Impact Of Baseline Characteristics Research Articles

Complications of Implantable Cardioverter Defibrillator and Their Potential Risk Factors in Patients with Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) has different complications such as cardiac arrhythmia and sudden cardiac death (SCD). Insertion of an implantable cardioverter defibrillator (ICD) is recommended for HCM patients who are at high risk of SCD and malignant arrhythmias, despite having their own potential complications. Hypothesis. We aimed to investigate the prevalence of different complications of ICD insertion and the impact of the potential influential baseline characteristics in a one-year follow-up period. This was a retrospective study with a total of 71 HCM patients with ICD insertion. We evaluated the prevalence of different complications of ICD implantation and the impact of baseline characteristics on the occurrence of ICD complications using multivariate regression analysis in three 4-month periods. In a one-year follow-up, 13 patients (18.3%) experienced at least one of the complications including pneumothorax, lead failure, ICD infection, inappropriate shocks, perforation, and upper limb deep vein thrombosis (DVT) with no mortality. Inappropriate shocks were reported as the most common (11.3%) complication during this period, with a gradual increase in the second (4.2%) and third (5.6%) follow-up sessions. Among all of the baseline characteristics that were investigated in this study, a positive history of hypertension was the only risk factor with significant impact on the occurrence of complications (P = 0.01). We demonstrated the occurrence of complications during a one-year follow-up as 18.3% in HCM patients with ICD insertion. A positive history of hypertension was the only baseline characteristic affecting the occurrence of complications, and inappropriate shocks were the most common complication.

639P Conditional survival in MM and impact of prognostic factors over time

Overall Survival (OS) estimates from diagnosis are important for predicting prognosis and guiding treatment selection in newly diagnosed patients, but do not consider the number of years already survived. Conditional survival (CS) estimates provide updated survival predictions over the disease course. Previous studies suggest that improvement in CS is less pronounced in multiple myeloma (MM) compared to other malignancies. It is unclear whether high-risk (HR) factors in MM retain their prognostic impact over time. This study was conducted to estimate CS at 1 to 5 years from diagnosis and evaluate the impact of baseline prognostic factors on CS over time in newly diagnosed MM patients. This is a retrospective study including 2556 MM patients diagnosed between 2004-2019. CS (t|s), defined as the probability of surviving additional t years given survival of s years, was estimated at 1 to 5 years from diagnosis using the conditional Kaplan-Meier method. The impact of baseline characteristics on CS was estimated using conditional Cox proportional hazards model. The median age was 64 years and 62% were male; >90% received novel-agent based induction; 46% had transplant within 1 year of diagnosis. The median follow-up was 6.2 years, and median OS was 7.5 years. The 5-year CS estimates at s=0, 1, 2, 3, and 5 years were 0.64, 0.61, 0.61, 0.61, and 0.58, respectively. On multivariate analysis, age ≥ 65 and proteasome inhibitor (PI)+Immunomodulatory (IMiD)-based induction retained prognostic significance at 5 years from diagnosis. The adverse impact of HR IgH translocations, 1q gain and ISS 3 was not significant at 5 years. Chromosome 17 abnormality predicted worse CS at 1 year, but not at 3 or 5 years from diagnosis (table).Table: 639PMultivariate CSVariableDiagnosisyear 1year 3year 5HRPHRPHRPHRPAge≥651.60<0.011.57<0.011.48<0.011.95<0.01Calcium ≥111.59<0.011.63<0.011.05NS1.05NSISS III1.74<0.011.75<0.011.80<0.011.52NSEarly transplant0.57<0.010.64<0.010.61<0.010.69NSPI+IMiD induction0.59<0.010.630.010.660.040.530.04LDH > 2221.29NS1.15NS1.13NS0.89NSCh17 abnormality1.53<0.011.430.021.32NS1.16NSHR IgH translocation1.90<0.011.97<0.011.550.041.51NSMonosomy 131.13NS1.09NS1.05NS0.86NS1q gain1.34<0.011.310.031.500.011.38NSSignificant P values are bolded. NS: not significant. Open table in a new tab Significant P values are bolded. NS: not significant. In a large cohort of MM patients treated with novel agents, CS was stable at 1 to 5 years from diagnosis. The adverse prognostic impact of HR cytogenetic factors and advanced ISS stage decreased over time.

Large multicenter randomized trials in autism: key insights gained from the balovaptan clinical development program

BackgroundAutism spectrum disorder (ASD) is a common and heterogeneous neurodevelopmental condition that is characterized by the core symptoms of social communication difficulties and restricted and repetitive behaviors. At present, there is an unmet medical need for therapies to ameliorate these core symptoms in order to improve quality of life of autistic individuals. However, several challenges are currently faced by the ASD community relating to the development of pharmacotherapies, namely in the conduct of clinical trials. Balovaptan is a V1a receptor antagonist that has been investigated to improve social communication difficulties in individuals with ASD. In this viewpoint, we draw upon our recent first-hand experiences of the balovaptan clinical development program to describe current challenges of ASD trials.Discussion pointsThe balovaptan trials were conducted in a wide age range of individuals with ASD with the added complexities associated with international trials. When summarizing all three randomized trials of balovaptan, a placebo response was observed across several outcome measures. Placebo response was predicted by greater baseline symptom severity, online recruitment of participants, and less experienced or non-academic trial sites. We also highlight challenges relating to selection of outcome measures in ASD, the impact of baseline characteristics, and the role of expectation bias in influencing trial results.ConclusionTaken together, the balovaptan clinical development program has advanced our understanding of the key challenges facing ASD treatment research. The insights gained can be used to inform and improve the design of future clinical trials with the collective aim of developing efficacious therapies to support individuals with ASD.

Age-dependent risk for thromboembolism in atrial fibrillation: The Fushimi AF registry.

BackgroundThe risk for thromboembolism depending on the different age subgroups in patients with atrial fibrillation (AF) has not been fully elucidated.MethodsThe Fushimi AF Registry is a community-based prospective survey of patients with AF in Fushimi-ku, Kyoto. Follow-up data were available for 4,466 patients by the end of 2019. Clinical determinants and the description of variables which interact and lead to the incidence of thromboembolism (the composite of ischemic stroke and systemic embolism [SE]) were identified in overall population and in age subgroups (≤64, 65–74, and ≥ 75 years).ResultsA total of 314 patients developed thromboembolism during the median follow-up of 1,610 days (1.56 per 100 person-years). The independent determinants were age advance (per 10 years, hazard ratio [HR]: 1.51, 95% confidence interval [CI]: 1.22–1.86, P < 0.001), low body weight (HR: 1.91, 95% CI: 1.35–2.70, P < 0.001), history of stroke or SE (HR: 2.06, 95% CI: 1.54–2.76, P < 0.001), chronic kidney disease (HR: 1.34, 95% CI: 1.01–1.78, P = 0.043), and left atrial enlargement (HR: 1.57, 95% CI: 1.18–2.10, P = 0.0021). With regard to the age subgroup analysis, diabetes mellitus (P = 0.043), vascular disease (P = 0.005), male sex (P = 0.022), and sustained AF (P = 0.014) indicated significantly relevant interactions between the age subgroups and thromboembolism.ConclusionThe risk and the impact of baseline characteristics on thromboembolism in patients with AF varied depending on the age subgroups.

Impact of Baseline Characteristics on the Efficacy and Safety of Eptinezumab in Patients With Migraine: Subgroup Analyses of PROMISE-1 and PROMISE-2

In the PROMISE-1 (Prevention of Migraine via Intravenous ALD403 Safety and Efficacy-1) and PROMISE-2 (Prevention of Migraine via Intravenous ALD403 Safety and Efficacy-2) clinical trials, eptinezumab 100 mg and 300 mg met the primary efficacy end point, significantly reducing mean monthly migraine days across weeks 1 to 12. Clinical efficacy was also shown across key secondary end points. However, to determine if clinical efficacy varies across subgroups, it is necessary to determine efficacy in patients with different sociodemographic features and headache characteristics. These post hoc analyses of patients in PROMISE-1 and PROMISE-2 evaluated the impact of intrinsic factors on the efficacy and safety of eptinezumab in subgroups defined according to baseline demographic and migraine disease characteristics. PROMISE-1 and PROMISE-2 were Phase III, parallel-group, double-blind, randomized, placebo-controlled trials of repeat quarterly intravenous infusions of eptinezumab or placebo in adults with episodic (PROMISE-1) or chronic (PROMISE-2) migraine. Demographic and baseline characteristics were similar across treatment groups in both the PROMISE-1 and the PROMISE-2 studies. Analyses did not show a clear pattern of baseline demographic characteristics driving treatment effects except for the obesity subgroups. For the ≥50% migraine responder rate in the obese class I (body mass index 30.0-35.0 kg/m2) subgroup, although separation from placebo was not as large (<10% separation compared with ≥10% separation across most baseline demographic factors), both doses showed improved ≥50% migraine responder rate compared with placebo, with slightly better results in patients receiving eptinezumab 300 mg. Eptinezumab treatment showed consistent clinically relevant reductions from baseline in mean monthly migraine days compared with placebo based on ≥50% migraine responder rate across clinically important intrinsic subgroups of adults with episodic or chronic migraine. gov identifiers: NCT02559895 (PROMISE-1) and NCT02974153 (PROMISE-2).

Prediction of Postoperative Mortality in Patients With Organ Failure Following Pancreaticoduodenectomy.

Failure to rescue (FTR) patients with postoperative complications contribute to a significant proportion of postoperative mortality. Our main objective was to determine the risk factors for FTR among patients undergoing pancreaticoduodenectomy who suffered a life-threatening complication requiring intensive care unit (ICU) management. Consecutive patients undergoing pancreaticoduodenectomy from 2011 to 2020 were reviewed retrospectively. Causes of organ failure were described as the one that most commonly contributed to patient's transfer to ICU or death. Two groups were created based on whether patients had FTR and risk factors for FTR were compared. The impact of baseline characteristics, operative characteristics, and risk scoring on FTR was analyzed using multiple logistic regression. There were 19/58 (33%) FTR patients. Baseline, operative characteristics, postoperative complications, and length of hospital and ICU stay were similar between groups. However, a higher proportion of FTR patients experienced a postoperative pancreatic fistula (POPF) (16% vs 2.6%, P = .062). Among patients who experienced a POPF, the FTR group had a trend in delayed time from diagnosis to treatment (7 vs 23 hours, P=.131). Renal complications (OR 6.12, 95% CI, 1.23 to 38.43, P = .035) and time from POPF diagnosis to treatment (OR 1.05, 95% CI, 1.00 to 1.11, P = .036) were independent predictors of FTR by multivariable analysis. The occurrence of certain postoperative complications such as renal complications as well as delayed timing of the management of POPF is predictive of FTR following pancreaticoduodenectomy, especially as delayed timing to treatment is a risk factor for FTR.

Low haemoglobin is associated with increased risk of complications in left atrial appendage closure patients

Abstract Introduction Left atrial appendage closure is associated with a relevant procedural complication rate. Baseline risk factors, such as pre-procedural lab results, may identify patients that develop acute complications. Methods We performed a retrospective analysis of the impact of baseline characteristics and preprocedural lab results on the acute procedural outcome in patients undergoing left atrial appendage closure from the Austrian Left Atrial Appendage Closure Registry between 2010 and 2019. The endpoint for procedural complications was defined as death, stroke, major bleeding, necessity for intensive care, other complications requiring invasive interventions or failure to implant the device. We also evaluated a modified endpoint with the exclusion of bleeding events. Logistic regression was performed using stepwise approach (backward method with p_out = 0.1) and forced inclusion of age, left-ventricular function and kidney function. Results A total of 320 consecutive patients from 9 centres with a median age of 75 years (36.6% female) were included. Seventy-eight percent had a history of bleeding and 35% had a history of stroke. Median CHA2DS2-VASc score was 5 (interquartile range, 3–5) and median HAS-BLED score was 3 (2–4). Procedural complications occurred in 15.3% of cases. Low haemoglobin and low activated partial thromboplastin time were associated with an increased complication rate. Other significant baseline factors were liver disease, absence of intracranial haemorrhage and severe aortic stenosis. In multivariate analysis, low haemoglobin remained a significant predictor, even after adjustment for age, left-ventricular function and kidney function (Table). In the modified procedural complication endpoint excluding major bleeding events (14.1%), low haemoglobin remained a significant predictor (haemoglobin 11.9±2.0 vs. 12.8±2.0 g/dL in patients with vs. without modified endpoint, p=0.013). A baseline haemoglobin lower than 12 g/dL was present in 39.4% and it increased relative risk of procedural complications by 89% (21.4 vs. 11.3% in patients with reduced vs. normal haemoglobin), and risk of complications without bleeding by 92% (19.8 vs. 10.3%). Conclusion Low baseline haemoglobin is independently associated with a higher complication rate after left appendage closure compared to patients with normal haemoglobin levels, even in a modified endpoint excluding bleeding and requirement for transfusion. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Boston Scientific - unrestricted grant Table 1

Profiles of patients\u2019 self-reported health after acute stroke

BackgroundWe aimed to identify groups of patients with similar health status after stroke, assessed by patient reported outcome measures (PROMs), to improve initial risk stratification.MethodsIn a prospective study, inpatients were recruited during acute stroke treatment. Demographics, history, and cardio-vascular risk factors were assessed at baseline. Self-reported functional status, physical and mental health as well as anxiety and depressive symptoms were assessed 3 and 12 months after stroke and used to identify latent classes. The association of patient characteristics with latent class membership was investigated with multinomial logistic regression.ResultsOf the 650 patients included with a mean age of 75 years and 48% female, 70% had ischemic, 6% hemorrhagic strokes, and 24% transient ischemic attacks. Median NIHSS on admission was 2 (IQR:0,5). Values of PROMs remained comparable at 3 and 12 months. A three-class model was developed, differentiating between patients with mildly (75%), moderately (17%), and severely (8%) impaired self-reported health status. Adjusted for univariately significant baseline characteristics, initial NIHSS distinguished mild- from moderate-, and moderate- from severe-class-membership (p < 0.001). Length of inpatient stay (p < 0.001;OR = 1.1), diabetes (p = 0.021;OR = 1.91), and atrial fibrillation (p = 0.004;OR = 2.20) predicted allocation to the moderately vs. mildly affected class.ConclusionsGrading stroke patients by a standard set of PROMs up to 1 year after stroke allows to distinguish the diverse impact of baseline characteristics on differently affected groups. In addition to initial stroke severity, longer inpatient stay, presence of diabetes and atrial fibrillation correlate with greater impairment of self-reported health in the less affected groups.Trial registrationhttp://www.ClinicalTrials.gov; Unique identifier: NCT03795948.

Spk-9001: Adeno-Associated Virus Mediated Gene Transfer for Hemophilia B - 1 Year Follow up and Impact of Baseline Characteristics on Transgene-Derived Factor IX Activity and Persistence

▪Background: Prior work demonstrated long term expression of factor IX (mean FIX:C ~5.1%) after AAV8-mediated gene transfer in hemophilia B (Nathwani et al., 2014), but transgene-derived FIX:C fell short of trough values obtained by long-acting FIX prophylaxis (Santagostino et al . 2016) and natural history data supporting levels of ~12% sufficiently eliminate spontaneous hemarthroses (den Uijl et al. 2011). We developed an efficient capsid and expression cassette that could be administered at low doses to achieve FIX:C adequate to prevent bleeding without use of exogenous FIX. Here we report 1 year follow up data in 7 subjects following SPK-9001 infusion at a dose of 5 x 1011vg/kg. These data represent the largest cohort of hemophilia B subjects treated with gene transfer using the same vector and dose with available 1 year follow up data. We additionally report observations of subject baseline pre-vector characteristics relative to steady-state transgene-derived FIX:C and clinical outcomes.Objective: To obtain long term transgene-derived FIX:C > 12% able to prevent spontaneous bleeding without the need for prophylactic FIX infusions with consistent and predictable results among all subjects, irrespective of baseline characteristics.Methods: The study vector, SPK-9001, consists of a liver specific, bioengineered AAV capsid (Spark100) and a single-stranded codon optimized expression cassette encoding FIX-Padua. FIX-Padua is a naturally occurring variant that confers ~8-12-fold greater specific activity compared to wild-type FIX (Simioni et al. 2009, Crudele et al. 2015). Subject baseline characteristics were determined at study screening. FIX:C and clinical data were prospectively collected after vector infusion.Results: To date, 7 subjects completed 1 year follow up after SPK-9001 infusion at a dose of 5 x1011 vg/kg. No subjects developed a FIX inhibitor or experienced vector related adverse events (AEs). Subject mean FIX:C following vector infusion through 52 weeks is outlined in figure 1. Subjects were males ages 18-52 yrs with FIX:C ≤2%. One subject had a Spark 100 neutralizing antibody (NAb) of 1:1 and the remaining were <1:1. Five patients were CRM+ and 2 were CRM-. The FIX:C at steady state, defined as the average of all values measured starting at week 12, for the 5 CRM+ subjects was 32.3±11.0% (mean±SD) and 21.0±5.7% for the 2 CRM- subjects. However, the analysis is confounded by a 1:1 NAb in one CRM- subject and partial loss of FIX:C due to immune response in one of the CRM+ subjects. Steady state FIX:C for the 6 subjects with <1:1 NAb was 31.1±10.3% and 17% for the one subject with NAb 1:1. FIX:C in subjects with a history of HCV and stage 1-2 liver fibrosis (29.7±12.7%), was comparable to that of subjects with no history of HCV (28.2±10.2%). FIX:C in the one patient with HCV exposure on HIV anti-retroviral therapy did not differ from other participants (25% vs. 29.7%±11.7%). All subjects discontinued prophylaxis at vector infusion. One subject self-reported bleeding that was incongruent with the remaining cohort, including those with the similar vector-derived FIX:C and baseline hemophilic arthropathy, who did not experience bleeding events or require factor (Table 1). The 1 subject (subject 7) who experienced a suspected capsid immune response had no known baseline characteristics that differed from the cohort; the subject completed a course of steroids, had a stable, sustained FIX:C of 14% and did not experience bleeding post vector. All subjects reported significantly improved quality of life (QoL) at 1-year (p<0.023).Conclusion: As of 8/1/17, we report the highest, most consistent and sustained vector derived FIX:C following gene transfer. Despite heterogenous baseline characteristics, all subjects achieved consistent clinical results, including no vector related AEs, improved QoL, termination of prophylaxis, near complete elimination of bleeding and factor use. Low grade liver fibrosis and prior HCV exposure did not appear to affect steady-state FIX:C. Individual subject data may imply effects of CRM status and NAb titer on achieved FIX, but the current dataset is too small to define the relationship. In summary, these preliminary data suggest SPK-9001 safely, consistently, and independent of subject baseline characteristics, achieved FIX:C able to substantially ameliorate clinical manifestations of hemophilia. [Display omitted] DisclosuresGeorge:Pfizer: Consultancy; Spark Therapeutics: Other: Principal Investigator of Ongoing Phase I/II Gene Therapy Trials for Hemophilia A and B. Ducore:Octapharma: Research Funding; Bayer, Shire, HemaBiologics, Bioverativ, Octapharma, Spark Therapeutics: Other: Advisory board. Cuker:T2 Biosystems: Research Funding; Spark Therapeutics: Research Funding. Von Mackensen:LFB: Honoraria. McGuinn:Shire / Baxalta, Spark, Biogen, Roche/Genetehc: Research Funding; Shire/Baxalta: Consultancy. Wright:Spark Therapeutics: Employment, Equity Ownership, Patents & Royalties. Dasen:Spark Therapeutics: Employment. Barber:Spark Therapeutics: Employment. Chen:Spark Therapeutics: Employment. Hui:Spark Therapeutics: Employment. Patel:Spark Therapeutics: Employment. Liu:Spark Therapeutics: Employment. Wachtel:Spark Therapeutics: Employment. Takefman:Spark Therapeutics: Employment. Couto:Spark Therapeutics: Employment. Reape:Spark Therapeutics: Employment. Carr:Spark Therapeutics: Employment. Anguela:Spark Therapeutics: Employment, Equity Ownership, Patents & Royalties. High:Spark Therapeutics: Employment, Equity Ownership, Patents & Royalties.

Presence of interferon-λ 4, male gender, absent/mild steatosis and low viral load augment antibody levels to hepatitis C virus

Objectives Despite recombinant interferon-λ 4 (IFN-λ4) demonstrating anti-viral activity in vitro and the ancestral functional gene (IFNL4) being conserved in all other primates, there has been speculation that IFN-λ4 may be detrimental in humans. In light of recent rekindled interest in humoral immunity, this study aimed at evaluating the impact of baseline characteristics, including IFNL4, on antibody levels to hepatitis C virus (HCV). Materials and methods Pretreatment sera from 279 well-characterized North European Caucasians with chronic HCV genotype 2 or 3 infection having undergone liver biopsy were analyzed regarding IFNL4 (rs12979860) and anti-HCV antibody levels using a commercially available assay. Results Patients producing IFN-λ4 had higher signal to cut-off (S/CO) anti-HCV antibody ratios as compared with those lacking IFN-λ4 (IFNL4 rs12979860 CT/TT versus CC, p<.0001, Mann–Whitney U-test). Additionally, in univariate analyses S/CO was significantly higher in men than women (p<.001), as well as in patients with absent/mild interface hepatitis (Ishak grade 0–2 versus 3–4, p = .009), and absent/mild steatosis (grade 0–1 versus 2–3, p = .0005). Also, an inverse correlation with HCV RNA level (rs = −0.14, p = .02) was noted. In multivariate analysis IFN-λ4, gender, steatosis and viral load remained independently associated. Conclusions To our knowledge, this is the first report that demonstrates that the ability to produce IFN-λ4, in addition to male gender, absent/mild steatosis, and lower viral load, augments antibody levels against HCV. This indicates that IFN-λ4 may be associated with T helper cell 2 (Th2) immune skewing, which might have clinical implications beyond HCV infection. ClinicalTrials.gov Identifier: NCT00143000

A prognostic model to predict survival after hepatic arterial infusion chemotherapy for hepatocellular carcinoma with portal vein invasion.

e16157 Background: We aimed to establish a prognostic model to predict survival for the patient with advanced hepatocellular carcinoma (HCC) after the treatment with hepatic arterial infusion chemotherapy (HAIC) of oxaliplatin plus fluorouracil/leucovorin. Methods: 164 patients diagnosed of HCC with portal vein invasion and treated with HAIC of oxaliplatin plus fluorouracil/leucovorin between 1/2018 and 1/2021 at the Guangdong provincial people’s hospital and were randomly divided to training(N=82) and validation(N=82) cohort. We investigated the impact of baseline characteristics and tumour load on overall survival (OS, log-rank test) and developed a prognostic model in the training cohort by using a stepwise Cox regression model and validated in validation cohort. Results: The final presentation of the model was “NCV-score= 0.974* serum neutrophil/lymphocyte ratio+ 1.239* Child-pugh stage+ 0.661* portal Vein invasion grade”, which further selected the first quartile of the linear predictor, namely 5.7, as cut-off values. The NCV-score differentiated two risk categories(≥5.7, ＜5.7) with distinct prognosis (median OS: 6.6 vs. 11.2 months, p &lt;0.001). The prognostic model was used to develop nomogram for predicting individual survival of HAIC candidates and was validated in validation cohort to identify patients who obtain satisfying survival benefit for HAIC. Conclusions: The NCV-score identifies advanced HCC patients who obtain satisfying survival benefit for HAIC of oxaliplatin plus fluorouracil/leucovorin and provides individual survival predicting.[Table: see text]

Quality of Life 3 and 12 Months Following Acute Pulmonary Embolism: Analysis From a Prospective Multicenter Cohort Study

Few data are available on the long-term course and predictors of quality of life (QoL) after acute pulmonary embolism (PE). What are the kinetics and determinants of disease-specific and generic health-related QoL 3 and 12 months after acute PE? and methods. The FOllow-up after aCUte pulmonary emboliSm (FOCUS) study prospectively followed consecutive adult patients with objectively diagnosed PE. We considered patients who completed the Pulmonary Embolism QoL (PEmb-QoL) Questionnaire at predefined visits 3 and 12 months after PE. We studied the course of disease-specific QoL as assessed by PEmb-QoL and the impact of baseline characteristics using multivariable mixed-effects linear regression, along with the course of generic QoL as assessed by the EQ-5D-5L utility index and Visual Analogue Scale (VAS). In 620 patients (44% women, median age 62 years), overall disease-specific QoL improved from 3 to 12 months, with a decrease of the median PEmb-QoL score from 19.4% to 13.0% and a mean individual change of -4.3% (95% CI: -3.2% to -5.5%). Female sex, cardiopulmonary disease, and higher body-mass index were associated with worse QoL at both 3 and 12 months. Over time, the association with body-mass index became weaker, while older age and previous venous thromboembolism were associated with worsening QoL. Generic QoL also improved: the mean EQ-5D-5L utility index increased from 0.85 (standard deviation (SD) 0.22) to 0.87 (SD 0.20), the VAS from 72.9 (SD 18.8) to 74.4 (SD 19.1). In a large cohort of survivors of acute PE, we quantified the change of QoL between months 3 and 12 after diagnosis, and identified factors independently associated with lower QoL and slower recovery of QoL. This information may facilitate the planning and interpretation of clinical trials assessing QoL and help guide patient management.

Impact of Baseline Characteristics on the Effectiveness of Disorder-Specific Cognitive Behavioral Analysis System of Psychotherapy (CBASP) and Supportive Psychotherapy in Outpatient Treatment for Persistent Depressive Disorder.

Importance: In the treatment of persistent depressive disorder (PDD), disorder-specific Cognitive Behavioral Analysis System of Psychotherapy (CBASP) has been shown to be superior to Supportive Psychotherapy (SP) in outpatients. It remains to clear which subgroups of patients benefit equally and differentially from both psychotherapies.Objective: To identify those patient-level baseline characteristics that predict a comparable treatment effectiveness of CBASP and SP and those that moderate the differential effectiveness of CBASP compared to SP.Design, setting and participants: In this analysis of a 48-week multicenter randomized clinical trial comparing CBASP to SP in adult antidepressant-free outpatients with early-onset PDD, we evaluated baseline variables from the following domains as potential predictors and moderators of treatment effectiveness: socio-demography, clinical status, psychosocial and global functioning, life quality, interpersonal problems, childhood trauma, treatment history, preference for psychotherapy, and treatment expectancy.Interventions: A 48-week treatment program with 32 sessions of either CBASP or SP.Main outcomes and measures: Depression severity measured by the 24-item Hamilton Rating Scale for Depression (HRSD-24) at week 48.Results: From N = 268 randomized outpatients, N = 209 completed the 48-week treatment program. CBASP completers had significantly lower post-treatment HRSD-24 scores than SP completers (meanCBASP=13.96, sdCBASP= 9.56; meanSP= 16.69, sdSP= 9.87; p = 0.04). A poor response to both therapies was predicted by higher baseline levels of clinician-rated depression, elevated suicidality, comorbid anxiety, lower social functioning, higher social inhibition, moderate-to-severe early emotional or sexual abuse, no preference for psychotherapy, and the history of at least one previous inpatient treatment. Moderator analyses revealed that patients with higher baseline levels of self-rated depression, comorbidity of at least one Axis-I disorder, self-reported moderate-to-severe early emotional or physical neglect, or at least one previous antidepressant treatment, had a significantly lower post-treatment depression severity with CBASP compared to SP (all p < 0.05).Conclusions and relevance: A complex multifactorial interaction between severe symptoms of depression, suicidality, and traumatic childhood experiences characterized by abuse, social inhibition, and anxiety may represent the basis of non-response to psychotherapy in patients with early onset PDD. Specific psychotherapy with CBASP might, however, be more effective and recommendable for a variety of particularly burdened patients compared to SP.

Effect of multidomain interventions on estimated dementia and cardiovascular risk reduction: An individual‐participant data meta‐analysis from FINGER, MAPT, and pre‐DIVA

AbstractBackgroundMultidomain interventions based on management of vascular and lifestyle risk factors could potentially reduce the risk of dementia and cardiovascular disease. Given the slow progressive nature of these conditions, dementia in particular, clinical endpoints may not be achievable within trials’ time‐frame. Well‐established risk scores could be useful surrogate outcomes. In this individual‐participant data meta‐analysis, we assessed the effect of three multidomain dementia prevention interventions on the CAIDE and FINRISK risk scores for dementia and cardiovascular disease, and the impact of baseline characteristics on the response to such interventions.MethodBaseline and 24‐month data from the FINGER, MAPT, and preDIVA dementia/cognitive decline prevention trials carried out in three European cohorts of older adults, were pooled at individual‐participant level (N=6465). Linear mixed‐model with maximum likelihood estimation and random effect by trial and study‐site was used to estimate changes in CAIDE and FINRISK risk scores in the intervention group vs control. Subgroup‐treatment effect interactions were tested to assess the influence of sex, baseline age, education, MMSE, and dementia or cardiovascular disease risk on the response to the interventions. The effect of the interventions on individual modifiable risk factors relevant for both risk scores was also investigated.ResultThe interventions led to a significant reduction of both CAIDE (estimated effect: ‐0.173; 95% CI: ‐0.268 to ‐0.077; P&lt;0.001) and FINRISK (estimated effect: ‐0.108; 95% CI: ‐0.181 to ‐0.035; P=0.001) scores. A significantly larger reduction of CAIDE score was reported in women compared to men (P value for interaction=0.007) and a similar, but not significant, pattern was reported for FINRISK score. Interactions by other baseline characteristics were also not significant. Significant reduction of blood pressure (P≤0.001), and waist circumference (P=0.027), but not of BMI nor serum cholesterol, was observed. No baseline characteristic affected the response on these outcomes.ConclusionMultidomain interventions had beneficial effects on the estimated risk of dementia and cardiovascular disease, measured by the CAIDE and FINRISK scores. Women benefited more than men in terms of dementia risk, whereas effects of baseline age, education, cognitive status, and risk of dementia or cardiovascular disease on the response to the interventions could not be demonstrated.

Quality of life 3 and 12 months after acute pulmonary embolism: analysis of 617 patients from the prospective multicentre FOCUS study

Abstract Background Few data are available on the long-term course and predictors of quality of life (QoL) after acute pulmonary embolism (PE). Aims To evaluate the kinetics and determinants of QoL at 3 and 12 months after acute PE. Methods The Follow-Up after acute pulmonary embolism (FOCUS) study prospectively followed consecutive adult patients with objectively diagnosed PE. For this analysis, we considered patients who completed the Pulmonary Embolism QoL (PEmb-QoL) Questionnaire at two predefined visits 3 and 12 months after PE. PEmb-QoL, studied as total score and in its six dimensions, ranges from 0% (best QoL) to 100% (worst QoL). We studied the course of PEmb-QoL and the impact of baseline characteristics using multivariable linear regression. Results In 617 included patients (44% women, median age 62 years), overall QoL improved from 3 to 12 months, with a decrease of the mean PEmb-QoL score from 25.3% to 21.5% (p-value &amp;lt;0.001). Intra-individual correlation between PEmb-QoL score at 3 and 12 months was high; Figure A. The improvement was consistent across all PEmb-QoL dimensions; Figure B. Female sex, cardiopulmonary diseases, and higher body mass index were the main factors associated with a worse QoL; Table. Age and smoking affected QoL only at 12 months. The improvement in QoL was faster in patients without cardiopulmonary diseases (−4.2%; 95% CI: −5.2% to −3.1%), without previous VTE (−4.3%; −5.5% to −3.2%), and in non-smokers (−4.2%; −5.3% to −3.1%). Conclusions In a large cohort of patients with pulmonary embolism, we quantified the improvement of QoL between 3 and 12 months after diagnosis. We identified factors independently associated with lower QoL and slower recovery of QoL that may reflect special patient needs. These estimates may facilitate the planning and interpretation of clinical trials with QoL as a study outcome. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): University Medical Center of the Johannes Gutenberg University, Mainz, Germany; German Federal Ministry of Education and Research

The impact of age and socioeconomic factors on response to exercise training in patients with ischemic heart disease, heart failure and after valve replacement

Abstract The impact of baseline characteristics on response to exercise training in patients with ischemic heart disease. Background Exercise training improves peak oxygen uptake, an important predictor of mortality in patients with coronary artery disease (CAD). Unfortunately, some patients do not response with an increase in peak oxygen uptake after exercise training. If it is possible to identify these patients it would be possible to tailor their exercise training. Purpose To investigate if baseline characteristics can predict response to exercise training in patients with heart disease. Methods A retrospective analysis of 1443 CAD patients (age 64±11 y (mean (±SD)), 74% male, participated and completed an eight-week supervised outpatient exercise intervention with two weekly training sessions of 1.5 hours with high intensity interval- (&amp;gt;80% of VO2peak) and resistance training. Patient characteristics were entered in the local database as the patients entered cardiac rehabilitation (CR). VO2peak was assessed before and after CR using a cardiopulmonary exercise test (CPET) with a maximal symptom limited bicycle ergometer test. Breathing gases were collected and analysed breath-by-breath. Each test aimed at physical exhaustion and a respiratory exchange ratio of more than 1.1 to ensure the validity of the CPET test. Patients were divided into responders defined as an improvement in aerobic capacity (change in VO2peak) after CR and non-responders if no improvement (change in VO2peak of 0.0ml/kg/min or less) post CR. We performed a multivariable logistic regression analysis using responders vs. non-responders as the endpoint. Explanatory variables were identified according to previous literature and comprised the following variables; age, sex, baseline VO2peak, tobacco use, diabetes, COPD, revascularization, working status, educational attainment, ethnicity and hypercholesteremia. Results 1097 patients were responders and 346 (24%) non-responders to the exercise training despite no difference in attendance. Logistic regression analysis of responders vs. non-responders in relation to baseline characteristics are shown in the table. Conclusion In summarize, 24% of these heart patients were exercise non-responders. High baseline VO2peak, older age, having COPD, being on disability pension, low educational attainment and non-western ethnicity were predictors of training non-response. Identification of patients with a large likelihood of non-response is a beginning towards patient tailored exercise programmes. Baseline characteristics in responders. CABG: coronary artery bypass graft; COPD: chronic obstructive pulmonary disease; PCI: percutaneous coronary intervention; SD: standard deviation; VO2peak: change in peak oxygen uptake. P-values of &amp;lt;0.05 are considered significant and shown in bold. 95% confidence intervals are shown in last column. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): Helsefonden

Risk Stratification for 2-Year Mortality in Patients with Chronic Limb-Threatening Ischemia Undergoing Endovascular Therapy.

Aim: The latest Global Vascular Guidelines (GVG) recommend assessing the 2-year mortality risk in patients with chronic limb-threatening ischemia (CLTI) before revascularization. This study aimed to reveal whether the Wound, Ischemia and foot Infection (WIfI) classification, developed originally as a risk assessment tool for limb prognosis, would be useful in predicting the 2-year mortality risk in patients with CLTI in the era of GVG and WIfI. Methods: We retrospectively analyzed 849 patients with CLTI who were primarily treated with endovascular therapy (EVT) between April 2010 and December 2016. The impact of baseline characteristics, including the WIfI classification on mortality risk, was investigated using the Cox proportional hazards regression model. Results: During a mean follow-up of 19.3 months, 243 deaths were observed. The 2-year mortality rate was 32.3%. Multivariate analysis demonstrated that WIfI classification stages ( p =0.037), in addition to male sex ( p =0.010), age ( p ＜0.001), non-ambulatory status ( p ＜0.001), body mass index ( p =0.002), and hemodialysis ( p ＜0.001), were independent predictors for an increased risk of mortality, while the Rutherford classification was not. Conclusions: WIfI classification stages were independently associated with mortality risk in patients with CLTI undergoing EVT, while the Rutherford classification was not. The WIfI classification would be a practical tool for planning the revascularization strategy in CLTI treatment.

Predictors of disease flare after discontinuation of concomitant methotrexate in Japanese patients with rheumatoid arthritis treated with tocilizumab.

To investigate predictors of disease flare after methotrexate discontinuation in Japanese rheumatoid arthritis (RA) patients with sustained low disease activity undergoing tocilizumab plus methotrexate combination therapy. Participants of this multicenter, open-label, uncontrolled, prospective study were RA patients maintaining low disease activity (Clinical Disease Activity Index [CDAI]≤10) for≥12weeks with tocilizumab plus methotrexate. Methotrexate was discontinued after 12weeks of biweekly administration while continuing tocilizumab therapy. Disease flare was defined as either a CDAI score>10 or intervention with rescue treatments for any reason even if the CDAI score was≤10. The impact of baseline characteristics on disease flare at week 64 (52weeks after methotrexate discontinuation) was assessed with logistic regression models. Efficacy analyses were performed in 49 patients, of whom 15 had a disease flare by week 64. The proportion (95% confidence interval [CI]) of patients who maintained low disease activity without a flare at week 64 was 69.4% (54.6-81.8%). The dosing interval of tocilizumab was longer than that described on the drug label in Japan (i.e., intravenously every 4weeks, or subcutaneously every 2weeks) in 27% and 6% of patients with and without a flare, respectively. Multivariate analysis revealed that male sex (odds ratio [OR]: 18.00, 95% CI: 2.80-115.56) and extended dosing interval of tocilizumab (OR: 12.00, 95% CI: 1.72-83.80) were independent predictors of disease flare. Male patients and those receiving tocilizumab at an extended dosing interval are at high risk of disease flare after discontinuation of concomitant methotrexate. jRCTs041180071, UMIN000021247.

THU0088 PREDICTORS OF DISEASE FLARE AFTER DISCONTINUATION OF CONCOMITANT METHOTREXATE IN JAPANESE PATIENTS WITH RHEUMATOID ARTHRITIS TREATED WITH TOCILIZUMAB

Background:All biologics should primarily be combined with a conventional synthetic DMARD, such as methotrexate (MTX), in rheumatoid arthritis (RA) patients. However, the use of MTX may lead to the development of adverse events (AEs), and de-escalation of MTX while maintaining a favorable disease activity state may be beneficial from the perspective of reducing AEs during long-term RA treatment. Several studies have evaluated the impact of MTX discontinuation in RA patients who achieved good clinical response with tocilizumab (TCZ) plus MTX combination therapy, finding that discontinuing MTX is noninferior to continuing MTX in terms of maintaining clinical response (1-3). However, information on risk factors for disease flare after MTX discontinuation is lacking.Objectives:To investigate predictors of disease flare after MTX discontinuation in Japanese RA patients with sustained low disease activity undergoing TCZ plus MTX combination therapy.Methods:Participants of this multicenter, open-label, uncontrolled, prospective study were RA patients maintaining low disease activity (Clinical Disease Activity Index [CDAI] ≤10) for ≥12 weeks with TCZ plus MTX. Patients had to be receiving MTX orally at a stable dose of ≥6 mg/week, and TCZ at a stable dosage regimen irrespective of the route of administration, for ≥12 weeks prior to obtaining informed consent. MTX was discontinued after 12 weeks of biweekly administration while continuing TCZ therapy (Fig. 1). Disease flare was defined as a CDAI score &gt;10 or intervention with rescue treatments for any reason. The impact of baseline characteristics on disease flare at week 64 (52 weeks after MTX discontinuation) was assessed with logistic regression models.Results:Efficacy analyses were performed in 49 patients, of whom 15 had a disease flare by week 64. The proportion [95% confidence interval (CI)] of patients who maintained low disease activity without a flare at week 64 was 69.4% (54.6 – 81.8%) (Fig. 2A). According to Kaplan-Meier estimates, the cumulative flare-free rate was 70.0% at week 64 (Fig. 2B). The dosing interval of TCZ was longer than that described on the drug label (i.e., intravenously every 4 weeks, or subcutaneously every 2 weeks) in 27% and 6% of patients with and without a flare, respectively (Table 1). Multivariate analysis revealed that male sex [odds ratio (OR): 18.00, 95% CI: 2.80-115.56] and extended dosing interval of TCZ (OR: 12.00, 95% CI: 1.72-83.80) were independent predictors of disease flare.Table 1.Impact of baseline variables on disease flareNon-flareFlareOdds ratio (95% confidence interval)(n=34)(n=15)UnivariateMultivariateAge, years62 ± 1163 ± 91.01 (0.95-1.08)aMale, %64010.67 (1.83-62.18)*18.00 (2.80-115.56)*Weight, kg54 ± 858 ± 151.03 (0.98-1.09)aDisease duration, years11 ± 813 ± 91.03 (0.95-1.11)aRF positive, %76861.85 (0.34-10.04)ACPA positive, %85100-bRoute of TCZ, intravenous, %59802.80 (0.66-11.79)Extended TCZ dosing interval, %6275.82 (0.93-36.28)†12.00 (1.72-83.80)*MTX dose, mg/week8.2±2.28.0±2.60.95 (0.73-1.25)aUse of glucocorticoids, %26331.39 (0.37-5.18)Use of csDMARDs other than MTX, %9335.17 (1.04-25.57)*-Previous biologic use, %56803.16 (0.75-13.26)CDAI remission, %65731.50 (0.39-5.75)CRP, mg/dl0.04 ± 0.060.04 ± 0.060.42 (0.00-15115.38)aMMP-3, ng/ml58.5 ± 22.476.6 ± 37.61.02 (1.00-1.05)a†-Data are shown as mean ± SD or percentage.aOdds ratio for 1-unit increase in each item.bOdds ratio was not evaluated. *P&lt;0.05. †P&lt;0.10.Conclusion:Male patients and those receiving TCZ at an extended dosing interval are at high risk of disease flare after discontinuation of concomitant MTX.This work was supported by Chugai Pharmaceutical Co., Ltd.

Impact of Baseline Characteristics on Future Episodes of Bloodstream Infections: Multistate Model in Septic Patients With Bloodstream Infections.

Looking only at the index infection, studies have described risk factors for infections caused by resistant bacteria. We hypothesized that septic patients with bloodstream infections may transition across states characterized by different microbiology and that their trajectory is not uniform. We also hypothesized that baseline risk factors may influence subsequent blood culture results. All adult septic patients with positive blood cultures over a 7-year period were included in the study. Baseline risk factors were recorded. We followed all survivors longitudinally and recorded subsequent blood culture results. We separated states into bacteremia caused by gram-positive cocci, susceptible gram-negative bacilli (sGNB), resistant GNB (rGNB), and Candida spp. Detrimental transitions were considered when transitioning to a culture with a higher mortality risk (rGNB and Candida spp.). A multistate Markov-like model was used to determine risk factors associated with detrimental transitions. A total of 990 patients survived and experienced at least 1 transition, with a total of 4282 transitions. Inappropriate antibiotics, previous antibiotic exposure, and index bloodstream infection caused by either rGNB or Candida spp. were associated with detrimental transitions. Double antibiotic therapy (beta-lactam plus either an aminoglycoside or a fluoroquinolone) protected against detrimental transitions. Baseline characteristics that include prescribed antibiotics can identify patients at risk for subsequent bloodstream infections caused by resistant bacteria. By altering the initial treatment, we could potentially influence future bacteremic states.