Greater Mean Reduction Research Articles

Does stereotactic thrombolysis with alteplase for intracerebral haemorrhage alter intraventricular haematoma volume? A secondary analysis of the MISTIE-III trial

BackgroundStereotactic thrombolysis reduces intracerebral haemorrhage (ICH) volume in patients with spontaneous ICH. Whether intrahaematomal alteplase administration is associated with a change in intraventricular haemorrhage volume (deltaIVH) and functional outcomes is...

An Assessment of the Efficacy of an Online Pain Management Programme During the Covid-19 Pandemic.

Following the outbreak of the Covid-19 pandemic and associated social distancing requirements, Pain Services were no longer able to deliver face-to-face Pain Management Programmes (PMP). As an alternative, the Bury Integrated Pain Service developed an interactive, online programme, delivered via Microsoft Teams videoconferencing technology. However, the efficacy of such programmes is unclear. The aim of this project was to assess whether comparable results were observed with online PMPs as with face-to-face PMPs. A non-inferiority study comparing patients attending an online PMP to a historical cohort of patients attending face-to-face PMPs. Analyses of variance were performed to assess between group differences and chi squared tests to compare the proportion of patients making clinically meaningful changes in pain, musculoskeletal health, anxiety, depression and self-efficacy. 24% of patients (n=9) deemed suitable for the online PMP were unable to participate due to technological difficulties. This resulted in 28 people attending the online PMP. Greater mean reductions in anxiety (GAD-7 mean difference=1.9; p<0.05) and depression (PHQ-9 mean difference 3.3; p<0.05) were observed with face-to-face PMP and a greater proportion of patients made clinically meaningful improvements in musculoskeletal health (face-to-face=13; online=5), anxiety (face-to-face=7; online=1), and depression (face-to-face=11; online=2). Some patients appear to obtain significant benefit from online PMPs, but this appeared to be to a lesser extent than face-to-face PMPs. It is possible that factors related to the experience of the pandemic influenced these results. However, online PMPs appear to show some promise and further research is warranted to explore the value of online PMPs.

Efficacy and safety of tirzepatide in people with type 2 diabetes by baseline body mass index: An exploratory subgroup analysis of SURPASS-AP-Combo.

To assess the efficacy and safety of tirzepatide versus insulin glargine in people with type 2 diabetes (T2D) by baseline body mass index (BMI). Participants with T2D from the Phase 3 SURPASS-AP-Combo trial (NCT04093752) were categorized into three BMI subgroups (normal weight [<25 kg/m2 ], overweight [≥25 and <30 kg/m2 ], and obese [≥30 kg/m2 ]) according to World Health Organization criteria. Exploratory outcomes including glycaemic control, body weight, cardiometabolic risk, and safety were compared among three tirzepatide doses (5, 10 or 15 mg) and insulin glargine. Of 907 participants, 235 (25.9%) had a BMI <25 kg/m2 , 458 (50.5%) a BMI ≥25 to <30 kg/m2 , and 214 (23.6%) a BMI ≥30 kg/m2 at baseline. At Week 40, all tirzepatide doses led to a greater reduction in mean glycated haemoglobin (HbA1c; -2.0% to -2.8% vs. -0.8% to -1.0%, respectively) and percent change in body weight (-5.5% to -10.8% vs. 1.0% to 2.5%, respectively) versus insulin glargine, across the BMI subgroups. Compared with insulin glargine, a higher proportion of tirzepatide-treated participants achieved treatment goals for HbA1c and body weight reduction. Improvements in other cardiometabolic indicators were also observed with tirzepatide across all the BMI subgroups. The safety profile of tirzepatide was similar across all subgroups by BMI. The most frequent adverse events with tirzepatide were gastrointestinal-related events and decreased appetite, with relatively few events leading to treatment discontinuation. In participants with T2D, regardless of baseline BMI, treatment with tirzepatide resulted in statistically significant and clinically meaningful glycaemic reductions and body weight reductions compared with insulin glargine, with a safety profile consistent with previous reports.

Cardiovascular and metabolic effects of MANP. a novel GC-A activator, in human hypertension with metabolic syndrome

Abstract Background/Introduction Hypertension (HTN) and metabolic syndrome (MetS) are both leading risk factors for major cardiovascular diseases, which frequently coexist as a complicated cardiometabolic disorder. The cardiac hormone atrial natriuretic peptide (ANP) plays a key role in both blood pressure and metabolic regulation through activation of the guanylyl cyclase-A receptor (GC-A) and the second messenger 3’,5’ cyclic guanosine monophosphate (cGMP). Indeed, ANP decreases blood pressure, induces lipolysis by increasing plasma levels of non-esterified fatty acids (NEFA) and improves insulin-sensitivity. MANP is a new Mayo Clinic designed natriuretic peptide consisting of the native ANP with a 12-amino-acid C-terminus extension and its biological actions are mediated by the GC-A/cGMP pathway. MANP is less susceptible to neprilysin degradation and exert more sustained cGMP dependent biological actions than ANP. Purpose In a proof-of-principle human study, for the first time we aimed to determine the cardiovascular and metabolic properties of MANP, a novel ANP analog, in the clinical setting of HTN with MetS. Methods We conducted a double-blind, placebo-controlled trial in 22 patients (17 receiving MANP) with HTN and MetS involving single subcutaneous injection of MANP (2.5 µg/kg) or placebo (NCT03781739). Blood pressure (BP) and circulating cGMP were monitored for 24 hours post treatment. Circulating metabolic parameters including insulin, glucose, non-esterified fatty acids (NEFA) and insulin resistance (HOMA-IR) and insulin sensitivity (HOMA-IS) indexes were assessed for the first 4 hours post treatment. Results Compared to baseline, MANP increased plasma cGMP at 30 minutes (delta: 4.8 ± 2.0 pmol/mL, P = 0.02) and 1 hour (delta: 2.9 ± 1.3 pmol/mL, P = 0.03) post injection. At 6 hours, systolic BP decreased by 5.7 ± 2.9 mmHg (P = 0.06) in the MANP group, whereas no reduction in BP was observed in placebo group. Among the 17 subjects receiving MANP, lower baseline cGMP levels were associated with greater mean reductions in systolic BP (ρ = 0.66, P = 0.005). After MANP injection, glucose levels decreased at 2 (delta: -4.7 ± 2.1 mg/mL, P = 0.04) and 4 hours (delta: -13.1 ± 3.9 mg/mL, P = 0.003) compared to baseline while insulin levels remained stable. During the first 4 hours post injection, we also observed a trend of increase in insulin sensitivity index (HOMA2-IS) and decrease in insulin resistance index (HOMA2-IR) with MANP, both were opposite to the trends in placebo. At 1 hour post MANP administration, NEFA increased by 108.2 ± 37.4 µM compared to baseline (P = 0.01). Conclusion(s) Our findings support the favorable cardiovascular and metabolic actions of MANP as a potential therapeutic strategy for HTN with MetS.

Clinical Effects of Subgingivally Delivered Achyranthes Aspera Gel in Chronic Periodontitis: A Clinical and Microbiological Study.

Periodontitis is an inflammatory disease of microbial origin. Local drug delivery agents help reduce subgingival microflora. Achyranthes aspera is a medicinal herb with antimicrobial, antioxidant, anti-inflammatory, and wound-healing properties. A split-mouth study was conducted, in which 60 sites were included. Clinical parameters included measurements of probing depth (PD), gingival index, and clinical attachment level (CAL). Gingival crevicular fluid (GCF) samples were collected, followed by microbiological analysis of Porphyromonas Gingivalis. Clinical and microbiological parameters were recorded at baseline and after 3 months. Statistical analysis was done using the Statistical Package of Social Science (SPSS Version 22; Chicago Inc., USA). At 3 months, Group A resulted in greater mean reductions in clinical parameters: PD (3.77) as compared to Group B (5.23), and also greater mean CAL gain (3.18) in group A as compared to Group B (5.16). Group A also showed a significant reduction in the number of sites harboring periodontopathogens as compared to Group B. A. aspera gel can be used as a nonsurgical local drug delivery agent in patients with chronic periodontitis as an effective adjunct to SRP.

Evaluation of the change in efficacy of erenumab when used long-term for migraine prevention after initial established benefit in a veteran population.

With the increased use of erenumab and other calcitonin gene-related peptide antagonists for migraine prevention, increased evidence on long-term efficacy and real-world effectiveness is needed. Some reports of a wearing-off effect or waning efficacy over time have been observed with erenumab use. This study evaluated the change in efficacy of erenumab after initial established benefits for migraine prevention in a veteran population. This retrospective chart review evaluated patients who were prescribed erenumab for migraine prevention at a Veterans Affairs neurology clinic between June 1, 2018, and May 31, 2021. Patients with an initial 50% or greater reduction in mean monthly headache days (MHDs) by 12 weeks after erenumab 70 mg initiation were then followed forward to determine the change in MHDs until erenumab dose was increased, changed to galcanezumab, or by November 30, 2021, to ensure a minimum 6-month follow-up for all patients. Ninety-three patients were included for analysis. A significant reduction in mean MHDs from 16.1 to 5.7 days was found by 12 weeks after erenumab 70 mg initiation (p < 0.0001). Following this initial response to erenumab, 69% of patients experienced a significant increase in MHDs over an average time of 7.8 months and required a subsequent dose increase to erenumab 140 mg or change to galcanezumab. The remaining 31% of patients continued erenumab 70 mg monthly with a further nonstatistically significant decline in MHDs. A decrease in efficacy with the long-term use of erenumab was observed for the majority of patients evaluated in this analysis. This suggests that patients with initial benefits on lower dose erenumab should be monitored for change to effectiveness.

Effect of pharmacological interventions for the treatment of people with post‐COVID‐19 condition: A rapid review

AbstractObjectiveLittle is known about the treatment of post‐coronavirus disease 2019 (COVID‐19) condition (PCC). This article examines the effectiveness of pharmacological interventions for treating people with PCC.MethodsWe searched Medline, EMBASE, ClinicalTrials. gov, and the International Clinical Trials Registry Platform. Two independent review authors screened citations, extracted data, and assessed the quality of the included studies. Due to heterogeneity in participants, interventions, and outcomes, we synthesized data narratively. We assessed the certainty of evidence using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation).ParticipantsPeople with PCC.InterventionsPharmacological interventions include corticosteroids, ivabradine, and inhaled hydrogen.Outcome MeasuresOlfactory function, sinus tachycardia, respiratory function.ResultsWe identified 5 completed studies and 41 ongoing studies. Oral corticosteroids and olfactory training had higher olfactory scores after 10 weeks (MD: 5.60, 95% confidence interval [CI]: 1.41 to 9.79). Patients allocated oral corticosteroid, and nasal irrigation demonstrated improved recovery of olfactory function compared with the control group at 40 days (median 60, interquartile range [IQR]: 40 vs. median 30, IQR: 25, p = 0.024). Patients allocated to topical corticosteroid nasal spray and olfactory training had improved recovery of olfactory function after 2 weeks (median 7, IQR: 5−10 vs. median 5, IQR: 2−8, p = 0.08). Participants allocated to ivabradine had a greater mean reduction in heart rate compared with participants randomized to carvedilol (MD: −4.24, 95% CI: −10.09 to 1.61). Participants allocated to inhaled hydrogen therapy had an improved vital capacity (MD: 0.20, 95% CI: 0.07 to 0.33), forced expiratory volume (MD: 0.19, 95% CI: 0.04 to 0.34), 6‐minute walk test (MD: 55.0, 95% CI: 36.04 to 73.96).ConclusionsThe evidence is of low to very low certainty about the effect of all pharmacological interventions investigated for the treatment of people with PCC. There is currently a significant body of research underway that could expand the evidence to inform treatment decisions on pharmacological interventions for PCC.

Effect of Selective Personality-Targeted Alcohol Use Prevention on 7-Year Alcohol-Related Outcomes Among High-risk Adolescents

Alcohol consumption is one of the leading preventable causes of burden of disease worldwide. Selective prevention of alcohol use can be effective in delaying the uptake and reducing harmful use of alcohol during the school years; however, little is known about the durability of these effects across the significant transition from early adolescence into late adolescence and early adulthood. To examine the sustained effects of a selective personality-targeted alcohol use prevention program on alcohol outcomes among adolescents who report high levels of 1 of 4 personality traits associated with substance use. A cluster randomized clinical trial was conducted to assess the effectiveness of the selective personality-targeted PreVenture program on reducing the growth of risky alcohol use and related harms from early to late adolescence and early adulthood. Participants included grade 8 students attending 14 secondary schools across New South Wales and Victoria, Australia, in 2012 who screened as having high levels of anxiety sensitivity, negative thinking, impulsivity, and/or sensation seeking. Schools were block randomized to either the PreVenture group (7 schools) or the control group (7 schools). The primary end point of the original trial was 2 years post baseline; the present study extends the follow-up period from July 1, 2017, to December 1, 2019, 7 years post baseline. Data were analyzed from July 22, 2021, to August 2, 2022. The PreVenture program is a 2-session, personality-targeted intervention designed to upskill adolescents to better cope with their emotions and behaviors. Self-reported monthly binge drinking, alcohol-related harms, and hazardous alcohol use measured by the Alcohol Use Disorders Identification Test-Concise consumption screener. Of 438 participants (249 male [56.8%]; mean [SD] age, 13.4 [0.5] years) from 14 schools, 377 (86.2%) provided follow-up data on at least 2 occasions, and among those eligible, 216 (54.0%) participated in the long-term follow-up. Compared with the control condition, the PreVenture intervention was associated with reduced odds of any alcohol-related harm (odds ratio [OR], 0.81 [95% CI, 0.70-0.94]) and a greater mean reduction in the frequency of alcohol-related harms (β = -0.22 [95% CI, -0.44 to -0.003]) at the 7.0-year follow-up. There were no differences in the odds of monthly binge drinking (OR, 0.80 [95% CI, 0.56-1.13]) or hazardous alcohol use (OR, 0.87 [95% CI, 0.59-1.27]) at the 7.0-year follow-up. Exploratory analyses at the 5.5-year follow-up showed that compared with the control condition, the PreVenture intervention was also associated with reduced odds of monthly binge drinking (OR, 0.87, [95% CI, 0.77-0.99]) and hazardous alcohol use (OR, 0.91 [95% CI, 0.84-0.99]), but this was not sustained. This study demonstrated that a brief selective personality-targeted alcohol use prevention intervention delivered in the middle school years can have sustained effects into early adulthood. anzctr.org.au Identifier: ACTRN12612000026820.

Safety and effectiveness of a novel nonpneumatic active compression device for treating breast cancer-related lymphedema: A multicenter randomized, crossover trial (NILE)

ObjectiveAdvanced pneumatic compression devices (APCDs) have been shown to be an effective intervention for lymphedema when used as part of a self-care maintenance treatment regimen. However, adherence to self-care has been poor, and APCDs require patients to be immobile during treatment. We evaluated the safety and efficacy of a novel nonpneumatic compression device (NPCD) for treating lymphedema vs an APCD. MethodsA randomized, crossover head-to-head investigation was performed at five U.S. sites in 2021. The patients had been randomized to either the NPCD or a commercially available APCD. The patients used the randomly assigned initial device for 28 days with a 4-week washout period before a comparable 28-day use of the second device. ResultsData from 50 adult women with unilateral breast cancer-related lymphedema were analyzed. Compared with the APCD, the NPCD was associated with a greater mean reduction in the limb edema volume (64.6% vs 27.7%; P < .001), significantly greater mean improvements in quality of life scores, greater adherence (95.6% vs 49.8%; P < .001), and greater satisfaction with the device (90% vs 14%; P < .001). The patients indicated that use of the NPCD facilitated exercise and was convenient for travel. No adverse events were reported. ConclusionsThe results have shown that the novel NPCD is an effective maintenance treatment for reducing the limb volume in patients with breast cancer-related lymphedema. The NPCD device was more effective than an APCD and resulted in greater adherence to self-care interventions and greater patient satisfaction.

Rates of Response to Atogepant for Migraine Prophylaxis Among Adults

Some patients with migraine, particularly those in primary care, require effective, well-tolerated, migraine-specific oral preventive treatments. To examine the efficacy of atogepant, an oral, small-molecule, calcitonin gene-related peptide receptor antagonist, using 4 levels of mean monthly migraine-day (MMD) responder rates. This secondary analysis of a phase 3, double-blind, placebo-controlled randomized clinical trial evaluated the efficacy and safety of atogepant for the preventive treatment of migraine from December 14, 2018, to June 19, 2020, in adults with 4 to 14 migraine-days per month at 128 sites in the US. Patients were administered 10 mg of atogepant (n = 222), 30 mg of atogepant (n = 230), 60 mg of atogepant (n = 235), or placebo (n = 223) once daily in a 1:1:1:1 ratio for 12 weeks. These analyses evaluated treatment responder rates, defined as participants achieving 50% or greater (α-controlled, secondary end point) and 25% or greater, 75% or greater, and 100% (prespecified additional end points) reductions in mean MMDs during the 12-week blinded treatment period. Of 902 participants (mean [SD] age, 41.6 [12.3] years; 801 [88.8%] female; 752 [83.4%] White; 825 [91.5%] non-Hispanic), 873 were included in the modified intention-to-treat population (placebo, 214; 10 mg of atogepant, 214; 30 mg of atogepant, 223; and 60 mg of atogepant, 222). For the secondary end point, a 50% or greater reduction in the 12-week mean of MMDs was achieved by 119 of 214 participants (55.6%) treated with 10 mg of atogepant (odds ratio, 3.1; 95% CI, 2.1-4.6), 131 of 223 participants (58.7%) treated with 30 mg atogepant (odds ratio, 3.5; 95% CI, 2.4-5.3), 135 of 222 participants (60.8%) treated with 60 mg of atogepant (odds ratio, 3.8; 95% CI, 2.6-5.7), and 62 of 214 participants (29.0%) given placebo (P < .001). The numbers of participants who reported a 25% or greater reduction in the 12-week mean of MMDs were 157 of 214 (73.4%) for 10 mg of atogepant, 172 of 223 (77.1%) for 30 mg of atogepant, and 180 of 222 (81.1%) for 60 mg of atogepant vs 126 of 214 (58.9%) for placebo (P < .002). The numbers of participants who reported a 75% or greater reduction in mean MMDs were 65 of 214 (30.4%) for 10 mg of atogepant, 66 of 223 (29.6%) for 30 mg of atogepant, and 84 of 222 (37.8%) for 60 mg of atogepant compared with 23 of 214 (10.7%) for placebo (P < .001). The numbers of participants reporting 100% reduction in mean MMDs were 17 of 214 (7.9%) for 10 mg of atogepant (P = .004), 11 of 223 (4.9%) for 30 mg of atogepant (P = .02), and 17 of 222 (7.7%) for 60 mg of atogepant (P = .003) compared with 2 of 214 (0.9%) for placebo. At all doses, atogepant was effective during the 12-week double-blind treatment period beginning in the first 4 weeks, as evidenced by significant reductions in mean MMDs at every responder threshold level. Higher atogepant doses appeared to produce the greatest responder rates, which can guide clinicians in individualizing starting doses. ClinicalTrials.gov Identifier: NCT03777059.

The effects of MDMA-assisted therapy on alcohol and substance use in a phase 3 trial for treatment of severe PTSD

BackgroundPost-traumatic stress disorder (PTSD) is commonly associated with alcohol and substance use disorders (ASUD). A randomized, placebo-controlled, phase 3 trial demonstrated the safety and efficacy of MDMA-assisted therapy (MDMA-AT) for the treatment of severe PTSD. This analysis explores patterns of alcohol and substance use in patients receiving MDMA-AT compared to placebo plus therapy (Placebo+Therapy). MethodsAdult participants with severe PTSD (n = 90) were randomized to three blinded trauma-focused therapy sessions with either MDMA-AT or Placebo+Therapy. Eligible participants met DSM-5 criteria for severe PTSD and could meet criteria for mild (current) or moderate (early remission) alcohol or cannabis use disorder; other SUDs were excluded. The current analyses examined outcomes on standardized measures of hazardous alcohol (i.e., Alcohol Use Disorder Identification Test; AUDIT) and drug (i.e., Drug Use Disorder Identification Test; DUDIT) use at baseline prior to randomization and at study termination. ResultsThere were no treatment group differences in AUDIT or DUDIT scores at baseline. Compared to Placebo+therapy, MDMA-AT was associated with a significantly greater reduction in mean (SD) AUDIT change scores (Δ = −1.02 (3.52) as compared to placebo (Δ = 0.40 (2.70), F (80, 1) = 4.20, p = 0.0436; Hedge’s g= .45). Changes in DUDIT scores were not significantly different between treatment groups. ConclusionsMDMA-AT for severe PTSD may also lead to subclinical improvements in alcohol use. MDMA-AT does not appear to increase risk of illicit drug use. These data provide preliminary evidence to support the development of MDMA-AT as an integrated treatment for co-occurring PTSD and ASUD.

Patient-Reported Outcomes (PROs) Among Patients With Steroid-Refractory or -Dependent Chronic Graft-vs-Host Disease (cGVHD) Randomized to Ruxolitinib (RUX) vs Best Available Therapy (BAT)

Patient-Reported Outcomes (PROs) Among Patients With Steroid-Refractory or -Dependent Chronic Graft-vs-Host Disease (cGVHD) Randomized to Ruxolitinib (RUX) vs Best Available Therapy (BAT)

A Randomized, Placebo-Controlled Clinical Trial of Bamlanivimab and Etesevimab Together in High-Risk Ambulatory Patients With COVID-19 and Validation of the Prognostic Value of Persistently High Viral Load.

BackgroundBased on interim analyses and modeling data, lower doses of bamlanivimab and etesevimab together (700/1400 mg) were investigated to determine optimal dose and expand availability of treatment.MethodsThis Phase 3 portion of the BLAZE-1 trial characterized the effect of bamlanivimab with etesevimab on overall patient clinical status and virologic outcomes in ambulatory patients ≥12 years old, with mild-to-moderate coronavirus disease 2019 (COVID-19), and ≥1 risk factor for progressing to severe COVID-19 and/or hospitalization. Bamlanivimab and etesevimab together (700/1400 mg) or placebo were infused intravenously within 3 days of patients’ first positive COVID-19 test.ResultsIn total, 769 patients were infused (median age [range]; 56.0 years [12, 93], 30.3% of patients ≥65 years of age and median duration of symptoms; 4 days). By day 29, 4/511 patients (0.8%) in the antibody treatment group had a COVID-19-related hospitalization or any-cause death, as compared with 15/258 patients (5.8%) in the placebo group (Δ[95% confidence interval {CI}] = −5.0 [−8.0, −2.1], P < .001). No deaths occurred in the bamlanivimab and etesevimab group compared with 4 deaths (all COVID-19-related) in the placebo group. Patients receiving antibody treatment had a greater mean reduction in viral load from baseline to Day 7 (Δ[95% CI] = −0.99 [−1.33, −.66], P < .0001) compared with those receiving placebo. Persistently high viral load at Day 7 correlated with COVID-19-related hospitalization or any-cause death by Day 29 in all BLAZE-1 cohorts investigated.ConclusionsThese data support the use of bamlanivimab and etesevimab (700/1400 mg) for ambulatory patients at high risk for severe COVID-19. Evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants will require continued monitoring to determine the applicability of this treatment.Clinical Trials RegistrationNCT04427501.

MitraClip NTR vs XTR system for transcatheter tricuspid valve repair of tricuspid regurgitation

Abstract Background Transcatheter tricuspid valve repair (TTVr) is a novel modality for treatment of severe tricuspid regurgitation (TR) in patients at high surgical risk. So far, the most frequently used system is the MitraClip® providing two different clip types (NTR vs XTR). Purpose To compare XTR vs NTR clip systems for TTVr regarding safety, feasibility, and effectiveness. Methods 35 consecutive high-risk patients (78.4±7.9 years, EUROScore II 10.7±10.8%, STS Score 7.9±4.1) with symptomatic TR were treated using the MitraClip® system between 2017–2020. with an NTR (N=18, 51.4%) or XTR (N=17, 48.6%) system. The primary outcome was successful TTVr with TR reduction of ≥1 grade with no mortality, single leaflet device attachment (SLDA), or conversion to surgery until hospital discharge. At 30-day follow-up, TR severity grade and NYHA functional class were assessed. Results We found more severe initial TR grades in the XTR group compared to the NTR group expressed with wider TR V. contracta (14.8±4.3 vs 11.1±3.8 mm, p=0.011), larger EROA (0.99±0.4 vs 0.72±0.3 cm2, p=0.032), wider coaptation depth (9.6±2.8 vs 7.3±0.4 mm, p=0.036) and V. cava inferior (30.7±3.6 vs. 25.8±6.4 mm in NTR, p=0.013). 5 patients (29.4%) in the XTR and 3 patients (16.7%) in the NTR group presented initially with torrential TR. No significant differences were observed for clinical characteristics, comorbidities, co-medication, laboratory parameters or initial NYHA functional class (3.0±0.5 in NTR vs 3.2±0.4 in XTR, p=0.45). TTVr was safe with no intraprocedural deaths, emergency surgery or major vascular complications. Duration of the procedure and fluoroscopy did not differ. Both, NTR and XTR system led to procedural success in 72.2% (N=13) and 76.5% (N=13), respectively. At discharge, a significant reduction of initial TR grade was observed in both groups (2.4±0.9 in NTR and 2.3±0.9 in XTR, p&amp;lt;0.001) with a tendency of greater mean reduction in the XTR group (1.9±1.0 vs. 1.3±0.9, p=0.09). All 5 patients with torrential TR in the XTR group (100%) and just 1 patient (33.3%) in the NTR group achieved the primary outcome. At 30-day follow-up, overall SLDA rate was 22% vs 17.6% for NTR and XTR, respectively. However, these cases were attributed to very high risk patients with poor anatomy. Mortality rate was 11.1% in NTR vs 5.9% in XTR group (p=0.59). Achieved reduction of TR was maintained in both groups (2.6±0.9 in NTR and 2.8±0.9 in XTR, p&amp;lt;0.001). Also, improvement of NYHA functional class was seen (2.5±0.5, p=0.001 in NTR and 2.9±0.6, p=0.055 in XTR). Conclusion MitraClip® NTR and XTR systems for TTVr of severe TR in high-risk patients are safe and effective leading to a significant reduction of TR and clinical improvement. The XTR system seems to allow successful treatment of more severe TR stages compared to NTR. Funding Acknowledgement Type of funding sources: None.

Reduction of Heavy Menstrual Bleeding in Women Not Designated as Responders to Elagolix Plus Add Back Therapy for Uterine Fibroids.

Objective:To assess outcomes of women with uterine fibroids (UFs) and heavy menstrual bleeding (HMB) treated with 300 mg elagolix twice daily plus add-back therapy (E2 1 mg/NETA 0.5 mg once daily) or placebo who were not considered responders in pooled analysis of two phase 3, 6-month randomized clinical trials (Elaris UF-1 and UF-2).Methods:Responders were defined as women who met both primary end point bleeding criteria (<80 mL menstrual blood loss [MBL] during the final month and ≥50% reduction in MBL from baseline to the final month) and either completed the study or discontinued due to predefined reasons. Thus, women termed nonresponders who were analyzed in this study who met neither or one bleeding end point or met both criteria but prematurely discontinued treatment because of adverse events, perceived lack of efficacy, or required surgical or interventional treatment for UFs were analyzed in this study. This post hoc analysis assessed mean changes from baseline in MBL, as well as adverse events.Results:Among 367 women receiving elagolix with add-back with observed data, 89 (24%) were not considered responders. Within this subset, 17 (19%) women met both bleeding criteria but prematurely discontinued treatment for the reasons mentioned above, while 23 (26%) met one bleeding criterion and 49 (55%) met neither bleeding criteria, regardless of discontinuation status. Among all nonresponders, a numerical trend toward greater mean reductions in MBL was observed in those receiving elagolix with add-back, compared with placebo group nonresponders. No differences in adverse events were observed between responders and nonresponders.Conclusion:Forty of 89 (45%) women with HMB and UFs who were classified as nonresponders in the UF-1 or UF-2 trials may have had a clinically meaningful response to elagolix with add-back therapy because they met at least one of the objective bleeding criteria. Clinical Trial Registration: Clinicaltrials.gov, NCT02654054 and NCT02691494. (NEJM 2020; 382:328–340) DOI: 10.1056/NEJMoa1904351

High-versus low-dose clonidine for sedation and analgesia in critically ill adults: A retrospective cohort study.

Limited data suggest clonidine may be useful for sedation and analgesia in critically ill patients. Our objectives were to describe clonidine dosing regimens used for sedation and analgesia in critically ill adults, the associated adverse effects (i.e., hypotension), and whether clonidine dose was associated with dosage reductions of traditional sedatives and analgesics. We conducted a retrospective cohort study of all critically ill adults who received enteral clonidine for sedation and analgesia during a five-year study period (2011-2016). We categorized patients as low-dose (LD ≤0.4mg/day) or high-dose (HD >0.4mg/day) based on the maximum total daily clonidine dose. In total, 166 patients received clonidine for sedation analgesia; the median age was 56years, 36% were female, and 96% were mechanically ventilated (median 10days). Eighty-eight patients (53%) received HD clonidine. There were no significant differences in hypotension, bradycardia, rebound hypertension or tachycardia between groups. The HD group had a greater reduction in mean daily opioid requirements throughout clonidine use compared with the LD group (-218.8mcg vs. -42.5mcg fentanyl equivalents, p=0.049), while antipsychotic doses increased (5.7mg vs. 0mg olanzapine equivalents, p=0.04) and sedative doses did not differ. Clonidine doses >0.4mg/day were associated with a decrease in patients' opioid but not sedative requirements without causing significant adverse effects. Antipsychotic doses increased in conjunction with HD clonidine use.

Safety and Efficacy of Mepolizumab in Hypereosinophilic Syndrome: An Open-Label Extension Study

A double-blind, placebo-controlled, phase III study (200622) showed that mepolizumab reduces disease flares for patients with uncontrolled FIP1-like-1-platelet-derived growth factor receptor α-negative hypereosinophilic syndrome (HES) and two or more flares in the previous year. To further characterize the safety, clinical benefit, and pharmacodynamics of mepolizumab. Eligible patients from both treatment arms of the double-blind study could enter an open-label extension study (205203; NCT03306043) to receive 4-weekly mepolizumab (300mg subcutaneously) plus background therapy for 20 weeks. Primary end points were safety-based; other end points included flare rates and changes from baseline in mean daily oral corticosteroid (OCS) dose and blood eosinophil count. Of 104 patients who completed the double-blind study, 98% (previous placebo, n= 52; previous mepolizumab, n= 50) enrolled in the open-label extension. Overall, 66 of patients reported adverse events (AEs) (65%), 15 reported treatment-related AEs (15%), and nine reported serious AEs (9%). No events were fatal. The annualized flare rate (95% confidence interval) in the previous placebo and previous mepolizumab groups was 0.37 (0.16-0.86) and 0.14 (0.04-0.49) events/y, respectively. Of 72 patients receiving OCS during weeks 0 to 4, 20 (28%; previous placebo, n= 14; previous mepolizumab, n= 6) achieved 50% or greater reductions in mean daily dose during weeks 16 to 20. At week 20, blood eosinophil count was reduced by 89% in patients previously receiving placebo and remained reduced for those previously receiving mepolizumab. Extended mepolizumab treatment was associated with a positive benefit-risk profile. Continued control of disease flares and blood eosinophil counts, plus reductions in OCS use, were observed with mepolizumab in patients with FIP1-like-1-platelet-derived growth factor receptor α-negative HES.

Phase II, Multiple-Dose Study of Anti-FcRn Antibody, Rozanolixizumab (UCB7665), in Patients with Primary Immune Thrombocytopenia: Interim Analysis

Phase II, Multiple-Dose Study of Anti-FcRn Antibody, Rozanolixizumab (UCB7665), in Patients with Primary Immune Thrombocytopenia: Interim Analysis

Impact of a preventive cardiology clinic focusing on lifestyle and nutrition counseling: A pilot analysis

Standard cardiology practice often defers preventive strategies to primary care providers. We aimed to evaluate the effectiveness of a preventive cardiology clinic focused on lifestyle and nutrition counseling combined with guideline-directed medical therapy on reducing cardiovascular disease (CVD) risk. We queried the University of Florida-Health database for patients enrolled in the preventive cardiology clinic, and a general and interventional cardiology clinic from January 2016 to October 2019. Mean change in weight and blood cholesterol including LDL cholesterol (LDL-C), total cholesterol (TC) and triglycerides (TG) were compared in the three clinics in the initial cohort and stratified into primary and secondary prevention. A propensity score-matched analysis was done to adjust for CVD risk factors and statin use. Among a cohort of 239 patients, enrollment in the preventive clinic (n = 99) was associated with greater weight loss at 6 months compared to other clinics (n = 140) (mean −1.7 vs +0.1 kg, p 0.007). Preventive clinic was also associated with greater mean reduction in LDL-C (−24.8 vs −7.1 mg/dl, p 0.021), TC (−29.3 vs −2.0, p 0.003) and TG (−19.7 vs +13.3, p 0.002) at both initial and last follow-up (median time 6 and 16 months). The association with reduction in TG was observed in both primary and secondary prevention, but reduction in LDL-C and TC was only significant in secondary prevention. In a propensity-matched linear regression analysis, preventive clinic was independently associated with LDL-C reduction (b −14.7, r −0.3, p 0.038). A preventive cardiology clinic focused on patient education can be effective in reducing CVD risk.

A tissue-engineered biocomplex for periodontal reconstruction. A proof-of-principle randomized clinical study.

To assess the safety/efficacy of a tissue-engineered biocomplex in periodontal reconstruction. Twenty-seven intrabony defects were block-randomized across three treatment groups: Group-A (NA =9) received autologous clinical-grade alveolar bone marrow mesenchymal stem cells (a-BMMSCs), seeded into collagen scaffolds, enriched with autologous fibrin/platelet lysate (aFPL). In Group-B (NB =10), the collagen scaffold/aFPL devoid of a-BMMSCs filled the osseous defect. Group-C (NC =8) received Minimal Access Flap surgery retaining the soft tissue wall of defects identically with Groups-A/-B. Subjects were clinically/radiographically assessed before anaesthesia (baseline) and repeatedly over 12months. Quality controls were satisfied before biocomplex transplantation. There were no adverse healing events. All approaches led to significant clinical improvements (p<.001) with no inter-group differences. At 12months, the estimated marginal means for all groups were as follows: 3.0 (95% CI: 1.9-4.1) mm for attachment gain; 3.7 (2.7-4.8) mm for probing pocket depth reduction; 0.7 (0.2-1.3) mm increase in recession. An overall greater mean reduction in the radiographic Cemento-Enamel Junction to Bottom Defect (CEJ-BD) distance was found for Groups-A/-C over Group-B (p<.023). Radiographic evidence of bone fill was less pronounced in Group-B, although clinical improvements were similar across groups. All approaches aimed to trigger the innate healing potential of tissues. Cell-based therapy is justified for periodontal reconstruction and remains promising in selected cases.