Meta-analysis Of Patient-level Data Research Articles

Patient-Level Meta-analysis of Clofarabine in Acute Lymphoblastic Leukemia.

Clofarabine monotherapy at a dose of 52mg/m2 per day was approved in the USA in 2004 for the treatment of relapsed or refractory acute lymphoblastic leukemia (R/R ALL) in patients aged 1-21years after at least two prior regimens. To address a post-marketing requirement for additional evidence of the clinical benefit of clofarabine in its approved indication, a meta-analysis of patient-level data was conducted. A systematic literature review was conducted, using the Dr.Evidence software platform, DOC Search, and Embase, to identify clinical trials with patients with R/R ALL who received clofarabine monotherapy at 52mg/m2. The primary endpoint was complete remission (CR). Secondary endpoints were overall remission (OR, defined by CR or CR with either incomplete platelet recovery or incomplete neutrophil and platelet recovery), duration of response, overall survival (OS), and safety. A total of 754 patients in 12 clinical studies were analyzed including 682 patients with R/R ALL treated with clofarabine monotherapy at 52mg/m2; of them, 374 were aged < 22years (pediatric population). Rates of CR and OR were 16% (95% confidence interval [CI] 7, 26) and 28% (95%CI 20, 37), respectively, in the pediatric population and 12% (95%CI 5, 21) and 21% (95%CI 13, 31) in the overall population. Median OS (evaluable in three studies in pediatric patients) was 3.7months (95%CI 0.1, 31.4), reaching 10.1months (95%CI 0.3, 68.9) for those achieving OR. Sensitivity analyses supported these findings. The most frequent grade3-4 adverse events were liver abnormalities, anemia, diarrhea, and febrile neutropenia. In this meta-analysis, CR duration and median OS in pediatric patients with R/R ALL appeared to be slightly longer than in the phaseII study. No new safety signals were identified. Results support the use of clofarabine monotherapy in its approved indication.

Impact of Post-PCI FFR Stratified by Coronary Artery

BackgroundLow fractional flow reserve (FFR) after percutaneous coronary intervention (PCI) has been associated with adverse clinical outcomes. Hitherto, this assessment has been independent of the epicardial vessel interrogated. ObjectivesThis study sought to assess the predictive capacity of post-PCI FFR for target vessel failure (TVF) stratified by coronary artery. MethodsWe performed a systematic review and individual patient-level data meta-analysis of randomized clinical trials and observational studies with protocol-recommended post-PCI FFR assessment. The difference in post-PCI FFR between left anterior descending (LAD) and non-LAD arteries was assessed using a random-effect models meta-analysis of mean differences. TVF was defined as a composite of cardiac death, target vessel myocardial infarction, and clinically driven target vessel revascularization. ResultsOverall, 3,336 vessels (n = 2,760 patients) with post-PCI FFR measurements were included in 9 studies. The weighted mean post-PCI FFR was 0.89 (95% CI: 0.87-0.90) and differed significantly between coronary vessels (LAD = 0.86; 95% CI: 0.85 to 0.88 vs non-LAD = 0.93; 95% CI: 0.91-0.94; P < 0.001). Post-PCI FFR was an independent predictor of TVF, with its risk increasing by 52% for every reduction of 0.10 FFR units, and this was mainly driven by TVR. The predictive capacity for TVF was poor for LAD arteries (AUC: 0.52; 95% CI: 0.47-0.58) and moderate for non-LAD arteries (AUC: 0.66; 95% CI: 0.59-0.73; LAD vs non-LAD arteries, P = 0.005). ConclusionsThe LAD is associated with a lower post-PCI FFR than non-LAD arteries, emphasizing the importance of interpreting post-PCI FFR on a vessel-specific basis. Although a higher post-PCI FFR was associated with improved prognosis, its predictive capacity for events differs between the LAD and non-LAD arteries, being poor in the LAD and moderate in the non-LAD vessels.

Comorbidities and clinical response to cardiac resynchronization therapy: Patient-level meta-analysis from eight clinical trials.

Patients with heart failure usually have several other medical conditions that might alter the effects of interventions. We investigated whether the burden of comorbidity modified the clinical response to cardiac resynchronization therapy (CRT). Original patient-level data from eight randomized trials exploring the effects of CRT versus no CRT were pooled (BLOCK-HF, MIRACLE, MIRACLE-ICD, MIRACLE-ICD II, RAFT, COMPANION, MADIT-CRT and REVERSE). A prior history of the following comorbidities was considered: episodic or persistent atrial fibrillation (n = 920), coronary artery disease (n = 3732), diabetes (n = 2171), and hypertension (n = 3353). Patients were classified into three groups based on the number of comorbidities: 0, 1-2, or ≥3. The outcomes of interest were time to all-cause mortality and time to the composite outcome of heart failure hospitalization (HFH) or all-cause mortality. Outcomes were evaluated within each comorbidity group using a Bayesian hierarchical Weibull survival regression model. Of 6324 patients, 970 (15%) had no comorbidities, 4052 (64%) had 1-2 and 1302 (21%) had ≥3 comorbidities. The adjusted hazard ratio (aHR) for CRT versus no CRT for all-cause mortality in the overall cohort was 0.79 (95% credible interval [CI] 0.68-0.93) (p = 0.010); for no comorbidities the aHR was 0.54 (95% CI 0.34-0.86), for 1-2 comorbidities was 0.81 (95% CI 0.67-0.97) and for ≥3 comorbidities was 0.83 (95% CI 0.64-1.07) (no significant interaction between CRT and comorbidity burden: p = 0.13). For the endpoint of HFH or all-cause mortality, the aHR for the overall cohort was 0.74 (95% CI 0.65-0.84) (p = 0.001), for no comorbidities was 0.69 (95% CI 0.50-0.94), for 1-2 comorbidities was 0.77 (95% CI 0.66-0.90) and for ≥3 comorbidities was 0.68 (95% CI 0.55-0.82) (no significant interaction between CRT and comorbidity burden: p = 0.081). In a meta-analysis of patient-level data from eight major trials, the totality of evidence suggests that CRT reduces HFH and/or all-cause mortality even when several comorbid diseases are present. NCT00271154, NCT00251251, NCT00267098, NCT00180271.

Prognostic value of pathogenic variants in Lafora Disease: systematic review and meta-analysis of patient-level data

BackgroundLafora disease (LD) is a fatal form of progressive myoclonic epilepsy caused by biallelic pathogenic variants in EPM2A or NHLRC1. With a few exceptions, the influence of genetic factors on disease progression has yet to be confirmed. We present a systematic review and meta-analysis of the known pathogenic variants to identify genotype–phenotype correlations.MethodsWe collected all reported cases with genetically-confirmed LD containing data on disease history. Pathogenic variants were classified into missense (MS) and protein-truncating (PT). Three genotype classes were defined according to the combination of the variants: MS/MS, MS/PT, and PT/PT. Time-to-event analysis was performed to evaluate survival and loss of autonomy.Results250 cases described in 70 articles were included. The mutated gene was NHLRC1 in 56% and EPM2A in 44% of cases. 114 pathogenic variants (67 EPM2A; 47 NHLRC1) were identified. The NHLRC1 genotype PT/PT was associated with shorter survival [HR 2.88; 95% CI 1.23–6.78] and a trend of higher probability of loss of autonomy [HR 2.03, 95% CI 0.75–5.56] at the multivariable Cox regression analysis. The population carrying the homozygous p.Asp146Asn variant of NHLRC1 genotype was confirmed to have a more favourable prognosis in terms of disease duration.ConclusionsThis study demonstrates the existence of prognostic genetic factors in LD, namely the genotype defined according to the functional impact of the pathogenic variants. Although the reasons why NHLRC1 genotype PT/PT is associated with a poorer prognosis have yet to be fully elucidated, it may be speculated that malin plays a pivotal role in LD pathogenesis.

12-Month Effectiveness and Tolerability of Brivaracetam in the Real-World: The International EXPERIENCE Pooled Analysis (P11-1.003)

12-Month Effectiveness and Tolerability of Brivaracetam in the Real-World: The International EXPERIENCE Pooled Analysis (P11-1.003)

Surgical Management of Hirayama Disease (Monomelic Amyotrophy): Systematic Review and Meta-Analysis of Patient-Level Data.

Hirayama disease or juvenile-onset monomelic amyotrophy is a clinical syndrome that disproportionately affects young males. Standard of care revolves around conservative management, but some patients experience disease progression that may benefit from surgical intervention. Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a systematic review of previous reports of surgical treatment for Hirayama disease was performed. Studies were included if they provided individual patient-level data, described the clinical presentation and surgical intervention, and reported neurological improvement at last follow-up. Comparison between those who improved and those with stable symptoms at last follow-up was performed. Decision-tree analysis was used to identify the best predictors of neurological improvement by last follow-up. Of 624 unique articles, 30 were included in the qualitative review and 23 in the meta-analysis. Among the 70 patients in the meta-analysis, mean age was 21.2±6.3years, 91% were male, and mean symptom duration at presentation was 43.3±61.8months. Fifty-nine patients (84.3%) had improvement in their neurological symptoms by last follow-up. Univariable analysis showed the only significant predictor of improvement in neurological symptoms by last follow-up was the use of stabilization-alone versus decompression with or without stabilization. Baseline clinical symptoms nor radiographic features predicted outcome. Decision-tree analysis showed surgical strategy (stabilization-alone vs. decompression±stabilization), age (<20 vs. ≥20), and surgical approach (anterior-only vs. posterior-only or anterior-posterior) predicted a higher likelihood of neurological improvement by last follow-up. Nearly 85% of patients experienced improvement in neurological symptoms. Improvement was best for those who underwent stabilization-alone, and decision-tree analysis suggested that the likelihood of improvement was also superior for patients under 20years of age and those treated with an anterior versus posterior or staged approach.

Patient-level data meta-analysis of a multi-modal artificial intelligence (MMAI) prognostic biomarker in high-risk prostate cancer: Results from six NRG/RTOG phase III randomized trials.

299 Background: Recently, an MMAI prognostic biomarker, ArteraAI Prostate, was trained and validated in localized prostate cancer to more accurately risk stratify patients for multiple endpoints compared to NCCN risk groups (Esteva et al., 2022). Prognostication within an NCCN risk group remains clinically important given the multiple treatment decisions required within each risk group (e.g., radiotherapy dose or hormone therapy use). Herein, we validated the MMAI biomarker in high-risk prostate cancer where an increasing number of therapeutic decisions is required. Methods: This study leveraged histopathology image and clinical data from patients with at least one high-risk feature (HRF; cT3-cT4, Gleason 8-10, PSA &gt; 20 ng/mL, primary Gleason pattern 5) from six NRG/RTOG phase III randomized trials (n=1,088). Patients from two trials not part of the initial MMAI biomarker training/validation (RTOG 0521 [n=344] and 9902 [n=318]) and the MMAI validation cohort (RTOG 9202, 9408, 9413, and 9910 [n=426]) were included. Fine-Gray, cumulative incidence, and time dependent area under the curve (tdAUC) analyses were performed for time to distant metastasis (DM) and prostate cancer-specific mortality (PCSM) for standard clinicopathologic variables (age, PSA, Gleason score, T-stage, number of HRFs) and the MMAI model, as a continuous score (per standard deviation increase) and categorically by quartile. Death from other causes were treated as competing risks. Results: The analyzed cohort had a median follow-up of 10.4 years. Median PSA was 21 ng/mL, 60% had Gleason 8-10 disease, 37% had cT3-T4 disease, and 20% were African American. On univariable analysis, the MMAI model was significantly associated with DM (subdistribution hazard ratio [sHR] 2.05, 95% CI 1.74-2.43, p&lt;0.001) and PCSM (sHR 2.04, 95% CI 1.73-2.42, &lt;0.001). On multivariable analysis, the MMAI model, adjusting for either age, PSA, Gleason score, T-stage, or number of HRFs, was the only variable significantly associated with DM. TdAUC was highest for the MMAI biomarker for both 5-year DM (0.71), compared to PSA (0.56), Gleason score (0.61), T-stage (0.63), or number of HRFs (0.64), and for 5-year PCSM (0.75), compared to clinicopathologic variables (range 0.53-0.63). The estimated 10-year DM and 15-year PCSM rates for MMAI quartile 1 vs 4 were 8% vs 31% and 8% vs 34%, respectively. Conclusions: Our novel MMAI prognostic biomarker was successfully validated across six phase III randomized trials with long-term follow-up to be independently prognostic over standard clinical and pathologic variables for men with high-risk prostate cancer. Despite all patients having high-risk disease, the MMAI biomarker identified those with highly variable risks for DM and PCSM. This tool can help enable personalized, shared decision making for patients and providers.

Efficacy of deep brain stimulation for the treatment of anorexia nervosa: a systematic review and network meta-analysis of patient-level data.

Deep brain stimulation (DBS) has been approved as a therapy for movement disorders and obsessive-compulsive disorder. Recently, DBS has been studied in patients with anorexia nervosa (AN), which is a debilitating and life-threatening psychiatric disorder. Several stimulation locations have been tested without a clear indication of the best region. In this systematic review and network meta-analysis, the authors used patient-level data to identify stimulation targets with the greatest evidence for efficacy in increasing body mass index (BMI). A systematic search was performed on or before August 4, 2022, using PubMed/MEDLINE, Ovid, and Scopus. Articles were included if patient-level data were presented, patients were diagnosed with AN and treated with DBS, and 6 months or more of postoperative follow-up data were reported. Quality and risk of bias were assessed with the NIH assessment tools. Patient data were collected and stratified by stimulation location. A network meta-analysis was performed. This review was written in accordance with PRISMA guidelines for systematic reviews. Eleven studies consisting of 36 patients were included. The mean age and BMI at the time of surgery were 38.07 (SD 11.64) years and 12.58 (SD 1.4) kg/m2, respectively. After 6 months of DBS, a significant difference in percentage change in BMI was found between the nucleus accumbens and subcallosal cingulate cortex (SCC) (SMD 0.78; 95% CI 0.10, 1.45) and between the SCC and ventral anterior limb of the internal capsule (SMD -1.51; 95% CI -2.39, -0.62). Similarly, at 9-12 months, a significant difference in percentage change in BMI was found between the SCC and ventral anterior limb of the internal capsule (SMD -1.18; 95% CI -2.21, -0.15). With hierarchical ranking, this study identified SCC as the most supported stimulation location for BMI change at 6 and 9-12 months (P-scores 0.9449 and 0.9771, respectively). Several DBS targets have been tested for AN, and this study identified the SCC as the most supported region for BMI change. However, further studies with blinded on/off periods are necessary to confirm this finding.

Development and validation of a decision support tool for the diagnosis of acute heart failure: systematic review, meta-analysis, and modelling study

ObjectivesTo evaluate the diagnostic performance of N-terminal pro-B-type natriuretic peptide (NT-proBNP) thresholds for acute heart failure and to develop and validate a decision support tool that combines NT-proBNP concentrations with...

Antihypertensive drug effects on long-term blood pressure: an individual-level data meta-analysis of randomised clinical trials

ObjectiveEvidence from randomised trials of pharmacological treatments on long-term blood pressure (BP) reduction is limited. We investigated the antihypertensive drug effects on BP over time and across different participant characteristics.MethodsWe...

Decreases in Suicidality Following Psychedelic Therapy: A Meta-Analysis of Individual Patient Data Across Clinical Trials.

Objective: Suicide is a global health concern, and innovative interventions that target suicidality are needed. While psychedelic therapy shows promise for a range of mental health concerns, including suicidality, not all psychedelic therapy trials have published their suicidality results and no meta-analysis has been published on the topic. Therefore, we completed the first meta-analysis of patient-level data on the effects of psychedelics on suicidality.Data Sources: We conducted a systematic search of MEDLINE, PsycINFO, and PubMed for all psychedelic therapy clinical trials (last search: November 5, 2020).Study Selection: We identified all psychedelic therapy trials that included a measure or measure-item that assesses suicidality.Data Extraction: Suicidality data were requested from study authors and extracted using a data extraction form developed for this study.Results: We identified 8, and successfully collected data from 7, relevant trials. Analysis of standardized mean differences (SMDs) indicated that, relative to baseline, psychedelic therapy was associated with large effect sizes for acute (80-240 min) and sustained (1 day, 1-8 weeks, and 3-4 months) decreases in suicidality (SMD range = -1.48 to -2.36; 95% CI range, -4.30 to 0.23). At 6 months, the effect size was medium (SMD = -0.65; 95% CI, -1.14 to -0.16). Reductions in suicidality were significant at all time points except for 7-8 weeks. Acute and post-acute elevations in suicidality were rare (6.5% and 3.0%, respectively).Conclusions: Limitations include heterogeneous samples and interventions, as well as limited sample size and number of studies. Results provide preliminary support for the safety of psychedelic therapy and its positive effect on suicidality. Controlled trials that specifically evaluate the effect of psychedelic therapy on suicidality may be warranted.

Immune-related acute myocarditis in patients treated with immune checkpoints inhibitors: Systematic review with individual patient-level data meta-analysis.

e24096 Background: Immune checkpoint inhibitors can sometimes lead to fatal outcomes or significant morbidity due to immune-related adverse events (IRAE). Cardiac IRAE, especially myocarditis, are among the most fatal IRAE. There are scarce of the trials addressing the optimal therapeutic approaches for patients with IR-myocarditis. Initial therapy with high-dose steroids (1000 mg of prednisolone for 3-5 days) may be beneficial for many patients with this IRAE and this approach is endorsed by NCCN guidelines. We conducted a systematic review with individual patient-level data meta-analysis of published clinical cases to assess impact of various initial therapeutic modalities and adherence to NCCN guidelines on outcomes of immune-related myocarditis, associated with checkpoint inhibitors. Methods: We searched PubMed database for all full-text articles and abstracts on the treatment of patients with cardiac-related IRAE treated with various PD-1/PD-L1 or CTLA-4 inhibitors for years between 2012 and 2020 in English. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) tool was used to ensure transparent reporting. Main study inclusion criteria were: 1) morphologically confirmed immune-related myocarditis or highly clinically suspected autoimmune myocarditis (based on Bonaca et al, 2019 criteria); 2) clear association of IRAE and administration of check-point inhibitors; 3) availability of individual patient and treatment data. Pooled analysis of outcomes and multiple logistic regression analysis were conducted. The primary outcome of this study was rate of major cardiac adverse events (MACE) due to immune-related autoimmune myocarditis according to adherence to NCCN guidelines. MACE was defined as death or persisting significant disabilities due to myocarditis (ie, chronic heart failure, rhythm abnormalities or deterioration leading to impossibility of further anticancer treatment). Results: We identified 277 articles and screened them for title and abstract. After the review process we selected 81 studies for further analysis which described treatment course for 111 patients. Overall, 26 and 85 patients were treated with high-dose and non-high dose steroids. Among patients treated high-dose steroids therapy and non-high dose steroids 10 (38.5%) and 57 (67.1%) of patients respectively experienced MACE (HR 0.185; 95% CI 0.07-0.47; p = 0.0091). Initial treatment failure was associated with high rate of morbidity; however, 9 patients were rescued with various immunosuppressive drugs (eg, tacrolimus, alemtuzumab, tocilizumab). Conclusions: Our results support use of high-dose pulse therapy as a preferred therapeutic approach for all patients with suspected or proven immune-related myocarditis.

Association of Germline BRCA Pathogenic Variants With Diminished Ovarian Reserve: A Meta-Analysis of Individual Patient-Level Data.

To determine whether germline BRCA (gBRCA) pathogenic variants are associated with decreased ovarian reserve. An individual patient-level data meta-analysis was performed using five data sets on 828 evaluable women who were tested for gBRCA. Of those, 250 carried gBRCA, whereas 578 had tested negative and served as controls. Of the women with gBRCA, four centers studied those affected with breast cancer (n = 161) and one studied unaffected individuals (n = 89). The data were adjusted for the center, age, body mass index, smoking, and oral contraceptive pill use before the final analysis. Anti-Müllerian hormone (AMH) levels in affected women were drawn before presystemic therapy. The mean age of women with versus without gBRCA1/2 (34.1 ± 4.9 v 34.3 ± 4.8 years; P = .48) and with gBRCA1 versus gBRCA2 (33.7 ± 4.9 v 34.6 ± 4.8 years; P = .16) was similar. After the adjustments, women with gBRCA1/2 had significantly lower AMH levels compared with controls (23% lower; 95% CI, 4 to 38; P = .02). When the adjusted analysis was limited to affected women (157 with gBRCA v 524 without, after exclusions), the difference persisted (25% lower; 95% CI, 9 to 38; P = .003). The serum AMH levels were lower in women with gBRCA1 (33% lower; 95% CI, 12 to 49; P = .004) but not gBRCA2 compared with controls (7% lower; 95% CI, 31% lower to 26% higher; P = .64). Young women with gBRCA pathogenic variants, particularly those affected and with gBRCA1, have lower serum AMH levels compared with controls. They may need to be preferentially counseled about the possibility of shortened reproductive lifespan because of diminished ovarian reserve.

STRATIFIED EFFECTS OF BLOOD PRESSURE-LOWERING TREATMENT ON LONG-TERM BLOOD PRESSURE: A META-ANALYSIS OF INDIVIDUAL-LEVEL DATA OF 334,219 PARTICIPANTS FROM 50 RANDOMIZED TRIALS

Objective: Evidence on the magnitude of blood pressure (BP)-lowering treatment effects in large-scale randomised clinical trials is limited but is pertinent for explaining treatment effects on cardiovascular outcomes and for policy planning. We determined the effects of BP-lowering treatment on long-term BP overall and across important patient subgroups defined by their characteristics. Design and method: We conducted a one-stage individual patient-level data meta-analysis (N = 50 trials). We analysed data separately by trial design, and fitted mixed models (with fixed treatment effects, fixed time effect, random intercepts at trial and participant level, and a random slope for time at participant level). Models were adjusted for age, sex and baseline BP (except when used as stratification factor) and compared using likelihood ratio test and Akaike information criterion. Results: The analysis included 334,219 (42% women) participants with mean age = 65 years, and among whom 18% were current smokers, 47% had CVD, 29% had diabetes, and 73% were previously on BP-lowering medication. Over 4 years of follow-up, participants had an average of 8 BP measurements. For BP-lowering intensity trials (N = 8), mean differences (95% confidence interval) in systolic BP (SBP) and diastolic BP (DBP) between comparison arms were 8.2 (8.0 to 8.4) mmHg and 3.7 (3.6 to 3.9) mmHg, respectively, for placebo-controlled trials (N = 21) the SBP and DBP differences were 4.2 (4.0 to 4.3) mmHg and DBP 1.9 (1.9 to 2.0) mmHg, respectively, and for drug comparison trials (N = 28) the SBP and DBP differences were 1.3 (1.2 to 1.3) mmHg and 0.5 (0.5 to 0.5) mmHg, respectively. The reduction in BP differed by follow-up duration and patient characteristics, particularly for placebo-controlled and BP-lowering intensity trials, which showed substantial heterogeneity in BP reductions according to baseline BP, age, sex, prior CVD, diabetes and non-randomised anti-hypertensive use. Conclusions: Pharmacologic agents are effective in reducing long-term BP across individuals with different characteristics. In large-scale trials, the magnitude of BP reduction varied by several patient characteristics, which could have implications on interpretation of any differential effects of BP treatment on major clinical outcomes.

Validation of the Rule of 7's for Identifying Children at Low-risk for Lyme Meningitis.

The Rule of 7's classifies children as low-risk for Lyme meningitis with the absence of the following: ≥7 days of headache, any cranial neuritis or ≥70% cerebrospinal fluid mononuclear cells. We sought to broadly validate this clinical prediction rule in children with meningitis undergoing evaluation for Lyme disease. We performed a patient-level data meta-analysis of 2 prospective and 2 retrospective cohorts of children ≤21 years of age with cerebrospinal fluid pleocytosis who underwent evaluation for Lyme disease. We defined a case of Lyme meningitis with a positive 2-tier serology result (positive or equivocal first-tier enzyme immunoassay followed by a positive supplemental immunoblot). We applied the Rule of 7's and report the accuracy for the identification of Lyme meningitis. Of 721 included children with meningitis, 178 had Lyme meningitis (24.7%) and 543 had aseptic meningitis (75.3%). The pooled data from the 4 studies showed the Rule of 7's has a sensitivity of 98% [95% confidence interval (CI): 89%-100%, I2 = 71%], specificity 40% (95% CI: 30%-50%, I2 = 75%), and a negative predictive value of 100% (95% CI: 95%-100%, I2 = 55%). The Rule of 7's accurately identified children with meningitis at low-risk for Lyme meningitis for whom clinicians should consider outpatient management while awaiting Lyme disease test results.

Modeling intra-abdominal volume and respiratory driving pressure during pneumoperitoneum insufflation-a patient-level data meta-analysis.

During pneumoperitoneum, intra-abdominal pressure (IAP) is usually kept at 12-14 mmHg. There is no clinical benefit in IAP increments if they do not increase intra-abdominal volume IAV. We aimed to estimate IAV (ΔIAV) and respiratory driving pressure changes (ΔPRS) in relation to changes in IAP (ΔIAP). We carried out a patient-level meta-analysis of 204 adult patients with available data on IAV and ΔPRS during pneumoperitoneum from three trials assessing the effect of IAP on postoperative recovery and airway pressure during laparoscopic surgery under general anesthesia. The primary endpoint was ΔIAV, and the secondary endpoint was ΔPRS. The endpoints' response to ΔIAP was modeled using mixed multivariable Bayesian regression to estimate which mathematical function best fitted it. IAP values on the pressure-volume (PV) curve where the endpoint rate of change according to IAP decreased were identified. Abdomino-thoracic transmission (ATT) rate, that is, the rate ΔPRS change to ΔIAP was also estimated. The best-fitting function was sigmoid logistic and linear for IAV and ΔPRS response, respectively. Increments in IAV reached a plateau at 6.0 [95%CI 5.9-6.2] L. ΔIAV for each ΔIAP decreased at IAP ranging from 9.8 [95%CI 9.7-9.9] to 12.2 [12.0-12.3] mmHg. ATT rate was 0.65 [95%CI 0.62-0.68]. One mmHg of IAP raised ΔPRS 0.88 cmH2O. During pneumoperitoneum, IAP has a nonlinear relationship with IAV and a linear one with ΔPRS. IAP should be set below the point where IAV gains diminish.NEW & NOTEWORTHY We found that intra-abdominal volume changes related to intra-abdominal pressure increase reached a plateau with diminishing gains in commonly used pneumoperitoneum pressure ranges. We also found a linear relationship between intra-abdominal pressure and respiratory driving pressure, a known marker of postoperative pulmonary complications.

Stratified effects of blood pressure-lowering treatment on long-term blood pressure: an individual patient-level meta-analysis involving 50 randomised trials and 334,219 participants

Abstract Background Meta-analyses of randomised controlled trials (RCT) have shown the efficacy of pharmacologic lowering of blood pressure (BP) in reducing cardiovascular disease (CVD) risk. While efficacy has been shown across important patient characteristics, meta-analysis based on aggregate data could not fully account for potential sources of variation due to individual-level characteristics. Moreover, it is unclear if any variation in treatment effects due to patient characteristics are reflected in differential effects of BP-lowering treatment on long-term BP according to these characteristics. Purpose We determined the effects of BP-lowering treatment on repeated measures of blood pressure, identified trial- and participant-level sources of heterogeneity, and examined consistency of these BP-lowering effects across different patient characteristics. Methods We conducted an individual patient-level data meta-analysis (N=50 trials) using one-stage approach. We classified trials according to trial design: drug comparison (N=28), placebo-controlled (N=21) and BP-lowering intensity (N=8) trials. We fitted mixed models with fixed treatment effects and fixed time effect, random intercepts at trial and participant level, and a random slope for time at participant level. We adjusted for age, sex and baseline BP (except when used as stratification factor). We used likelihood ratio test and Akaike information criterion to compare models. Results This meta-analysis included 334,219 (42% women) participants. At baseline, mean age=65 (SD=9) years, among whom 18% were current smokers, 47% had cardiovascular disease, 29% had diabetes, and 73% were previously on BP-lowering medication. Participants had an average of 8 BP measurements over 4 years of mean follow-up. For drug comparison trials, mean differences (95% confidence interval) in systolic BP (SBP) and diastolic BP (DBP) between comparison arms were 1.3 (1.2 to 1.3) mmHg and 0.5 (0.5 to 0.5) mmHg, respectively; for placebo-controlled trials, the SBP and DBP differences were 4.2 (4.0 to 4.3) mmHg and 1.9 (1.9 to 2.0) mmHg, respectively; and for BP-lowering intensity trials, the SBP and DBP differences were 8.2 (8.0 to 8.4) mmHg and 3.7 (3.6 to 3.9) mmHg, respectively. However, BP reduction differed by duration of follow-up, type of trial. In particular, for placebo-controlled and BP-intensity trials, heterogeneity in BP reductions according to patient characteristics such as baseline BP, age, sex, prior CVD, diabetes and non-randomised anti-hypertensive use were observed. Conclusion This study shows the role of pharmacologic agents in effectively reducing long-term BP across individuals with a wide range of characteristics. The magnitude of BP reduction varied by several patient characteristics. This might have implications for investigation and explanation of any differential effects of BP treatment on major clinical outcomes. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): British Heart Foundation; NIHR Oxford Biomedial Research Centre

Impact Of Sequencing Of Androgen Receptor-Signaling Inhibition (ARSI) And Ionizing Radiotherapy (RT) In Prostate Cancer: Importance Of Homologous Recombination (HR) Disruption

The benefit of combining ARSI with RT for the treatment of localized prostate cancer is well established. The mechanism of action has been attributed to disruption of non-homologous end-joining (NHEJ) repair via impaired DNA-dependent protein kinase (DNA-PK) function. However, clinical trials have demonstrated inconsistent benefits from combining ARSI and RT, which we hypothesized might be explained by the treatment sequence of ARSI and RT. We exposed four prostate cancer cell lines (LNCaP, LNCaP-AR, C42B, LAPC-4) to ARSI via charcoal stripped serum and/or enzalutamide, a next-generation anti-androgen. ARSI was combined with fractionated RT in three sequences: neoadjuvant, concurrent, or adjuvant. The effects of ARSI sequencing were measured with clonogenic assays, immunoblotting for signaling proteins, qPCR of AR target genes, cell cycle analysis, DNA damage and repair pathway assays, and xenograft animal studies. Clinical validation was performed by meta-analysis of individual patient data from two randomized trials comparing neoadjuvant versus adjuvant ARSI with RT. Across all prostate cancer cell lines, adjuvant sequencing of ARSI after RT was significantly more effective at killing colony forming cells (20 to 50-fold, p<0.01) and decreasing the transcription and translation of downstream AR target genes (5-fold, p<0.01). This effect was recapitulated in xenograft studies showing that adjuvant ARSI was the only regimen that slowed prostate cancer tumor growth more than RT alone. Adjuvant inhibition of the NHEJ pathway with a DNA-PK inhibitor (NU 7441) did not recapitulate the effect of adjuvant ARSI as confirmed with functional NHEJ assays. Rather, we found adjuvant ARSI treatment impaired HR by decreasing the phosphorylation of nuclear ATM, CHK2, and p53 in addition to decreasing nuclear Rad51 and increasing γH2AX staining. Adjuvant ARSI doubled (p<0.05) the proportion of cells in the G2/M phase which—in the setting of double-strand breaks (DSBs) unrepaired by HR—may explain the greater cell death seen with adjuvant treatment. Finally, we validated our preclinical findings in a meta-analysis of patient-level data, confirming that adjuvant ARSI was associated with superior progression-free survival compared to neoadjuvant/concurrent ARSI (HR: 1.25 (95%CI: 1.07-1.47), p = 0.01). We demonstrate that sequencing of ARSI and RT is of critical importance and clarify a possible mechanism. Adjuvant ARSI—rather than neoadjuvant or concurrent—is associated with the greatest tumor control with RT. The beneficial effect of adjuvant ARSI is not explained by impaired NHEJ. Rather it appears to be mediated through disruption of HR and cell cycle checkpoints in response to DNA damage, which allows prostate cancer cells to proceed to G2 and mitosis with unrepaired DSBs.

A CASE OF PHLEGMASIA CERULEA DOLENS AND MAY-THURNER SYNDROME IN A YOUNG MALE WITH TRIPLE-POSITIVE ANTIPHOSPHOLIPID ANTIBODY SYNDROME

SESSION TITLE: Medical Student/Resident Critical Care Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Phlegmasia cerulea dolens (PCD) is an uncommon form of deep vein thrombosis (DVT) typically presenting with acute limb swelling, pain, and cyanosis. Diagnosis of PCD should be made promptly as these patients may develop limb-threatening complications such as gangrene and compartment syndrome. We describe a young male presenting with his first episode of provoked venous thromboembolism (VTE) as PCD complicated with May-Thurner syndrome (MTS) and Antiphospholipid antibody syndrome (APS). CASE PRESENTATION: A 37-year-old obese male with type 2 diabetes, hypertension, and hyperlipidemia was directly admitted to the medicine floor with extensive left lower extremity DVT (including ileofemoral vein thrombosis) found on outpatient duplex ultrasonography. At initial hospitalization, he was tachycardic but without respiratory distress or hemodynamic instability. His left lower extremity was tender and edematous with cyanosis. Diagnosis of PCD was made and patient was treated with subcutaneous enoxaparin. He received catheter-directed thrombolysis for PCD with alteplase and heparin infusion. During left leg venogram, he was discovered to have MTS, and subsequently underwent stent placement of left common iliac vein, external iliac vein, and common femoral vein. After stent placement, patient received bridging to warfarin with enoxaparin and was discharged home two days later. Patient’s family history was significant for Systemic Lupus Erythematosus. During hospitalization, his antibody testing revealed positivity for anti-cardiolipin, anti-beta-2 glycoprotein antibodies in addition to positive functional lupus anticoagulant assay. Positivity confirmed with repeat testing of anti-cardiolipin antibodies and lupus anticoagulant assay at 15 weeks after hospitalization - confirming the diagnosis of triple-positive APS. DISCUSSION: Treatment of PCD is anticoagulation therapy with adjunctive catheter-directed thrombolysis. Outcomes comparing additional catheter-directed thrombolysis versus anticoagulation alone have shown that combination treatment reduces the incidence of post-thrombotic syndrome in patients with acute iliofemoral DVT. Recognition of DVT associated with MTS is important as treatment includes stent placement to maintain venous outflow. Recognition of triple-positive APS is an indication for extended anticoagulation as this portends a high risk of recurrent VTE. Patient was discharged with warfarin therapy because the use of direct oral anticoagulation in patients with APS remains controversial. Recent studies showed increased risk of recurrent thrombosis, particularly in patients with APS who are triple-positive. CONCLUSIONS: We reported a case, 37 year old male with phlegmasia cerulea dolens and May-Thurner syndrome resulting from triple-positive antiphospholipid antibody syndrome. Reference #1: Casey ET, Murad MH, Zumaeta-garcia M, et al. Treatment of acute iliofemoral deep vein thrombosis. J Vasc Surg. 2012;55(5):1463-73 Reference #2: Haig Y, Enden T, Grøtta O, et al. Post-thrombotic syndrome after catheter-directed thrombolysis for deep vein thrombosis (CaVenT): 5-year follow-up results of an open-label, randomised controlled trial. Lancet Haematol. 2016;3(2):e64-71 Reference #3: Dufrost V, Risse J, Reshetnyak T, et al. Increased risk of thrombosis in antiphospholipid syndrome patients treated with direct oral anticoagulants. Results from an international patient-level data meta-analysis. Autoimmun Rev. 2018;17(10):1011-1021 DISCLOSURES: No relevant relationships by Waqas Adeel, source=Web Response No relevant relationships by Robert Decker, source=Admin input No relevant relationships by Shuisen Li, source=Web Response No relevant relationships by Preysi Patel, source=Web Response No relevant relationships by Chun Siu, source=Web Response

Effect of tranexamic acid by baseline risk of death in acute bleeding patients: a meta-analysis of individual patient-level data from 28 333 patients

BackgroundEarly administration of the antifibrinolytic drug tranexamic acid reduces death from bleeding in trauma and postpartum haemorrhage. We examined how the effectiveness and safety of antifibrinolytic drugs varies by the baseline risk of death as a result of bleeding. MethodsWe performed an individual patient-level data meta-analysis of randomised trials including more than 1000 patients that assessed antifibrinolytics in acute severe bleeding. We identified trials performed between January 1, 1946 and July 5, 2018 (PROSPERO, number 42016052155). ResultsTwo randomised trials were selected where 28 333 patients received tranexamic acid treatment within 3 h after the onset of acute bleeding. Baseline characteristics to estimate the risk of death as a result of bleeding were divided into four categories: Low (0–5%), intermediate (6–10%), high (11–20%), and very high (>20%). Most patients had a low baseline risk of death as a result of bleeding (23 008 [81%]). Deaths as a result of bleeding occurred in all baseline risk categories with 240 (1%), 202 (8%), 232 (14%), and 357 (30%) deaths in the low-, intermediate-, high-, and very high-risk categories, respectively. The effectiveness of tranexamic acid did not vary by baseline risk when given within 3 h after bleeding onset (P=0.51 for interaction term). There was no increased risk of vascular occlusive events with tranexamic acid and it did not vary by baseline risk categories (P=0.25). ConclusionsTranexamic acid appears to be safe and effective regardless of baseline risk of death. Because many deaths are in patients at low and intermediate risk, tranexamic acid use should not be restricted to the most severely injured or bleeding patients.