Mixed-effects Cox Models Research Articles

Association between antipsychotic use and acute ischemic heart disease in women but not in men: a retrospective cohort study of over one million primary care patients

BackgroundResearch comparing sex differences in the effects of antipsychotic medications on acute ischemic heart disease (IHD) is limited and the findings ambiguous. This study aimed to investigate these associations within a primary care setting.MethodsHong Kong public general outpatient electronic records of patients aged 45+ during 2007–2010 were extracted, with the last consultation date as the baseline for a 4-year follow-up period to observe acute IHD hospitalizations (2011–2014). Antipsychotic use was defined as any prescription over the previous 12 months from a list of 16 antipsychotics, while acute IHD was defined by ICD-9: 410.00–411.89. Both sex-specific and sex-combined (both sexes) mixed-effects Cox models (random intercept across 74 clinics) were implemented to examine the association and test the interaction between antipsychotics and sex.ResultsAmong 1,043,236 included patients, 17,780 (1.7%) were prescribed antipsychotics, and 8342 (0.8%) developed IHD. In sex-specific analyses, antipsychotic prescription was associated with a 32% increased hazard rate of acute IHD among women (95% CI 1.05–1.67) but not among men. A likelihood ratio test comparing sex-combined models with and without the interaction between antipsychotic use and sex suggested significant interaction (χ2 = 4.72, P = 0.030). The association between antipsychotic use and IHD among women attenuated and became non-significant when haloperidol was omitted from the operationalization of antipsychotic use (HR = 1.23, 95% CI 0.95–1.60).ConclusionOur results suggest that antipsychotic prescription is moderately associated with an increased risk of acute IHD among women in primary care and this relationship may be explained by specific antipsychotics. Further research should observe and capture the potential intermediary mechanisms and the dose-response relationship of this association to provide more rigorous evidence to establish causality and inform clinical practices.

Efficacy of rivaroxaban compared to standard of care in preventing ischemic stroke in adults with coronary or peripheral vascular disease: an integrated analysis using patient-level data

Abstract Background Ischemic stroke is a leading cause of morbidity and mortality. Rivaroxaban has been evaluated in multiple studies of patients with coronary artery disease and/or peripheral artery disease (CAD/PAD) in which ischemic stroke was assessed. Purpose To determine the efficacy of rivaroxaban compared with standard of care (SOC) in reducing ischemic stroke in adults with CAD/PAD. Methods Randomized, active- or placebo-controlled Phase 2 or 3 studies evaluating rivaroxaban (2.5 mg twice daily) in adults with CAD/PAD in which ischemic stroke was collected as an efficacy endpoint were included using patient-level data. All stroke was also evaluated as a secondary outcome. ISTH major bleeding (MB) was assessed on treatment + 2 days. Hazard ratios (HR) and p-values for the treatment effect were estimated using Cox proportional hazards models and log-rank tests, respectively, with study as the stratification factor. Mixed effect Cox models (frailty models) were used with treatment as the fixed effect and study as the random effect. Cumulative risk of time-to-first event was assessed using the Kaplan-Meier method. Results Six studies were included: ATLAS-1, ATLAS-2, COMPASS, COMMANDER HF, GEMINI ACS1 and PIONEER AF-PCI (n=38,283). Compared with SOC, rivaroxaban significantly reduced the risk of ischemic stroke (HR, 0.63, 95% CI, 0.52–0.77, P<0.001) and all stroke (HR, 0.71, 95% CI, 0.59–0.84, P<0.001), without significant heterogeneity. The frailty model results were consistent. The risk of MB was significantly higher with rivaroxaban compared with SOC (HR, 1.58, 95% CI, 1.37–1.83, P<0.001). Conclusion Rivaroxaban (2.5 mg twice daily) significantly reduced ischemic stroke and all stroke compared with SOC in patients with acute or chronic CAD/PAD while increasing MB. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Janssen Research and Development

Long Term Clinical Outcomes Of Multi-Level Spinal SBRT For Vertebral Metastases

Currently, sSBRT is commonly limited to solitary, 2 contiguous or 3 non-contiguous vertebral levels because of concerns regarding setup accuracy, efficacy, and toxicity when 2-3 non-contiguous levels are treated. There is, however, a paucity of data regarding the clinical outcomes of multilevel sSBRT. LC and toxicity are particularly important endpoints to ensure that standard clinical target volume (CTV), planning target volume (PTV), and planning organ-at-risk volume (PRV) expansions are appropriate in the multilevel setting. We sought to compare efficacy and toxicities of single- vs multilevel (≥2-5) treatment in a cohort of patients with malignant spinal tumors. Radioresistant histologies, Bilsky grade 0 to 1 epidural spinal cord compression,5 and a life expectancy >6 mo. are treated by SBRT. Single level and Multi-level spinal SBRT are defined as sSBRT delivered to a malignant lesion spanning single and ≥2 contiguous vertebral levels. All patients underwent treatment rigid immobilization for C1-D4 targets / body fix immobilization for D5 and below targets. For intact cases, GTVs were delineated using the registered T1-weighted precontrast and postcontrast MRI sequences, with reference to additional diagnostic studies (PET and perfusion MRI). CTVs were expanded 2mm circumferentially to create PTVs, with the goal of≥95% PTV coverage with ≥100% of the prescription dose. For cord delineation done on either CT myelography / T2-weighted MRI fused to the planning CT with 1-mm cord PRV. The same PTV and PRV expansions were used regardless of surgical status or number of treated vertebral levels. All patients underwent multi-isocenter VMAT planning using dual arcs and treatment delivered on C-Arm Linac using 6 DOF robotics with pretreatment, Intrafraction and posttreatment imaging. We analyzed consecutive cases of sSBRT treated from 2013 to 2017. Time-to event outcomes for single-level and multilevel cases were compared using mixed effect Cox models and differences in toxicity rates were evaluated using linear mixed effect models. All models incorporate a patient-level random intercept to account for any within patient. There were 101 single-level and 84 multilevel sSBRT cases (2-5 continuous vertebral levels). One-year LC was 95% vs 85%, respectively. After adjusting for baseline covariates, dose delivered, and accounting for within-patient correlation, there was no significant difference in time to local failure (hazard ratio, HR 1.79 [0.59-5.4]; P = .30). Pain improved in 83.5% of the 139 initially symptomatic tumors. There were no significant differences in grade 2+ acute or late toxicities between single-level and multilevel sSBRT Multilevel sSBRT provides high rates of LC, similar to single-level treatment, without need for larger planning volume margins. Efforts to improve prognostication and case selection for multilevel sSBRT are warranted to ensure that the benefits of improved LC over palliative radiation are justified.

Time-Course Changes in Optic Nerve Head Blood Flow and Retinal Nerve Fiber Layer Thickness in Eyes with Open-angle Glaucoma

To determine whether decreased optic nerve head (ONH) blood flow (BF) precedes or follows decreased circumpapillary retinal nerve fiber layer thickness (cpRNFLT) in eyes with open-angle glaucoma (OAG). Retrospective, longitudinal study. This study followed up 350 eyes of 225 OAG patients for at least 2 years and collected data from each patient from at least 5 examinations obtained with laser speckle flowgraphy (LSFG) and OCT. In the superior, temporal, and inferior ONH quadrants, tissue area mean blur rate (MT), representing ONH tissue BF, was measured with LSFG, whereas cpRNFLT was measured with OCT. A multivariate linear mixed-effects model was used to identify potential predictors of faster MT decrease, adjusting for possible confounding factors. Based on these results, each quadrant of each patient was assigned a risk point if the quadrant was the superior or temporal, if patient age was older than the median (61 years), and if patient pulse rate was higher than median (74 beats per minute). The quadrants were then compared with a mixed-effects Cox model for MT and cpRNFLT changes, defined as a difference between the baseline value and the values from the latest 2 consecutive follow-up visits of more than 1.96× the corresponding coefficient of variation. Ophthalmic and systemic variables and MT and cpRNFLT in the superior, temporal, and inferior quadrants. The multivariate model showed that MT decrease was faster in older patients with higher pulse rate and slower in inferior quadrants (P < 0.05). Quadrants with 0 risk points showed primary cpRNFLT decrease (P= 0.048), 1-risk point quadrants showed simultaneous cpRNFLT and MT decrease (P= 0.260), and 2-risk point and 3-risk point quadrants showed primary MT decrease (P < 0.001). Older patients with higher pulse rate are at greater risk of a primary reduction in ONH tissue BF, that is, preceding cpRNFLT decrease, in the superior and temporal quadrants.

How Can Gene-Expression Information Improve Prognostic Prediction in TCGA Cancers: An Empirical Comparison Study on Regularization and Mixed Cox Models.

BackgroundPrevious cancer prognostic prediction models often consider only the most important transcriptomic expressions, and their power is limited. It is unknown whether prediction power can be further improved when additional transcriptomic information is incorporated.MethodsTo integrate transcriptomes, four models are compared based on 32 types of cancer in the Cancer Genome Atlas, including the general Cox model with only clinical covariates, the Cox model with a lasso penalty (coxlasso), the Cox model with an elastic net penalty (coxenet), and the mixed-effects Cox model (coxlmm). Furthermore, we partition the survival variance into the relative contribution of clinical and transcriptomic components within the framework of coxlmm. Finally, the influence of different numbers of genes was evaluated in the context of coxlmm.ResultsCompared with the clinical covariates–only Cox model, the average prediction gain was 2.4% for coxlasso, 4.2% for coxenet, and 7.2% for coxlmm across 16 low-censored cancers; a significant elevation of prediction power was observed for SARC, SKCM, LGG, PAAD, and HNSC. Similar findings were observed for all 32 cancers with the average prediction gain of 2.7, 3.8, and 5.8% for coxlasso, coxenet, and coxlmm. Coxlmm always had comparable or better prediction performance relative to coxlasso and coxenet with an average of 2.8% prediction improvement across the 16 low-censored cancers. In addition, it is shown that the predictive accuracy of coxlmm generally increases with the number of genes included. The survival variance partition analysis demonstrates that the transcriptomic contribution was higher for some cancers (e.g., LGG, CESC, PAAD, SKCM, and SARC) and lower for others (e.g., BRCA, COAD, KIRC, and STAD).ConclusionThis study demonstrates that the integration of transcriptomic information can substantially improve prognostic prediction accuracy, but the prediction performance is cancer-specific and varies across cancer types. It further reveals that gene expression exhibits distinct contributions to survival variation across cancers.

In-Hospital Use of Statins Is Associated with a Reduced Risk of Mortality among Individuals with COVID-19

SummaryStatins are lipid-lowering therapeutics with favorable anti-inflammatory profiles and have been proposed as an adjunct therapy for COVID-19. However, statins may increase the risk of SARS-CoV-2 viral entry by inducing ACE2 expression. Here, we performed a retrospective study on 13,981 patients with COVID-19 in Hubei Province, China, among which 1,219 received statins. Based on a mixed-effect Cox model after propensity score-matching, we found that the risk for 28-day all-cause mortality was 5.2% and 9.4% in the matched statin and non-statin groups, respectively, with an adjusted hazard ratio of 0.58. The statin use-associated lower risk of mortality was also observed in the Cox time-varying model and marginal structural model analysis. These results give support for the completion of ongoing prospective studies and randomized controlled trials involving statin treatment for COVID-19, which are needed to further validate the utility of this class of drugs to combat the mortality of this pandemic.

Sociodemographic moderation of the association between depression and stroke incidence in a retrospective cohort of 0.4 million primary care recipients with hypertension.

Previous research has suggested an association between depression and subsequent acute stroke incidence, but few studies have examined any effect modification by sociodemographic factors. In addition, no studies have investigated this association among primary care recipients with hypertension. We examined the anonymized records of all public general outpatient visits by patients aged 45+ during January 2007-December 2010 in Hong Kong to extract primary care patients with hypertension for analysis. We took the last consultation date as the baseline and followed them up for 4 years (until 2011-2014) to observe any subsequent acute hospitalization due to stroke. Mixed-effects Cox models (random intercept across 74 included clinics) were implemented to examine the association between depression (ICPC diagnosis or anti-depressant prescription) at baseline and the hazard of acute stroke (ICD-9: 430-437.9). Effect modification by age, sex, and recipient status of social security assistance was examined in extended models with respective interaction terms specified. In total, 396 858 eligible patients were included, with 9099 (2.3%) having depression, and 10 851 (2.7%) eventually hospitalized for stroke. From the adjusted analysis, baseline depression was associated with a 17% increased hazard of acute stroke hospitalization [95% confidence interval (CI) 1.03-1.32]. This association was suggested to be even stronger among men than among women (hazard ratio = 1.29, 95% CI 1.00-1.67). Depression is more strongly associated with acute stroke incidence among male than female primary care patients with hypertension. More integrated services are warranted to address their needs.

Extracorporeal Membrane Oxygenation Therapy for Critically Ill Coronavirus Disease 2019 Patients in Wuhan, China: A Retrospective Multicenter Cohort Study

Background: Currently, little in-depth evidence is known about the therapeutic considerations and the outcomes of extracorporeal membrane oxygenation (ECMO) therapy in coronavirus disease 2019 (COVID-19) patients. Methods: This retrospective multicenter cohort study included patients with COVID-19 and received ECMO therapy at seven designated hospitals in Wuhan, China. The patients were followed until April 30, 2020. The clinical characteristics, laboratory examinations, treatments, and outcomes were extracted from electronic medical records and compared between weaned and non-weaned ECMO patients. Logistic regression analyses were performed to identify the risk factors associated with unsuccessful ECMO weaning. Propensity score matching was used to match patients who received venovenous ECMO with those who received invasive mechanical ventilation (IMV)-only therapy. The primary endpoint, 60-day all-cause mortality after ICU admission during hospitalization, was compared using a mixed-effect Cox model. Findings: 88 patients received ECMO therapy were included in the descriptive study. Among them, 27 and 61 patients were and were not successfully weaned from ECMO, respectively. Additionally, 13, 11, and 61 patients were further weaned from IMV, discharged from hospital, or died during hospitalization, respectively. In the multivariate logistic regression analysis, a lymphocyte count ≤ 0·5 × 109/L and D-dimer concentration > 4 × the upper limit of normal at ICU admission, a peak PaCO2 > 60 mmHg at 24 hours before ECMO initiation, and no tracheotomy performed during the ICU stay were independently associated with lower odds of ECMO weaning. In the propensity score-matched analysis, the crude 60-day mortality rates were 67·1% in the ECMO group and 80·0% in the IMV group. A mixed-effect Cox model detected a lower hazard ratio for the primary endpoint in the ECMO group. Interpretation: Patients in Wuhan who received ECMO therapy had a relatively high mortality rate. This outcome may be largely attributable to resource-limited situations during the COVID-19 outbreak. In future, the presence of lymphocytopenia and higher D-dimer concentrations at ICU admission and hypercapnia at 24 hours before ECMO initiation could help to identify patients with a poor prognosis. Moreover, tracheotomy could facilitate weaning from ECMO. Despite the high mortality, ECMO was associated with improved outcomes relative to IMV-only therapy in critically ill COVID-19 patients. Funding Statement: This work was supported by grants from Emergent Key Projects for COVID-19 (NO. 2020kfyXGYJ091), the National Natural Science Foundation of China (NO. 81800256, 81873458, 81670050), and National Key Research and Development Program of China (2019YFC0121600). Declaration of Interests: The authors declare no competing interests for this study. Ethics Approval Statement: The institutional ethical committee of each participating hospital approved the study protocol and waived the requirement for informed patient consent.

Association of Inpatient Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Mortality Among Patients With Hypertension Hospitalized With COVID-19.

Use of ACEIs (angiotensin-converting enzyme inhibitors) and ARBs (angiotensin II receptor blockers) is a major concern for clinicians treating coronavirus disease 2019 (COVID-19) in patients with hypertension. To determine the association between in-hospital use of ACEI/ARB and all-cause mortality in patients with hypertension and hospitalized due to COVID-19. This retrospective, multi-center study included 1128 adult patients with hypertension diagnosed with COVID-19, including 188 taking ACEI/ARB (ACEI/ARB group; median age 64 [interquartile range, 55-68] years; 53.2% men) and 940 without using ACEI/ARB (non-ACEI/ARB group; median age 64 [interquartile range 57-69]; 53.5% men), who were admitted to 9 hospitals in Hubei Province, China from December 31, 2019 to February 20, 2020. In mixed-effect Cox model treating site as a random effect, after adjusting for age, gender, comorbidities, and in-hospital medications, the detected risk for all-cause mortality was lower in the ACEI/ARB group versus the non-ACEI/ARB group (adjusted hazard ratio, 0.42 [95% CI, 0.19-0.92]; P=0.03). In a propensity score-matched analysis followed by adjusting imbalanced variables in mixed-effect Cox model, the results consistently demonstrated lower risk of COVID-19 mortality in patients who received ACEI/ARB versus those who did not receive ACEI/ARB (adjusted hazard ratio, 0.37 [95% CI, 0.15-0.89]; P=0.03). Further subgroup propensity score-matched analysis indicated that, compared with use of other antihypertensive drugs, ACEI/ARB was also associated with decreased mortality (adjusted hazard ratio, 0.30 [95% CI, 0.12-0.70]; P=0.01) in patients with COVID-19 and coexisting hypertension. Among hospitalized patients with COVID-19 and coexisting hypertension, inpatient use of ACEI/ARB was associated with lower risk of all-cause mortality compared with ACEI/ARB nonusers. While study interpretation needs to consider the potential for residual confounders, it is unlikely that in-hospital use of ACEI/ARB was associated with an increased mortality risk.

Drug-Coated Balloon Angioplasty Versus Drug-Eluting Stent Implantation in Patients With Coronary Stent Restenosis

BackgroundIn patients with coronary in-stent restenosis (ISR) requiring reintervention, it is unclear if the choice of treatment should depend on whether the restenotic stent was a bare-metal stent (BMS) or a drug-eluting stent (DES). ObjectivesThis study aimed to assess the comparative efficacy and safety of the 2 most frequently used treatments — angioplasty with drug-coated balloon (DCB) and repeat stenting DES — in patients with BMS-and DES-ISR. MethodsThe DAEDALUS (Difference in Antirestenotic Effectiveness of Drug-Eluting Stent and Drug-Coated Balloon Angioplasty for the Occurrence of Coronary In-Stent Restenosis) study was a pooled analysis of individual patient data from all 10 existing randomized clinical trials comparing DCB angioplasty with repeat DES implantation for the treatment of coronary ISR. In this pre-specified analysis, patients were stratified according to BMS- versus DES-ISR and treatment assigned. The primary efficacy endpoint was target lesion revascularization (TLR) at 3 years. The primary safety endpoint was a composite of all-cause death, myocardial infarction, or target lesion thrombosis at 3 years. Primary analysis was performed by mixed-effects Cox models accounting for the trial of origin. Secondary analyses included nonparsimonious multivariable adjustment accounting also for multiple lesions per patient and 2-stage analyses. ResultsA total of 710 patients with BMS-ISR (722 lesions) and 1,248 with DES-ISR (1,377 lesions) were included. In patients with BMS-ISR, no significant difference between treatments was observed in terms of primary efficacy (9.2% vs. 10.2%; hazard ratio [HR]: 0.83; 95% confidence interval [CI]: 0.51 to 1.37) and safety endpoints (8.7% vs. 7.5%; HR: 1.13; 95% CI: 0.65 to 1.96); results of secondary analyses were consistent. In patients with DES-ISR, the risk of the primary efficacy endpoint was higher with DCB angioplasty than with repeat DES implantation (20.3% vs. 13.4%; HR: 1.58; 95% CI: 1.16 to 2.13), whereas the risk of the primary safety endpoint was numerically lower (9.5% vs. 13.3%; HR: 0.69; 95% CI: 0.47 to 1.00); results of secondary analyses were consistent. Regardless of the treatment used, the risk of TLR was lower in BMS- versus DES-ISR (9.7% vs. 17.0%; HR: 0.56; 95% CI: 0.42 to 0.74), whereas safety was not significantly different between ISR types. ConclusionsAt 3-year follow-up, DCB angioplasty and repeat stenting with DES are similarly effective and safe in the treatment of BMS-ISR, whereas DCB angioplasty is significantly less effective than repeat DES implantation in the treatment DES-ISR, and associated with a nonsignificant reduction in the primary composite safety endpoint. Overall, DES-ISR is associated with higher rates of treatment failure and similar safety compared with BMS-ISR.

Atrial Septal Aneurysm, Shunt Size, and Recurrent Stroke Risk in Patients With Patent Foramen Ovale

BackgroundIn patients with patent foramen ovale (PFO)–associated stroke, the presence of large shunt or atrial septal aneurysm (ASA) has been suggested to convey a high risk of stroke recurrence. ObjectivesThe purpose of this study was to assess the respective influence of PFO size and ASA status on stroke recurrence under medical therapy in patients with recent PFO-associated stroke without alternative cause. MethodsThe authors pooled individual patient data from 2 prospective observational studies and the medical arms of 2 randomized trials, in which shunt size and ASA status was assessed by independent reading of echocardiographic images. Associations between PFO anatomical features and recurrent ischemic stroke were assessed by mixed effects Cox models. ResultsOf 898 patients (mean age 45.3 years), 178 (19.8%) had ASA with large PFO, 71 (7.9%) ASA with nonlarge PFO, 397 (44.2%) large PFO without ASA, and 252 (28.1%) nonlarge PFO without ASA. Over a median follow-up of 3.8 years (interquartile range: 2.6 to 5.5 years), 47 (5.2%) patients experienced a recurrent stroke. There was a heterogeneity across studies for the association between PFO size and stroke recurrence (pinteraction = 0.01). In a model accounting for age, hypertension, antithrombotic therapy, and PFO anatomy, ASA was independently associated with recurrent stroke (adjusted hazard ratio: 3.27; 95% confidence interval: 1.82 to 5.86; p < 0.0001), whereas large PFO was not (average adjusted hazard ratio across studies: 1.43; 95% confidence interval: 0.50 to 4.03; p = 0.50). ConclusionsIn patients with PFO-associated stroke, ASA is a more important predictor of recurrent stroke than shunt size. These results can help to better identify those patients with a high risk of stroke recurrence under medical therapy who may derive the most benefit from PFO closure. (Patent Foramen Ovale Closure or Anticoagulants Versus Antiplatelet Therapy to Prevent Stroke Recurrence [CLOSE]; NCT00562289) (Device Closure versus Medical Therapy in Patients with Cryptogenic Stroke and High-Risk Patent Foramen Ovale [DEFENSE-PFO]; NCT01550588)

Urban green space and the risks of dementia and stroke

IntroductionIt is unknown whether urban green space is associated with reduced risk of major neurological conditions, especially dementia and stroke. MethodsRetrospective, population-based cohorts were created for each study outcome, including 1.7 and 4.3 million adults in Ontario, Canada for dementia and stroke, respectively. Residential green space was quantified using the satellite-derived Normalized Difference Vegetation Index. Incidence was ascertained using health administrative data with validated algorithms. Mixed-effects Cox models were used to estimate hazard ratios per interquartile range increase in green space exposure. ResultsBetween 2001 and 2013, 219,013 individuals were diagnosed with dementia and 89,958 had a stroke. The hazard ratio per interquartile range increase in green space was 0.97 (95% CI: 0.96–0.98) for dementia and 0.96 (0.95–0.98) for stroke. Estimates remained generally consistent in sensitivity analyses. DiscussionIncreased exposure to urban green space was associated with reduced incidence of dementia and stroke. To our knowledge, this is the first population-based cohort study to assess these relationships.

Ten-year outcomes after off-pump versus on-pump coronary artery bypass grafting: Insights from the Arterial Revascularization Trial

ObjectiveWe performed a post hoc analysis of the Arterial Revascularization Trial to compare 10-year outcomes after off-pump versus on-pump surgery. MethodsAmong 3102 patients enrolled, 1252 (40% of total) and 1699 patients received off-pump and on-pump surgery (151 patients were excluded because of other reasons); 2792 patients (95%) completed 10-year follow-up. Propensity matching and mixed-effect Cox model were used to compare long-term outcomes. Interaction term analysis was used to determine whether bilateral internal thoracic artery grafting was a significant effect modifier. ResultsOne thousand seventy-eight matched pairs were selected for comparison. A total of 27 patients (2.5%) in the off-pump group required conversion to on-pump surgery. The off-pump and on-pump groups received a similar number of grafts (3.2 ± 0.89 vs 3.1 ± 0.8; P = .88). At 10 years, when compared with on-pump, there was no significant difference in death (adjusted hazard ratio for off-pump, 1.1; 95% confidence interval, 0.84-1.4; P = .54) or the composite of death, myocardial infarction, stroke, and repeat revascularization (adjusted hazard ratio, 0.92; 95% confidence interval, 0.72-1.2; P = .47). However, off-pump surgery performed by low volume off-pump surgeons was associated with a significantly lower number of grafts, increased conversion rates, and increased cardiovascular death (hazard ratio, 2.39; 95% confidence interval, 1.28-4.47; P = .006) when compared with on-pump surgery performed by on–pump-only surgeons. ConclusionsThe findings showed that in the Arterial Revascularization Trial, off-pump and on-pump techniques achieved comparable long-term outcomes. However, when off-pump surgery was performed by low-volume surgeons, it was associated with a lower number of grafts, increased conversion, and a higher risk of cardiovascular death.

Abstract GS5-01: Residual cancer burden after neoadjuvant therapy and long-term survival outcomes in breast cancer: A multi-center pooled analysis

Abstract Background: Recent studies have demonstrated independent validation of the prognostic relevance of residual cancer burden (RCB) after neoadjuvant chemotherapy. However, a pooled subject-level analysis of multiple cohorts is needed to determine estimates of long-term prognosis for each class of RCB in each phenotypic subtype of breast cancer (BC) to better inform on patient outcomes. Also, a pooled subject-level analysis allows more detailed analyses of generalizability of the prognostic meaning of RCB assessments in a broader experience of practice settings. Method: Subject-level RCB results, with relevant clinical and pathologic stage, tumor subtype and grade, demographic, treatment and follow-up data from 11 institutes/trials are being collected for combined analysis. The association between the continuous RCB index and event-free survival (EFS), and distant recurrence free survival (DRFS) were assessed using mixed effect Cox models with the incorporation of random RCB coefficients to account for between-study heterogeneity. We will also allow for differences in baseline hazard across biological BC subtypes and, if needed, across studies as well. In addition to this stratified mixed effect model, a multivariate analysis adjusting for age, T-category, nodal status and grade was performed within each subtype. In addition, mixed effect Cox models will be employed to evaluate association between RCB index with EFS and DRFS within each HR/HER2 subtype. Kaplan Meier estimates of EFS and DRFS at 5 and 10 years were computed for each RCB class within subtype. Results: We analyzed subject-level data from 9 institutes/trials representing 4077 patients currently available from an anticipated final total of 4,800 patients (to be presented at the meeting). There were 950 EFS and 876 DRFS events during follow up (median 65 months, IQR: 70 months). RCB index (continuous) was independently prognostic within each subtype: HR+/HER2- (EFS HR (per unit increase in RCB index) =1.64, 95%CI 1.48-1.82; DRFS HR=1.68, 1.51-1.87), HR+/HER2+ (EFS HR=1.80, 1.57-2.05; DRFS HR=1.93, 1.67-2.24), HR-/HER2+ (EFS HR=2.15, 1.76-2.62; DRFS HR=2.10, 1.77-2.50), and HR-/HER2- (EFS HR=2.05, 1.89-2.22; DRFS HR=2.16, 1.90-2.46); and remained prognostic in multivariate models adjusting for age, grade, and clinical T and N stage at diagnosis. Table 1 contains the response rate and estimated EFS at 5 years and 10 years for each RCB class within each HR/HER2 phenotype (DRFS results were similar). Conclusions: Long-term prognosis after pCR was similarly excellent in all phenotypic subtypes. RCB index and classification was independently and strongly prognostic in all subtypes, and generalizable to multiple practice settings. Prognostic differences by RCB class occurred within 5 years in HR- BC, but extended to 10 years in HR+ BC. RCB-I had slightly worse EFS than pCR in HR- BC and HR+/HER2+ BC (after 5 years), but the same EFS as pCR in HR+/HER2- BC. Complete analysis of all subjects, including neoadjuvant treatments, will be presented at the meeting. PhenotypeOutcomepCRRCB-IRCB-IIRCB-IIIHR+/HER2-Frequency (%)11%10%52%27%(N=1467)5 yr EFS (95% CI)91% (86-96)93% (89-98)82% (79-85)70% (65-75)10 yr EFS (95% CI)84% (75-93)88% (82-95)71% (67-75)52% (46-58)HR+/HER2+Frequency (%)38%18%35%9%(N=762)5 yr EFS (95% CI)94% (91-97)93% (88-98)78% (73-84)49% (37-65)10 yr EFS (95% CI)91% (86-96)79% (70-90)65% (59-73)42% (29-60)HR-/HER2+Frequency (%)66%11%18%5%(N=550)5 yr EFS (95% CI)93% (90-96)88% (79-97)60% (50-71)45% (30-69)10 yr EFS (95% CI)90% (86-94)84% (74-95)56% (46-68)45% (30-69)HR-/HER2-Frequency (%)41%13%33%13%(N=1293)5 yr EFS (95% CI)92% (90-94)85% (79-91)68% (63-72)28% (21-36)10 yr EFS (95% CI)87% (82-91)80% (72-88)63% (58-68)24% (18-33) Citation Format: Christina Yau, Marieke van der Noordaa, Jane Wei, Marie Osdoit, Fabien Reyal, Anne-Sophie Hamy, Marick Lae, Miguel Martin, Maria del Monte, I-SPY 2 TRIAL Consortium, Judy C Boughey, Rebekah Gould, Jelle Wesseling, Tessa Steenbruggen, Maartje van Seijen, Gabe Sonke, Stephen Edge, Stephen-John Sammut, Elena Provenzano, Jean Abraham, Peter Hall, Ashley Graham, Lorna Mackintosh, David Cameron, Alice Wang, Priyanka Sharma, Kimberly Cole, Lajos Pusztai, Mi-Ok Kim, Laura van ‘t Veer, Laura Esserman, W. Fraser Symmans. Residual cancer burden after neoadjuvant therapy and long-term survival outcomes in breast cancer: A multi-center pooled analysis [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS5-01.

Local Control and Toxicity of Multilevel Spine Stereotactic Body Radiotherapy.

Spine stereotactic body radiotherapy (sSBRT) is commonly limited to 1 or 2 vertebral levels given a paucity of efficacy and toxicity data when more than 2 levels are treated. To prove our hypothesis that multilevel sSBRT could provide similar rates of local control (LC) (primary endpoint) and toxicity as single-level treatment using the same clinical target, planning target, and planning organ-at-risk volumes. We analyzed consecutive cases of sSBRT treated from 2013 to 2017. Time-to-event outcomes for single-level and multilevel cases were compared using mixed effect Cox models and differences in toxicity rates were evaluated using linear mixed effect models. All models incorporate a patient-level random intercept to account for any within-patient correlation across cases. There were 101 single-level and 84 multilevel sSBRT cases (2-7 continuous vertebral levels). One-year LC was 95% vs 85%, respectively. After adjusting for baseline covariates, dose delivered, and accounting for within-patient correlation, there was no significant difference in time to local failure (hazard ratio, HR 1.79 [0.59-5.4]; P=.30). Pain improved in 83.5% of the 139 initially symptomatic tumors. There were no significant differences in grade 2+acute or late toxicities between single-level and multilevel sSBRT. With rigorous patient immobilization, quality assurance, and image guidance, multilevel sSBRT provides high rates of LC, similar to single-level treatment, without need for larger planning volume margins. Efforts to improve prognostication and case selection for multilevel sSBRT are warranted to ensure that the benefits of improved LC over palliative radiation are justified.

Residential surrounding greenspace and the age at menopause

TPS 702: Green space and population health, Exhibition Hall, Ground floor, August 28, 2019, 3:00 PM - 4:30 PM Background / Aim: Menopause is associated with a number of adverse health effects and its timing has been reported to be influenced by several lifestyle factors. Whether greenspace exposure is associated with age at menopause has not yet been investigated. The aim was to investigate whether residential surrounding greenspace is associated with the age at menopause and thus reproductive aging. Methods: This longitudinal study was based on the 20-year follow-up of 1955 aging women from a large, population-based European cohort (ECRHS). Residential surrounding greenspace was abstracted as the average of satellite-based Normalized Difference Vegetation Index (NDVI) across a circular buffer of 300m around the residential addresses of each participant during the course of the study. We applied mixed effects Cox models with centre as random effect, menopause as the survival object, age as time indicator and residential surrounding greenspace as predictor. All models were adjusted for smoking habit, BMI, parity, age at menarche, ever-use of contraception and age at completed full-time education as socio-economic proxy. Results: An increase of one interquartile range of residential surrounding greenspace was associated with a 13% lower risk of being menopausal [Hazard Ratio 0.87 (95% Confidence Interval 0.79 – 0.95)]. Correspondingly the predicted median age at menopause was 1.4 years older in the highest compared to the lowest NDVI quartile. Conclusions: Living in greener neighbourhoods is associated with older age at menopause and might therefore decelerate reproductive aging. These are novel findings with broad implications. Further studies are required to replicate our findings while exploring the potential mechanisms underlying this association.

Pre-apneic capnography waveform abnormalities during procedural sedation and analgesia.

Capnography monitoring is recommended for use during procedural sedation. This study examined associations between capnography waveform abnormalities and the onset of apnea. Capnography waveforms from a sample of 102 participants undergoing moderate procedural sedation with bolus doses of midazolam and fentanyl were analyzed using a mixed effects Cox model. Patients were at increased risk of apnea (classified as end-tidal carbon dioxide concentration of zero) while demonstrating a capnography waveform abnormality classified as hypopnea (more than 10% increase or decrease from baseline end-tidal carbon dioxide concentration) (Hazard Ratio 2.14; 95% CI 1.75 to 2.62). Risk of apnea was not increased during capnography waveform abnormalities classified as bradypnea (capnography-derived respiratory rate less than 8 breaths/min) (Hazard Ratio 0.64; 95% CI 0.33 to 1.25). These estimates were similar when apneic episodes were defined as only those that lasted more than 20 s duration. Deciphering which capnography waveform abnormalities should promote intervention (and therefore alarms to signal the event to clinicians) from those that do not is an essential step towards successful implementation of this technology into practice. Our results indicate that using information about the history of previous capnography waveform abnormalities may be a promising solution to assist prediction of apneic episodes.

Residential surrounding greenspace and age at menopause: A 20-year European study (ECRHS)

BackgroundMenopause is associated with a number of adverse health effects and its timing has been reported to be influenced by several lifestyle factors. Whether greenspace exposure is associated with age at menopause has not yet been investigated. ObjectiveTo investigate whether residential surrounding greenspace is associated with age at menopause and thus reproductive aging. MethodsThis longitudinal study was based on the 20-year follow-up of 1955 aging women from a large, population-based European cohort (ECRHS). Residential surrounding greenspace was abstracted as the average of satellite-based Normalized Difference Vegetation Index (NDVI) across a circular buffer of 300 m around the residential addresses of each participant during the course of the study. We applied mixed effects Cox models with centre as random effect, menopause as the survival object, age as time indicator and residential surrounding greenspace as time-varying predictor. All models were adjusted for smoking habit, body mass index, parity, age at menarche, ever-use of contraception and age at completed full-time education as socio-economic proxy. ResultsAn increase of one interquartile range of residential surrounding greenspace was associated with a 13% lower risk of being menopausal (Hazard Ratio: 0.87, 95% Confidence Interval: 0.79–0.95). Correspondingly the predicted median age at menopause was 1.4 years older in the highest compared to the lowest NDVI quartile. Results remained stable after additional adjustment for air pollution and traffic related noise amongst others. ConclusionsLiving in greener neighbourhoods is associated with older age at menopause and might slow reproductive aging. These are novel findings with broad implications. Further studies are needed to see whether our findings can be replicated in different populations and to explore the potential mechanisms underlying this association.

Interaction effects between the agglomerative externalities affecting the survival of small startups

AbstractThe purpose of this study is to identify the relationship between the survival of firms and the influence of agglomeration economies on firm location using a mixed effect Cox model considering random effects, given the industrial conditions of South Korea. Each agglomerative externality had a negative effect on the survival proportion of small startups except the related variety of the tertiary sector. However, the interaction effects between each externality and the location potential and among agglomerative externalities mostly played a complementary role to the survivability of startups; however certain effects reduced the survivability, and the effects were differentiated for each industrial sector. This study provides an advanced understanding of small firm performance after entry into the market in developing and developed nations.

Patterns of peritoneal dialysis catheter practices and technique failure in peritoneal dialysis: A nationwide cohort study.

IntroductionOur objective was to assess whether clusters of centers with similar peritoneal dialysis (PD) catheter related practices were associated with differences in the risk of technique failure.MethodsPatients on incident PD in French centers contributing to the French Language PD Registry from 2012 to 2016 were included in a retrospective analysis of prospectively collected data. Centers with similar catheter cares practices were gathered in clusters in a hierarchical analysis. Clusters of centers associated with technique failure were evaluated using Cox and Fine and Gray models. A mixed effect Cox model was used to assess the influence of a center effect, as explained by the clusters.ResultsData from 2727 catheters placed in 64 centers in France were analyzed. Five clusters of centers were identified. After adjustment for patient-level characteristics, the fourth cluster was associated with a lower risk of technique failure (cause specific-HR 0.70, 95%CI 0.54–0.90. The variance of the center effect decreased by 5% after adjusting for patient characteristics and by 26% after adjusting for patient characteristics and clusters of centers in the mixed effect Cox model. Favorable outcomes were observed in clusters with a greater proportion of community hospitals, where catheters were placed via open surgery, first dressing done 6 to 15 days after catheter placement, and local prophylactic antibiotics was applied on exit-site.ConclusionSeveral patterns of PD catheter related practices have been identified in France, associated with differences in the risk of technique failure. Combinations of favorable practices are suggested in this study.