quality surgery for optimal outcomes. Patient, tumor, and pelvic factors are believed to determine difficulty, but previous studies were limited to postoperative data. OBJECTIVE: This study aimed to report factors predicting laparoscopic total mesorectal excision performance by using objective intraoperative assessment. DESIGN: Data from a multicenter laparoscopic total mesorectal excision randomized trial (ISRCTN59485808) were reviewed. SETTING: This study was conducted at 4 centers in the United Kingdom. PATIENTS AND INTERVENTION: Seventy-one patients underwent elective laparoscopic total mesorectal excision for rectal adenocarcinoma with curative intent: 53% were men, mean age was 69 years, body mass index was 27.7, tumor height was 8.5 cm, 24% underwent neoadjuvant therapy, and 25% had previous surgery. MAIN OUTCOME MEASURES: Surgical performance was assessed through the identification of intraoperative adverse events by using observational clinical human reliability analysis. Univariate analysis and multivariate binomial regression were performed to establish factors predicting the number of intraoperative errors, surgeon-reported case difficulty, and short-term clinical and histopathological outcomes. RESULTS: A total of 1331 intraoperative errors were identified from 365 hours of surgery (median, 18 per case; interquartile range, 16–22; and range, 9–49). No patient, tumor, or bony pelvimetry measurement correlated with total or pelvic error count, surgeon-reported case difficulty, cognitive load, operative data, specimen quality, number or severity of 30-day morbidity events and length of stay (all r s not exceeding ±0.26, p 〉 0.05). Mesorectal area was associated with major intraoperative adverse events (OR, 1.09; 95%CI, 1.01–1.16; p = 0.015) and postoperative morbidity (OR, 1.1; 95% CI, 1.01–1.2; p = 0.033). Obese men were subjectively reported as harder cases (24 vs 36 mm, p = 0.042), but no detrimental effects on performance or outcomes were seen. LIMITATIONS: Our sample size is modest, risking type II errors and overfitting of the statistical models. CONCLUSION: Patient, tumor, and bony pelvic anatomical characteristics are not seen to influence laparoscopic total mesorectal excision operative difficulty. Mesorectal area is identified as a risk factor for intraoperative and postoperative morbidity. See Video Abstract at http://links.lww.com/DCR/B35. FACTORES QUE PREDICEN LA DIFICULTAD OPERATIVA DE LA ESCISIÓN MESORRECTAL TOTAL LAPAROSCÓPICA ANTECEDENTES: La escisión mesorrectal total laparoscópica es un procedimiento desafiante. Para obtener resultados óptimos, se requiere cirugía de alta calidad. Se cree que, factores como el paciente, el tumor y la pelvis, determinan la dificultad, pero estudios previos solamente se han limitado a datos postoperatorios. OBJETIVO: Informar de los factores que predicen el resultado de la escisión mesorrectal total laparoscópica, mediante una evaluación intraoperatoria objetiva. DISEÑO: Datos de un ensayo multicéntrico y randomizado de escisión mesorrectal total laparoscópica (ISRCTN59485808). LUGAR: Cuatro centros del Reino Unido. PACIENTES E INTERVENCIÓN: Un total de 71 pacientes fueron sometidos a escisión mesorrectal total laparoscópica electiva, para adenocarcinoma rectal con intención curativa. 53% hombres, edad media, índice de masa corporal y altura del tumor 69, 27.7 y 8.5 cm respectivamente, 24% terapia neoadyuvante y 25% cirugía previa. PRINCIPALES MEDIDAS DE RESULTADO: Rendimiento quirúrgico evaluado mediante la identificación de eventos intraoperatorios adversos, mediante el análisis clínico observacional de confiabilidad humana. Se realizaron análisis univariado y la regresión binomial multivariada para establecer factores que predicen el número de errores intraoperatorios, reportes del cirujano sobre la dificultad del caso y los resultados clínicos e histopatológicos a corto plazo. RESULTADOS: Se identificaron un total de 1,331 errores intraoperatorios en 365 horas de cirugía (media de 18 por caso, IQR 16–22, rango 9–49). Ningún paciente, tumor o medición de pelvimetría pélvica, se correlacionó con la cuenta de errores pélvicos o totales, reporte del cirujano sobre dificultad del caso, carga cognitiva, datos operativos, calidad de la muestra, número o gravedad de eventos de morbilidad de 30 días y duración de la estadía (todos r s 〈 ± 0.26, p 〉 0.05). El área mesorrectal se asoció con eventos adversos intraoperatorios importantes (OR, 1.09; IC 95%, 1.01–1.16; p = 0.015) y morbilidad postoperatoria (OR, 1.1; IC 95%, 1.01–1.2; p = 0.033). Como información subjetiva, hombres obesos fueron casos más difíciles (24 mm frente a 36 mm, p = 0.042) pero no se observaron efectos perjudiciales sobre el rendimiento o los resultados. LIMITACIONES: Nuestro tamaño de muestra es un modesto riesgo de errores de tipo II y el sobreajuste de los modelos estadísticos. CONCLUSIÓN: No se observa que las características anatómicas del paciente, tumor y pelvis ósea influyan en la dificultad operatoria de la escisión mesorrectal laparoscópica total. El área mesorrectal se identifica como un factor de riesgo para la morbilidad intraoperatoria y postoperatoria. Vea el resumen del video en http://links.lww.com/DCR/B35.