Clinical Endpoints In Patients Research Articles

Associations of exercise-based cardiac rehabilitation with all-cause mortality among patients with atrial fibrillation

Abstract Funding Acknowledgements Type of funding sources: None. Background There is limited evidence of long-term impact of exercise-based CR on clinical endpoints for patients with AF. We therefore compared 18-month all-cause mortality, hospitalisation, stroke, and heart failure in patients with AF and an electronic medical record (EMR) of exercise-based CR to matched controls. Methods and Results This retrospective cohort study included patient data obtained on 11 December 2020, from a global federated health research network. AF patients undergoing exercise-based CR were propensity score matched to AF patients without exercise-based CR by age, sex, race, medication, and co-morbidities. We ascertained 18-month incidence of all-cause mortality, hospitalisation, stroke, and heart failure. Of 1,350,886 patients with AF, 10,625 patients had an EMR of exercise-based CR within 6-months of incident AF. The propensity score matched cohort of 21,250 patients with AF demonstrated that exercise-based CR was associated with 64% lower odds of all-cause mortality (odds ratio 0.36, 95% confidence interval (CI) 0.33-0.40), 41% lower odds of hospitalisation (0.59, 95% CI 0.56-0.63), and 17% lower odds of incident stroke (0.83, 95% CI 0.71-0.98) compared to propensity score matched controls. No significant associations were shown for heart failure at 18-months (0.92, 95% CI 0.81-1.02). The beneficial association of exercise-based CR on all-cause mortality was independent of sex, older age, comorbidities, and AF subtype. CONCLUSIONS Exercise-based CR among patients with incident AF was associated with lower odds of all-cause mortality, hospitalisation, and stroke at 18-months follow-up. The longitudinal nature of this retrospective follow-up study strongly supports the provision of exercise programmes for patients with incident AF.

Prognostic implications of epidermal and platelet-derived growth factor receptor alterations in 2 cohorts of IDHwt glioblastoma.

BackgroundGlioblastoma remains a deadly brain cancer with dismal prognosis. Genetic alterations, including IDH mutations, 1p19q co-deletion status and MGMT promoter methylation have been proven to be prognostic and predictive to response to treatment in gliomas. In this manuscript, we aimed to correlate other mutations and genetic alterations with various clinical endpoints in patients with IDH-wild-type (IDHwt) glioblastoma.MethodsWe compiled a comprehensive clinically annotated database of IDHwt GBM patients treated at the Ohio State University Wexner Medical Center for whom we had mutational data through a CLIA-certified genomic laboratory. We then added data that is publicly available from Memorial Sloan Kettering Cancer Center through cBioPortal. Each of the genetic alterations (mutations, deletions, and amplifications) served as a variable in univariate and multivariate Cox proportional hazard models.ResultsA total of 175 IDHwt GBM patients with available MGMT promoter methylation data from both cohorts were included in the analysis. As expected, MGMT promoter methylation was significantly associated with improved overall survival (OS). Median OS for MGMT promoter methylated and unmethylated GBM was 26.5 and 18 months, respectively (HR 0.45; P = .003). Moreover, EGFR/ERBB alterations were associated with favorable outcome (HR of 0.37 (P = .003), but only in MGMT promoter unmethylated GBM. We further found that patients with EGFR/ERBB alterations who also harbored PDGFRA amplification had a significantly worse outcome (HR 7.89; P = .025).ConclusionsOur data provide further insight into the impact of genetic alterations on various clinical outcomes in IDHwt GBM in 2 cohorts of patients with detailed clinical information and inspire new therapeutic strategies for IDHwt GBM.

PCN39 Impact of Medication Non-Adherence on Hard Clinical Endpoints in Patients with Breast Cancer: Results of a Systematic Literature Review

PCN39 Impact of Medication Non-Adherence on Hard Clinical Endpoints in Patients with Breast Cancer: Results of a Systematic Literature Review

Transcatheter Versus Surgical Aortic Valve Replacement in Patients with Cardiac Surgery: Meta-Analysis and Systematic Review of the Literature.

The number of patients with severe aortic stenosis (AS) and a history of prior cardiac surgery has increased. Prior cardiac surgery increases the risk of adverse outcomes in patients undergoing aortic valve replacement. To evaluate the impact of prior cardiac surgery on clinical endpoints in patients undergoing transcatheter aortic valve replacement (TAVR) versus surgical aortic valve replacement (SAVR), we performed a literature search using PubMed, Embase, Google Scholar, and Scopus databases. The clinical endpoints included in our study were 30-day mortality, 1–2-year mortality, acute kidney injury (AKI), bleeding, stroke, procedural time, and duration of hospital stay. Seven studies, which included a total of 8221 patients, were selected. Our study found that TAVR was associated with a lower incidence of stroke and bleeding complications. There was no significant difference in terms of AKI, 30-day all-cause mortality, and 1–2-year all-cause mortality between the two groups. The average procedure time and duration of hospital stay were 170 min less (p ≤ 0.01) and 3.6 days shorter (p < 0.01) in patients with TAVR, respectively. In patients with prior coronary artery bypass graft and severe AS, both TAVR and SAVR are reasonable options. However, TAVR may be associated with a lower incidence of complications like stroke and perioperative bleeding, in addition to a shorter length of stay.

Effects of two different glycoprotein platelet IIb/IIIa inhibitors and the clinical endpoints in patients with intracranial Pipeline flow diverter implant

ObjectiveTo compare the antiplatelet effect and major adverse cerebrovascular events of Pipeline for intracranial aneurysms using glycoprotein IIb/IIIa antagonists (GPI) eptifibatide and tirofiban. MethodsRetrospective analysis of relevant data of patients using GPIs combined with oral antiplatelet therapy in Nanfang Hospital of Southern Medical University from December 2017 to December 2019. The study was approved by the ethics Committee of Nanfang Hospital of Southern Medical University. According to the random use of GPIs drugs, they were assigned to the eptifibatide group and tirofiban group. Basic data, platelet inhibition rates at baseline, 24h and 72h after administration, short-term major adverse cerebrovascular events, and bleeding complications were compared between the two groups. ResultsA total of 47 patients were included in this study, including 24 patients in eptifibatide group and 23 patients in tirofiban group. There was no significant difference in average age (53.75 vs. 53.91 years) and body mass index (BMI) (24.39 vs. 22.73 ​kg/m2) between eptifibatide group and tirofiban group. There was no significant difference in coagulation factor function (R), fibrinogen function (K), fibrinolysis function (EPL), comprehensive coagulation index (Cl), arachidonic acid pathway inhibition rate (AA%) and adenosine diphosphate inhibition rate (ADP%). However, the baseline level of residual platelet function MA (ADP) in eptifibatide group was significantly higher than that in tirofiban group (50.79 vs. 35.29 ​mm, P ​= ​0.0026). There was a statistical difference in the platelet aggregation function MA (65.38 vs. 62.54 ​mm, p ​= ​0.0442), the rate of spontaneous hemorrhagic stroke (4.3% vs. 0%) and the rate of asymptomatic minor bleeding (26.08% vs. 4.1%) in the two groups (P ​< ​0.05). ConclusionBoth eptifibatide and tirofiban can effectively inhibit platelets, but the effect of etifeptide is better than that of tirofiban in preventing intracranial microhemorrhage and asymptomatic cerebral infarction.

Risk factors and associations with clinical outcomes of cytomegalovirus reactivation after haploidentical versus matched-sibling unmanipulated PBSCT in patients with hematologic malignancies.

In allogeneic hematopoietic stem cell transplantation recipients, cytomegalovirus (CMV) infection can cause overt CMV-associated disease, which is a main cause of transplantation-associated mortality. CMV infection correlates closely with donor's type. We therefore examined whether risk factors of CMV reactivation and clinical endpoints in patients with hematologic malignancies after allogeneic peripheral blood stem cell transplantation (PBSCT) differed between using matched-sibling donors (MSD-SCT) and haploidentical donors (HID-SCT). In this retrospective cohort study, we enrolled in 200 consecutive patients received an unmanipulated G-CSF-mobilized allogeneic PBSCT. Ninety (45%) patients received MSD-SCT and 110 (55%) received HID-SCT. Quantitative PCR was used for monitoring of CMV reactivation after transplantation. One-year cumulative incidence of CMV DNAemia was 55.0%, ranging from 23.5% in MSD-SCT group to 81.0% in HID-SCT group (p < 0.001). Although univariate analyses showed that non-myeloid malignancies, disease in complete remission status at transplantation, pretreatment with antithymocyte globulin, HLA-haploidentical donors, male donors, previous Epstein-Barr virus DNAemia, and absolute lymphocyte count on day 30 < 0.6 × 109/L were respectively associated with CMV reactivation after transplantation in total cohort of recipients (all p < 0.05), haploidentical donors were found to be the only independent predictor in multivariate analyses (Hazard ratio = 6.4, p < 0.001). Furthermore, univariate analyses revealed that non-myeloid malignancies and previous Epstein-Barr virus DNAemia were respectively associated with CMV reactivation in MSD-SCT recipients, and female was associated with CMV reactivation in HID-SCT recipients (all p < 0.05). In HID-SCT recipients, but not MSD-SCT recipients, previous CMV DNAemia was associated with a lower cumulative incidence of acute graft-versus-host disease (49.2% vs. 72.6%, p <0.001). CMV DNAemia did not play a role in the relapse rate, but it was strongly associated with an increased risk of non-relapse mortality either in total cohort of recipients (30.5% vs. 13.7%; p =0.003) or in the HID-SCT subgroup (36.0% vs. 16.7%; p =0.030). Relapse-free survival and overall survival in total cohort of recipients with CMV DNAemia were both inferior to those without CMV DNAemia (45.3% vs. 57.6% and 54.8% vs. 65.8%, respectively; both p < 0.05). However, in subgroup analysis according to donor's type, neither relapse-free survival nor overall survival was impacted by CMV status (both p >0.05). This study addressed differences in incidence, risk factors, and associations with clinical outcomes of CMV reactivation after haploidentical versus matched-sibling PBSCT.

COVID-19 Pandemic: Time to Revive the Cyclophilin Inhibitor Alisporivir.

December 2019 saw the emergence of a new epidemic of pneumonia of varying severity, called COVID-19, caused by a newly identified coronavirus, SARS-CoV-2. No therapeutic option is available to treat this infection that has already killed more than 235,000 people worldwide. This Viewpoint summarizes the strong scientific arguments supporting the use of alisporivir, a non-immunosuppressive analogue of cyclosporine A with potent cyclophilin inhibition properties that has reached Phase 3 clinical development, for the treatment of COVID-19. They include the strong cyclophilin dependency of the lifecycle of many coronaviruses, including SARS-CoV and MERS-CoV, and preclinical data showing strong antiviral and cytoprotective properties of alisporivir in various models of coronavirus infection, including SARS-CoV-2. Alisporivir should be tested without delay on both virological and clinical endpoints in patients with or at-risk of severe forms of SARS-CoV-2 infection.

Efficacy and Safety of PCSK9 Monoclonal Antibodies in Patients at High Cardiovascular Risk: An Updated Systematic Review and Meta-Analysis of 32 Randomized Controlled Trials

Proprotein convertase subtilisin/kexin type9 (PCSK9) monoclonal antibodies are powerful lipid-lowering drugs which have been shown to improve clinical endpoints in patients with hypercholesterolemia. However, it is not clear how effective PCSK9 monoclonal antibodies are for patients at high cardiovascular risk. Also, whether the effectiveness of PCSK9 monoclonal antibodies varies between different drug types, dosages, race, and indications for PCSK9 monoclonal antibodies remains unclear. Therefore, we used recently published studies to systematically evaluate the efficacy and safety of PCSK9 monoclonal antibodies by analyzing the lipid profiles, adverse events, and clinical endpoints in patients at high cardiovascular risk. Randomized controlled trials (RCTs) comparing PCSK9 monoclonal antibodies with placebos or active drugs in patients at high cardiovascular risk were retrieved from electronic databases from their inception until November 2019. Efficacy and safety outcomes included low-density lipoprotein cholesterol (LDL-C) and other lipid profiles, treatment-emergent adverse events (TEAEs) and adverse events of interests, and clinical endpoints. Subgroup analyses based on drug types, dosing, and race were conducted. Statistical analysis was performed using STATA15.1 and RevMan5.0. Thirty-two RCTs were included in the systematic review, and 25 of them (57,090 individuals) were included in the meta-analysis. PCSK9 monoclonal antibodies significantly improved LDL-C and other lipid profiles (P < 0.05), and no racial differences were found. A recommended dose of 140mg of evolocumab every 2weeks was likely to produce a relatively stronger effect than 150mg of alirocumab every 2weeks in terms of the absolute change (weighted mean differences (WMD) - 0.36; 95% confidence interval (CI) - 0.71 to - 0.01; P = 0.041) and percent change (WMD - 19.53; 95% CI - 32.02 to - 7.04; P = 0.002) in LDL-C levels. Overall, PCSK9 monoclonal antibodies were safe, except for the significantly increased risk of injection site reactions (relative risks (RR) 1.54; 95% CI 1.38-1.71; P < 0.001). Both alirocumab (RR 0.89; 95% CI 0.83-0.95; P < 0.001) and evolocumab (RR 0.86; 95% CI 0.80-0.92; P < 0.001) were associated with a lower risk of major cardiovascular events (MACEs), especially in secondary preventive patients (alirocumab group: RR 0.88; 95% CI 0.82-0.95; P < 0.001; evolocumab group: RR 0.86; 95% CI 0.80-0.92; P < 0.001). The reduction in MACEs was observed in White but not in Asian subjects. No significant reduction of all-cause mortality was found (RR 0.88; 95% CI 0.72-1.07; P = 0.182). Both alirocumab and evolocumab are well tolerated and can greatly improve lipid profiles for patients at high cardiovascular risk. Both PCSK9 monoclonal antibodies significantly reduce the risk of nonfatal MACEs in patients with previous cardiovascular events, but the effect on all-cause mortality remains uncertain.

Dual antiplatelet therapy in coronary artery disease: from the past to the future prospective.

Antiplatelet therapy, the cornerstone of post coronary stenting antithrombotic therapy, reduces the rate of hard clinical endpoints in patients treated both conservatively and invasively following an acute coronary syndrome, as well as in those patients with chronic stable coronary disease who receive a coronary stent. The development of newer antiplatelet and direct anticoagulant agents provides new options in the antithrombotic management of patients with coronary artery disease, enabling different therapeutic combinations to be tailored to an individual patient's bleeding and ischemic risk profile. In this review, we will summarize the history of dual antiplatelet therapy, discuss the latest evidence and future perspectives in treating patients with coronary artery disease.

Pharmacist Interventions in Improving Clinical Outcomes in Patients with Type 2 Diabetes Mellitus Among the Underrepresented Population: A Collaborative Ambulatory Care Pharmacy Practice (CAPP) Approach.

Objective:The objective of this study was to evaluate the impact of pharmacist's interventions through a collaborative ambulatory care pharmacy practice (CAPP) model in patients with type 2 diabetes mellitus (T2DM) among the underrepresented population.Methods:Eligible patients were 18 years and older with a diagnosis of T2DM with or without comorbid cardiovascular disease risk factors. Patients were enrolled through routine primary care provider referrals. During a one-on-one, face-to-face scheduled clinic visit, the pharmacist provided a comprehensive medication management by reviewing vital signs and laboratory values, provided medication reconciliation and management, followed by medication counseling through a CAPP approach in a primary care setting. The pharmacist worked in close collaboration with the primary care provider to intervene on medication therapy through recommendations to initiate, adjust, modify, or discontinue drug therapy and order laboratory tests and drug concentration levels as appropriate. Each visit was documented as a “PharmD Progress Note” in the patient's electronic medical record. Follow-up visits were scheduled until patients' targeted treatment goals were achieved. Primary and secondary outcome data were collected and then analyzed.Findings:A pharmacist saw 47 patients over 12 months. Sixty-four percent of the participating patients were able to achieve targeted treatment goals. A statistically significant decrease in the mean change in hemoglobin A1c, diastolic blood pressure, fasting blood glucose, and triglyceride levels was observed from the baseline which was −2.3%, −7.75 mmHg, −76.1 mg/dL, and −55.5 mg/dL, respectively. No significant changes in other clinical outcomes were observed.Conclusion:The CAPP model demonstrated a significant reduction in clinical endpoints in patients with T2DM among the high-risk underrepresented population.

Machine-Learning and Stochastic Tumor Growth Models for Predicting Outcomes in Patients With Advanced Non-Small-Cell Lung Cancer.

The prediction of clinical outcomes for patients with cancer is central to precision medicine and the design of clinical trials. We developed and validated machine-learning models for three important clinical end points in patients with advanced non-small-cell lung cancer (NSCLC)-objective response (OR), progression-free survival (PFS), and overall survival (OS)-using routinely collected patient and disease variables. We aggregated patient-level data from 17 randomized clinical trials recently submitted to the US Food and Drug Administration evaluating molecularly targeted therapy and immunotherapy in patients with advanced NSCLC. To our knowledge, this is one of the largest studies of NSCLC to consider biomarker and inhibitor therapy as candidate predictive variables. We developed a stochastic tumor growth model to predict tumor response and explored the performance of a range of machine-learning algorithms and survival models. Models were evaluated on out-of-sample data using the standard area under the receiver operating characteristic curve and concordance index (C-index) performance metrics. Our models achieved promising out-of-sample predictive performances of 0.79 area under the receiver operating characteristic curve (95% CI, 0.77 to 0.81), 0.67 C-index (95% CI, 0.66 to 0.69), and 0.73 C-index (95% CI, 0.72 to 0.74) for OR, PFS, and OS, respectively. The calibration plots for PFS and OS suggested good agreement between actual and predicted survival probabilities. In addition, the Kaplan-Meier survival curves showed that the difference in survival between the low- and high-risk groups was significant (log-rank test P < .001) for both PFS and OS. Biomarker status was the strongest predictor of OR, PFS, and OS in patients with advanced NSCLC treated with immune checkpoint inhibitors and targeted therapies. However, single biomarkers have limited predictive value, especially for programmed death-ligand 1 immunotherapy. To advance beyond the results achieved in this study, more comprehensive data on composite multiomic signatures is required.

Sodium Glucose Cotransporter 2 Inhibition Heralds a Call-to-Action for Diabetic Kidney Disease.

Diabetes is a global health emergency with 425 million people affected in the year 2017 and a projection for 629 million by 2045. Half develop diabetic kidney disease, and its prevalence is rising progressively in concert with the overall diabetes epidemic, largely driven by type 2 diabetes ([1][1

2427 A Case of Hepatitis B Virus-Related Membranous Nephropathy in an Adult With Low Hepatitis B Viral Load

INTRODUCTION: Hepatitis B virus (HBV) infection is an important etiologic factor for secondary membranous nephropathy (MN), especially in regions with endemic HBV infection. Though an uncommon occurrence, it is crucial to recognize HBV-related MN as it may progress to renal failure in untreated adults. In patients with HBV infection, it is critical to exclude other secondary causes of MN. This case describes a case of HBV-related MN in a HBeAg-negative patient with low HBV viral load. CASE DESCRIPTION/METHODS: Mr C is a 64 year old gentleman who has underlying chronic HBV infection and Stage 3b chronic kidney disease. He presented with bilateral lower limb swelling. He was found to have hypoalbuminemia and nephrotic range proteinuria associated with microscopic hematuria. He was in “inactive chronic HBV carrier infection” phase with negative hepatitis B e antigen (HBeAg), positive anti-HBe and low HBV viral load 2.68 log IU/ml with positive antinuclear antibody and low complement C3. Other workup for secondary causes of membranous nephropathy was unyielding. Renal biopsy showed membranous nephropathy with focal proliferative glomerulonephritis. Immunofluorescence was not suggestive of lupus nephritis and staining for antiphospholipase A2 receptor was negative. He was diagnosed as HBV-related MN and he was treated with Tenofovir Alafenamide. Six months after HBV treatment, his proteinuria has improved with stable renal function. HBV viral load was suppressed to less than 1.3 log IU/ml but he still had high titer of HBsAg (7000 IU/ml) as expected. DISCUSSION: In HBV-related MN, HBV treatment is recommended as previous studies showed that HBV treatment and HBeAg clearance are associated with remission of MN. However, treatment endpoint remains unclear. The pathogenesis of HBV-related glomerular disease is due to the deposition of HBV antigens immune complexes in the glomerulus, especially to HBeAg. Therefore, MN can occur in patients with low HBV viral load. In HBeAg-positive patients, it may be reasonable to consider stopping antiviral following clearance of HBeAg. In HBeAg-negative patients, HBsAg immune complexes may contribute to MN. As in this case, it may be prudent to continue with HBV therapy as he has persistently high HBsAg titer. Future research is needed to find reliable HBV markers to guide management and define clinical end points for patients with HBV-related MN.

The relationship between serum and sputum levels of azithromycin and clinical endpoints in patients with bronchiectasis using azithromycin maintenance treatment

The relationship between serum and sputum levels of azithromycin and clinical endpoints in patients with bronchiectasis using azithromycin maintenance treatment

Implant-based multi-parameter telemonitoring of patients with heart failure and a defibrillator with vs. without cardiac resynchronization therapy option: a subanalysis of the IN-TIME trial

AimsIn the IN-TIME trial, automatic daily implant-based multiparameter telemonitoring significantly improved clinical outcomes in patients with chronic systolic heart failure and implantable cardioverter-defibrillator (ICD) or cardiac resynchronization therapy defibrillator (CRT-D). We compared IN-TIME results for ICD and CRT-D subgroups.MethodsPatients with LVEF ≤ 35%, NYHA class II/III, optimized drug treatment, no permanent atrial fibrillation, and a dual-chamber ICD (n = 274) or CRT-D (n = 390) were randomized 1:1 to telemonitoring or no telemonitoring for 12 months. Primary outcome measure was a composite clinical score, classified as worsened if the patient died or had heart failure-related hospitalization, worse NYHA class, or a worse self-reported overall condition.ResultsThe prevalence of worsened score at study end was higher in CRT-D than ICD patients (26.4% vs. 18.2%; P = 0.014), as was mortality (7.4% vs. 4.1%; P = 0.069). With telemonitoring, odds ratios (OR) for worsened score and hazard ratios (HR) for mortality were similar in the ICD [OR = 0.55 (P = 0.058), HR = 0.39 (P = 0.17)] and CRT-D [OR = 0.68 (P = 0.10), HR = 0.35 (P = 0.018)] subgroups (insignificant interaction, P = 0.58–0.91).ConclusionDaily multiparameter telemonitoring has a potential to reduce clinical endpoints in patients with chronic systolic heart failure both in ICD and CRT-D subgroups. The absolute benefit seems to be higher in higher-risk populations with worse prognosis.

Pretreatment hematological markers predict clinical outcome in cancer patients receiving immune checkpoint inhibitors: A meta-analysis.

BackgroundImmune checkpoint inhibitors (ICIs) have revolutionized the clinical treatment of multiple cancers. Recent studies revealed the potential prognostic value of the neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) in patients receiving ICIs; however, the results were inconsistent. We conducted a meta‐analysis to identify the prognostic significance of baseline NLR and PLR in cancer patients treated with ICIs.MethodsWe conducted a thorough literature search of PubMed, Embase, and Cochrane databases for studies dealing with the prognostic impact of pretreatment NLR and/or PLR levels in cancer patients treated with ICIs. The clinical outcomes were progression‐free survival (PFS) and overall survival (OS). Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated, and sensitivity and subgroup analyses were performed to investigate heterogeneity.ResultsSeventeen articles involving 2092 patients were included in the final analysis. The pooled HRs of PFS and OS for NLR were 1.81(95% CI 1.36–2.41) and 2.26 (95% CI 1.68–3.03), respectively, suggesting that patients with higher baseline NLRs had significantly poorer PFS and OS. Similar results were detected in sensitivity and subgroup analyses. However, no significant relevance was found between PLR and clinical endpoints in patients treated with ICIs (HR = 1.14, 95% CI 0.88–1.48 for PFS; HR = 1.35, 95% CI 0.86–2.12 for OS).ConclusionThese results indicate that high pretreatment NLR but not PLR level, as a routinely obtained hematological parameter, is a potential prognostic predictor for poor PFS and OS in cancer patients receiving ICIs.

Clinical efficacy of the Toll-like receptor 9 agonist cobitolimod using patient-reported-outcomes defined clinical endpoints in patients with ulcerative colitis

BackgroundThe Toll-like-receptor 9 (TLR-9) agonist cobitolimod (DIMS0150, Kappaproct®) is a promising therapeutic option for ulcerative colitis (UC) patients. AimsThe objectives of this post-hoc analysis using the COLLECT study data was to investigate the clinical effects of cobitolimod using patient-reported-outcomes (PRO) defined endpoints. MethodsDual topical administration of cobitolimod was studied in a randomised, multicentre clinical trial named COLLECT in moderate-to-severe UC patients. Symptomatic remission (SR) was studied in 104 patients based on their e-diary records and was defined as absence of blood in stool and a mean daily stool frequency (SF) < 4. ResultsSR was achieved at week 4 in 17.1% of cobitolimod vs. 5.9% of placebo treated patients (p = 0.13), at week 8 in 35.7% vs. 17.6% (p = 0.07), and at week 12 in 38.6% vs. 17.6% (p = 0.04) of the patients, respectively.SR rates with cobitolimod and placebo in anti-TNFα experienced patients were smaller but with a broadly similar relative effect-size to anti-TNFα naïve patients. Clinical efficacy was higher in patients with moderate compared to severe disease. ConclusionsApplication of the Toll-like-receptor 9 (TLR-9) agonist cobitolimod is able to induce remission as assessed by PRO measures in UC patients with moderate-to-severe activity as well as in anti-TNFα experienced and naïve patients supporting the overall efficacy of the substance.

Cerebral protection devices in transcatheter aortic valve replacement: a clinical meta-analysis of randomized controlled trials.

Neurological complications after undergoing transcatheter aortic valve replacement (TAVR) may be reduced with cerebral protection (CP) devices. However, randomized controlled trials (RCTs) have failed to demonstrate convincing evidence of improvements in hard clinical endpoints in patients with CP. The aim of this study was to compare clinical outcomes of TAVR patients with and without CP devices. Electronic searches were performed using four electronic databases from their dates of inception to May 2017. RCTs that reported outcomes for patient cohorts that underwent TAVR procedures with and without CP were included. Crude odds ratios (ORs) and 95% confidence intervals were calculated using random effects model. A total of five RCTs were included, totalling 643 patients, 386 of whom were randomized to TAVR + CP and 257 with TAVR only. The primary composite endpoint of all-cause mortality and stroke at 30 days was lower in patients undergoing CP devices compared to those patients with TAVR alone (OR, 0.54; 95% CI, 0.30 to 0.98). Use of CP devices was also associated with lower new total lesion volume (standardised mean difference, -0.49; 95% CI, -0.96 to -0.03). There was a non-significant reduction in the risk of secondary clinical endpoints of all-cause mortality, stroke, life-threatening bleed, acute kidney injury and major vascular complications in patients randomized to TAVR + CP. Use of CP devices in TAVR appears to be safe and may be associated with a reduction in stroke/death.

Value of latent outflow obstruction to predict clinical course of patients with hypertrophic cardiomyopathy

Objective The frequency, significance and prognostic value of left ventricle obstruction (LVO) induced with provocation (latent LVO) is controversial for hypertrophic cardiomyopathy (HC) patients. This study was designed to assess the value of latent LVO in predicting the clinical course in 101 patients with HC.Methods and results Patients were followed for a mean of 82 ± 48 months (range 2 to 148 months) for clinical end points defined as a composite of cardiovascular death resuscitated cardiac arrest, appropriate defibrillator shock or hospitalization due to worsening of heart failure symptoms. Presence of LVO (hazard ratio 3.63; 95% confidence interval, 1.85 to 7.12; P = 0.0001) and log NT-proBNP levels (hazard ratio, 1.40; 95% confidence interval, 1.14 to 1.72; P = 0.001) were the independent variables associated with an increased risk of experiencing clinical end points. HC patients with latent LVO have a trend toward decreased survival when compared with HC patients without LVO (log rank P = 0.027), but better survival than patients with resting LVO (log rank P = 0.007). HC patients with NT-proBNP levels <1,000 pg/ml had also better survival. LVO and NT-proBNP levels are the major determinants of clinical end points in patients with HC.Conclusions Evaluation of patients without resting LVO to demonstrate latent obstruction is of critical importance in respect of outcome and selection of patients for septal reduction therapies, so routine provocative testing with physiological exercise and measurement of NT-proBNP is recommended in this patient population for risk stratification.

Translation from SCD Mouse to Man: Chronic Administration of Tucaresol Reduces RBC Sickling and Improves Hematological Parameters, but Does Not Impact Inflammatory Markers in SCD Model Mice

Sickle cell disease is a hematological disorder with significant unmet need that affects approximately ten million people worldwide. Currently, treatment for SCD is limited to a single approved drug, Hydroxyurea, and palliative treatments such as hydration and pain management. The limited treatment options have led to considerable interest in developing new therapies for SCD. One strategy for a disease-modifying treatment for SCD is stabilization of the oxygenated form of hemoglobin (OxyHb) by a small molecule allosteric modulator (Zaugg et. Al, JBC, 1977). One such compound, Tucaresol was advanced into clinical trials on the strength of the pre-clinical data, however a SCD mouse model was unavailable when the trial was initiated. The renewed interest in stabilizing OxyHb with a small molecule presents an opportunity to use Tucaresol as a mechanism for understanding the translation between effects seen in an animal model and clinical endpoints in patients. In this study, we treated Townes SCD mice with Tucaresol for 15 days, to evaluate its effect on hematology, oxygen affinity, sickling and markers of inflammation in vivo. These results are compared to the clinical data reported in the original trials.Tucaresol is a substituted benzaldehyde derived from a class of molecules known to preferentially bind to hemoglobin and stabilize the oxygenated state by formation of a Schiff base linkage at a site on the a-chains (Rolan et. Al, Br. J. Clin. Pharm., 1995). Earlier molecules acting by this mechanism had been shown to reduce Hb S polymerization and RBC sickling in vitro, and it was theorized that long-term treatment with such molecules would impact hemolysis and occurrence of vaso-occlusive crisis (VOC) (Beddell et. Al, Br. J. Pharmac. 1984). Preclinical studies demonstrated Tucaresol modification of Hb S delays the polymerization process and inhibits RBC sickling. In clinical trials, Tucaresol positively impacted hematological markers including hemoglobin and reticulocyte counts, and reduced the percentage of irreversibly sickled cells. However, trials of Tucaresol were halted due to a significant immune response and specific inflammatory markers were not measured during the trial.To study these effects in Townes SCD model, mice were dosed with Tucaresol at 30 mg/kg twice a day, for fifteen days. The dose was selected to be consistent with clinical dosing regimens. Blood was collected prior to study start from individual animals to obtain baseline levels for hematological parameters and soluble cell adhesion molecules in plasma. Blood was sampled at day 3 and day 10 of dosing to understand drug exposure and accumulation. At this dose, Tucaresol demonstrated a steady state achieved by day 10 and the blood concentration ranged from 0.5-1.6 mM on day 15. Following two week dosing with Tucaresol, we observed a 50% increase in hemoglobin, and 24% increase in mean corpuscular hemoglobin concentration (MCHC), relative to vehicle treated animals. Reticulocytes, a clinical indicator of hemolytic anemia, are highly elevated in SCD patients and mice, also showed a 47% decrease in Tucaresol treated relative to vehicle treated animals. Oxygen affinity measurements showed a decrease in P50 and P20 values for treated animals, indicating increased oxygen affinity, consistent with the proposed mode of action of Tucaresol- stabilization of the oxygenated state. The percentage of sickled erythrocytes was also decreased by 38% in Tucaresol treated SCD mice when compared to vehicle controls. The decrease in sickling is consistent with the clinical observation of a 52% (mean) decrease in irreversibly sickled cells. In contrast to the improvement seen with hematological parameters, inflammatory markers remained either unchanged or slightly elevated after 15 days of treatment with Tucaresol. Plasma levels of sICAM-1 and sVCAM-1 were unchanged while sE-Selectin was elevated. In summary, in this short course of treatment of SCD mice, Tucaresol had an impact on the hematological markers that was consistent with effects observed in the clinic, but did not modulate the inflammation response.All experiments were within guidelines and were reviewed and approved by Pfizer institutional animal care and use committee. DisclosuresKnee:Pfizer Inc: Employment. Jasuja:Pfizer: Employment. Barakat:Pfizer: Employment. Kelly:Pfizer: Employment. Singh:Pfizer Inc: Employment. Janz:Pfizer: Employment.