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Background Inclisiran, an siRNA administered twice-yearly, significantly reduced LDL cholesterol (LDL-C) in Phase III trials. Whether lowering LDL-C with inclisiran translates into a lower risk of cardiovascular (CV) events is not yet established. Methods and results Patient-level, pooled analysis of ORION-9, −10 and −11, included patients with heterozygous familial hypercholesterolaemia, atherosclerotic CV disease (ASCVD), or ASCVD risk equivalent on maximally tolerated statin-therapy, randomized 1:1 to receive 284 mg inclisiran or placebo on Days 1, 90, and 6-monthly thereafter for 18 months. Prespecified exploratory endpoint of major cardiovascular events (MACEs) included non-adjudicated CV death, cardiac arrest, non-fatal myocardial infarction (MI), and fatal and non-fatal stroke, evaluated as part of safety assessments using a standard Medical Dictionary for Regulatory Activities basket. Although not prespecified, total fatal and non-fatal MI, and stroke were also evaluated. Mean LDL-C at baseline was 2.88 mmol/L. At Day 90, the placebo-corrected percentage reduction in LDL-C with inclisiran was 50.6%, corresponding to an absolute reduction of 1.37 mmol/L (both P < 0.0001). Among 3655 patients over 18 months, 303 (8.3%) experienced MACE, including 74 (2.0%) fatal and non-fatal MIs, and 28 (0.8%) fatal and non-fatal strokes. Inclisiran significantly reduced composite MACE [OR (95% CI): 0.74 (0.58–0.94)], but not fatal and non-fatal MIs [OR (95% CI): 0.80 (0.50–1.27)] or fatal and non-fatal stroke [OR (95% CI): 0.86 (0.41–1.81)]. Conclusion This analysis offers early insights into the potential CV benefits of lowering LDL-C with inclisiran and suggests potential benefits for MACE reduction. These findings await confirmation in the larger CV outcomes trials of longer duration.

IMPORTANCEMany hospitalized patients with COVID-19 have been treated with convalescent plasma. However, it is uncertain whether this therapy lowers mortality and if so, if the mortality benefit is larger among specific subgroups, such as recipients of plasma with high antibody content and patients treated early in the disease course.OBJECTIVETo examine the association of COVID-19 convalescent plasma transfusion with mortality and the differences between subgroups in hospitalized patients with COVID-19.DATA SOURCESOn October 26, 2022, a systematic search was performed for clinical studies of COVID-19 convalescent plasma in the literature.STUDY SELECTIONRandomized clinical trials and matched cohort studies investigating COVID-19 convalescent plasma transfusion compared with standard of care treatment or placebo among hospitalized patients with confirmed COVID-19 were included. The electronic search yielded 3,841 unique records, of which 744 were considered for full-text screening. The selection process was performed independently by a panel of five reviewers.DATA EXTRACTION AND SYNTHESISThe study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data were extracted by 5 independent reviewers in duplicate and pooled using inverse-variance random-effects model.MAIN OUTCOMES AND MEASURESPrespecified end point was all-cause mortality during hospitalization.RESULTSThirty-nine randomized clinical trials enrolling 21,529 participants and 70 matched cohort studies enrolling 50,160 participants were included in the systematic review. Separate meta-analyses demonstrated that transfusion of COVID-19 convalescent plasma was associated with a significant decrease in mortality compared with the control cohort for both randomized clinical trials (odds ratio (OR), 0.87 [95% CI, 0.76-1.00]) and matched cohort studies (OR, 0.77 [95% CI, 0.64-0.94]). Meta-analysis of subgroups revealed two important findings. First, treatment with convalescent plasma containing high antibody levels was associated with a decrease in mortality compared to convalescent plasma containing low antibody levels (OR, 0.85 [95% CI, 0.73 to 0.99]). Second, earlier treatment with COVID-19 convalescent plasma was associated with a significant decrease in mortality compared with the later treatment cohort (OR, 0.63 [95% CI, 0.48 to 0.82]).CONCLUSIONS AND RELEVANCECOVID-19 convalescent plasma use was associated with a 13% reduced risk in mortality, implying a mortality benefit for hospitalized patients with COVID-19, particularly those treated with convalescent plasma containing high antibody levels treated earlier in the disease course.Key PointsQuestionWhat is the evidence regarding the potential mortality benefit associated with transfusion of convalescent plasma in hospitalized patients with COVID-19?FindingsIn this meta-analysis of 39 randomized clinical trials enrolling 21,529 participants and 70 matched cohort studies enrolling 50,160 participants, transfusion of convalescent plasma was associated with a 13% mortality benefit. Subgroup analyses revealed that patients treated with plasma containing higher levels of antibodies and patients treated earlier in the course of the disease had a greater mortality benefit associated with COVID-19 convalescent plasma transfusion.MeaningThese findings suggest that transfusion of COVID-19 convalescent plasma is associated with a mortality benefit for hospitalized patients, particularly those treated earlier in the disease course.

Objective To examine methods of assessing consent capacity in research protocols involving participants with impaired consent capacity, and examine instruments used to evaluate research consent capacity. Methods A retrospective review of 330 active research protocols involving participants lacking capacity to consent over a 10-year period (January 1, 2009, through March 1, 2019) was conducted to collect protocol characteristics (medical specialty, level of risk and type of study, consent and assent procedures, and type of vulnerable or protected population). Methods to assess consent capacity are described, and instruments to assess consent capacity are summarized. Results The specialties most frequently involving participants with impaired consent capacity in research were Neurology (27.3%), Critical Care (16.7%), and Surgery (10%). Type of studies are observational (43.9%), clinical trials (33%), chart review (11.5%), biobank (6.1%), and biomarker (5.5%). Minimal risk (53.3%) outnumbered greater than minimal risk (46.7%) studies. Most obtained written informed consent (77%) and assent (40.9%). The most common method to assess consent capacity was direct assessment by investigators (32.7%). Only 86 (26%) studies used instruments to assess consent capacity. Of the 13 instruments used, the most common was the Evaluation of Decision-Making Capacity for Consent to Act as a Research Subject, and is the only instrument that assesses all four components of decisional capacity: understanding, appreciation, reasoning, and choice. Conclusion Generally, there was lack of uniformity in determining capacity to consent to research participation. Very few studies used instruments to assess consent capacity. Institutional review boards can provide greater guidance for research consent capacity determination.

Purpose Patients with polyvascular disease (PVD) are at very high cardiovascular risk and require intensive lipid-lowering therapy. This analysis describes the lipid-lowering efficacy and safety of inclisiran versus placebo in patients with and without PVD. Methods In this post hoc analysis of the ORION-9, ORION-10, and ORION-11 trials, patients were randomized 1:1 to receive 284 mg inclisiran (300 mg inclisiran sodium) or placebo on day 1, day 90, and 6-monthly thereafter. Percentage change in low-density lipoprotein cholesterol (LDL-C) from baseline to day 510 and corresponding time-adjusted change from day 90 and up to day 540 were evaluated per patients’ PVD status. Safety was assessed over 540 days. Results Of 3454 patients, 470 (13.6%) had PVD, and 2984 (86.4%) did not. Baseline characteristics were generally balanced between the treatment arms in both cohorts. A greater proportion of patients with PVD had comorbidities versus those without. The mean (95% confidence interval [CI]) placebo-corrected LDL-C percentage change from baseline to day 510 was −48.9% (−55.6 to −42.2) in patients with PVD and −51.5% (−53.9 to −49.1) in patients without. Proportions of patients with reported treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events were similar between treatment arms, irrespective of PVD status, except for an excess of mild or moderate clinically relevant TEAEs at the injection site with inclisiran. Conclusion Twice-yearly inclisiran dosing (after the initial and 3-month doses) was well tolerated and provided effective and sustained lipid-lowering in patients, irrespective of PVD status.

Mitral valve replacement may be indicated in delayed MitraClip (Abbott) failure. Although it would be best to preserve the chordal apparatus during surgical mitral valve replacement, this has not been reported for delayed MitraClip failure, probably because there is almost always impressive inflammation around the MitraClip, which has likely precluded previous attempts at chordal preservation. A successful surgical chordal preservation mitral valve replacement in delayed MitraClip failure is reported here.

Whether long-term treatment with the twice-yearly, siRNA therapeutic inclisiran, which reduces hepatic production of proprotein convertase subtilisin/kexin type 9 (PCSK9), results in sustained reductions in LDL cholesterol with an acceptable safety profile is not known. The aim of this study was to assess the effect of long-term dosing of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol.ORION-3 was a 4-year open-label extension study of the placebo-controlled, phase 2 ORION-1 trial, conducted at 52 sites across five countries. Patients with prevalent atherosclerotic cardiovascular disease or high-risk primary prevention and elevated LDL cholesterol despite maximally tolerated statins or other LDL-lowering treatments, or with documented statin intolerance, who had completed the ORION-1 trial were eligible. Patients receiving inclisiran in ORION-1 received twice-yearly 300 mg subcutaneous inclisiran sodium throughout ORION-3 (inclisiran-only arm), whereas patients receiving placebo in ORION-1 first received subcutaneous evolocumab 140 mg every 2 weeks until day 360 thereafter transitioning to inclisiran twice-yearly for the remainder of ORION-3 study (switching arm). The primary efficacy endpoint was the percentage change in LDL cholesterol with inclisiran from the start of ORION-1 through to day 210 of the open label extension phase in the inclisiran-only arm (approximately 570 days of total inclisiran exposure in the modified intention-to-treat population). Secondary and exploratory endpoints included changes in LDL-C cholesterol and PCSK9 concentrations levels up to day 1440 (4 years) in each arm, and safety. ORION-3 is registered with ClinicalTrials.gov, NCT03060577.Of the original ORION-1 cohort of 497 patients, 290 of 370 patients allocated to drug continued into the inclisiran-only arm and 92 of 127 patients allocated to placebo entered the switching-arm in the ORION-3 extension study conducted between March 24, 2017, and Dec 17, 2021. In the inclisiran-only arm, LDL cholesterol was reduced by 47·5% (95% CI 50·7-44·3) at day 210 and sustained over 1440 days. The 4-year averaged mean reduction of LDL-C cholesterol was 44·2% (95% CI: 47·1-41·4), with reductions in PCSK9 ranging from 62·2% to 77·8%. Adverse events at the injection site were reported in 39 (14%) of 284 patients in the inclisiran-only arm and 12 (14%) of 87 patients in the switching arm. The incidence of treatment-emergent serious adverse events possibly related to the study drug was 1% (three of 284) in the inclisiran-only arm and 1% (one of 87) in the switching arm.Twice-yearly inclisiran provided sustained reductions in LDL cholesterol and PCSK9 concentrations and was well tolerated over 4 years in the extension study. This is the first prospective long-term study to assess repeat hepatic exposure to inclisiran.Novartis Pharma.

In this short narrative, we highlight some of our experiences leading the US Convalescent Plasma Program at the beginning of the pandemic in the spring and summer of 2020. This includes a brief summary of how the program emerged and high-level lessons we learned. We also share our impressions about why convalescent plasma was used at scale in the United States, early in the pandemic and share ideas that might inform the use of convalescent plasma in future outbreaks of novel infectious diseases.

Contains fulltext : 235066.pdf (Publisher’s version ) (Open Access) To determine the effect of COVID-19 convalescent plasma on mortality, we aggregated patient outcome data from 10 randomized clinical trials, 20 matched control studies, 2 dose-response studies, and 96 case reports or case series. Studies published between January 1, 2020, and January 16, 2021, were identified through a systematic search of online PubMed and MEDLINE databases. Random effects analyses of randomized clinical trials and matched control data demonstrated that patients with COVID-19 transfused with convalescent plasma exhibited a lower mortality rate compared with patients receiving standard treatments. Additional analyses showed that early transfusion (within 3 days of hospital admission) of higher titer plasma is associated with lower patient mortality. These data provide evidence favoring the efficacy of human convalescent plasma as a therapeutic agent in hospitalized patients with COVID-19.

OBJECTIVE: To provide an update on key safety metrics after transfusion of convalescent plasma in hospitalized coronavirus 2019 (COVID-19) patients, having previously demonstrated safety in 5000 hospitalized patients. PATIENTS AND METHODS: From April 3 to June 2, 2020, the US Food and Drug Administration Expanded Access Program for COVID-19 convalescent plasma transfused a convenience sample of 20,000 hospitalized patients with COVID-19 convalescent plasma. RESULTS: The incidence of all serious adverse events was low; these included transfusion reactions (n=78

Aims Small-interfering RNA (siRNA)-based targeting of proprotein convertase subtilisin/kexin type 9 (PCSK9) represents a novel therapeutic approach that may provide a convenient, infrequent, and safe dosing schedule to robustly lower low-density lipoprotein cholesterol (LDL-C). Given the long duration of action, however, establishing safety in particular with respect to immunogenicity is of paramount importance. In earlier clinical studies of other RNA-targeted treatment approaches (antisense oligonucleotide therapy) immunological and haematological adverse effects, in particular thrombocytopenia and pro-inflammatory effects, have been reported. Here, we present the pre-specified safety analysis from ORION-1 evaluating platelets, immune cells, immunological markers, antidrug antibodies, and clinical immunogenicity adverse events (AEs) under PCSK9 siRNA treatment with inclisiran. Methods and results The pre-specified safety analysis from ORION-1 was performed in six different inclisiran dosing regimens in patients at high risk of cardiovascular disease with elevated LDL-C levels. Patients received either a single dose (SD: 200 mg, n = 60; 300 mg, n = 62 or 500 mg, n = 66) or double-dose starting regimen (DD: 100 mg, n = 62; 200 mg, n = 63; or 300 mg, n = 61 on days 1 and 90) of inclisiran or placebo (SD: n = 65; DD: n = 62). The effects of inclisiran on haematological parameters including platelet counts, lymphocytes, and monocytes as well as on the immune markers interleukin 6 (IL-6) and tumour necrosis factor-α (TNF-α) were examined after 180 days. Immunogenicity was further evaluated by analysis of anti-drug-antibodies (ADAs) towards inclisiran in 6068 study samples and by careful analysis of immunogenicity AEs as part of the pharmacovigilance strategy. At day 180, no significant alterations of platelet counts were observed in any of the dosing groups (change from baseline, SD: 200 mg: 0.8%; 300 mg: −0.5%; 500 mg: −1.8%; DD: 100 mg: 1.3%; 200 mg: −0.5%; 300 mg: 1.0%; no significant difference for any group as compared with placebo). No significant effects on other immune cells, including leucocytes, monocytes, or neutrophils were detected. Notably, no significant increase of inflammatory biomarkers (IL-6 or TNF-α) with either the SD or DD regimen became evident. There was no evidence for immunogenicity based on ADA level analysis and careful review of clinical immunogenicity AEs in none of the treatment regimens. Conclusion In this pre-specified safety analysis of ORION-1 for the siRNA therapeutic inclisiran, no adverse effects on measures of inflammation or immune activation nor adverse effects on platelets or clinical immunogenicity AEs were observed over at least 6-month treatment. These safety findings in the largest analysis of an RNAi study in humans to date provide strong reassurance about the safety of inclisiran and the potential of cardiovascular RNA-targeted therapies.

Aims Patients with diabetes (DM) and metabolic syndrome (MS) have elevated risks for atherosclerotic cardiovascular disease (ASCVD). Aggressive LDL-C lowering reduces risks. Inclisiran, a new siRNA, lowers LDL-C and was evaluated in patients with Type 2 diabetes (DM), metabolic syndrome (MS) without DM or neither (N) in the ORION-10 trial. Methods ORION-10 was a double-blind, randomized, placebo controlled trial evaluating inclisiran in 1561 patients with ASCVD on maximally tolerated therapy for lowering LDL-C. 781 inclisiran (INC) participants and 780 placebo (P) patients received 1.5 mL SQ tx at Days 1, 90, then every 6 months until Day 540. We evaluated the time adjusted change in LDL-C from baseline after Days 90–540 in DM (n = 702), MS (n = 455) and N participants (n = 404). Results There were no differences in baseline demographics and background therapies between INC and P. Statins were utilized in 89.8% INC and 88.7% of P. High intensity statins were utilized in 67.2% of INC and 68.8% of P; ezetimibe in 10.2% of NC and 9.5% of P participants. INC reduced LDL-C by − 54.4% (−58.3, −50.6 95% CI) in DM, (P Conclusions Inclisiran potently and durably reduces LDL-C across patients with DM, MS and those with neither, demonstrating potent efficacy and durability across glycaemic categories. Inclisiran may also represent a potent LDL-C lowering treatment for those with DM and MS.

Background The United States (US) Expanded Access Program (EAP) to coronavirus disease 2019 (COVID-19) convalescent plasma was initiated in response to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. While randomized clinical trials were in various stages of development and enrollment, there was an urgent need for widespread access to potential therapeutic agents. The objective of this study is to report on the demographic, geographical, and chronological characteristics of patients in the EAP, and key safety metrics following transfusion of COVID-19 convalescent plasma. Methods and findings Mayo Clinic served as the central institutional review board for all participating facilities, and any US physician could participate as a local physician–principal investigator. Eligible patients were hospitalized, were aged 18 years or older, and had—or were at risk of progression to—severe or life-threatening COVID-19; eligible patients were enrolled through the EAP central website. Blood collection facilities rapidly implemented programs to collect convalescent plasma for hospitalized patients with COVID-19. Demographic and clinical characteristics of all enrolled patients in the EAP were summarized. Temporal patterns in access to COVID-19 convalescent plasma were investigated by comparing daily and weekly changes in EAP enrollment in response to changes in infection rate at the state level. Geographical analyses on access to convalescent plasma included assessing EAP enrollment in all national hospital referral regions, as well as assessing enrollment in metropolitan areas and less populated areas that did not have access to COVID-19 clinical trials. From April 3 to August 23, 2020, 105,717 hospitalized patients with severe or life-threatening COVID-19 were enrolled in the EAP. The majority of patients were 60 years of age or older (57.8%), were male (58.4%), and had overweight or obesity (83.8%). There was substantial inclusion of minorities and underserved populations: 46.4% of patients were of a race other than white, and 37.2% of patients were of Hispanic ethnicity. Chronologically and geographically, increases in the number of both enrollments and transfusions in the EAP closely followed confirmed infections across all 50 states. Nearly all national hospital referral regions enrolled and transfused patients in the EAP, including both in metropolitan and in less populated areas. The incidence of serious adverse events was objectively low (, In an observational study of registry data, Jonathon Senefeld and colleagues study factors related to patient enrollment in the Expanded Access Program for use of COVID-19 convalescent plasma in the United States., Author summary Why was this study done? There was a public health need to provide expedited and broad access to convalescent plasma for the treatment of coronavirus disease 2019 (COVID-19) during the early stages of this public health emergency in the United States. Convalescent plasma was initially administered through regulatory pathways that required per-patient approval, resulting in substantial administrative time. The Expanded Access Program (EAP) was initiated to provide broad access to COVID-19 convalescent plasma and to provide a framework for standardized collection of data describing the safety profile of convalescent plasma. What did the researchers do and find? The EAP provided rapid and broad access to convalescent plasma throughout the US and some US territories and was effective at providing therapy for demographic groups that were severely affected by COVID-19. In addition, the data provide evidence supporting that transfusion of convalescent plasma is safe in hospitalized patients with COVID-19. What do these findings mean? The study design of the EAP may serve as an example for future efforts in response to a rapidly developing infectious disease when broad access to a treatment is needed in areas and demographic groups that are often poorly represented in clinical trials.

Background:The US Food and Drug Administration authorized COVID-19 convalescent plasma (CCP) therapy for hospitalized COVID-19 patients via the Expanded Access Program (EAP) and the Emergency Use Authorization (EUA), leading to use in about 500,000 patients during the first year of the pandemic for the USA.Methods:We tracked the number of CCP units dispensed to hospitals by blood banking organizations and correlated that usage with hospital admission and mortality data.Results:CCP usage per admission peaked in Fall 2020, with more than 40% of inpatients estimated to have received CCP between late September and early November 2020. However, after randomized controlled trials failed to show a reduction in mortality, CCP usage per admission declined steadily to a nadir of less than 10% in March 2021. We found a strong inverse correlation (r = −0.52, p=0.002) between CCP usage per hospital admission and deaths occurring 2 weeks after admission, and this finding was robust to examination of deaths taking place 1, 2, or 3 weeks after admission. Changes in the number of hospital admissions, SARS-CoV-2 variants, and age of patients could not explain these findings. The retreat from CCP usage might have resulted in as many as 29,000 excess deaths from mid-November 2020 to February 2021.Conclusions:A strong inverse correlation between CCP use and mortality per admission in the USA provides population-level evidence consistent with the notion that CCP reduces mortality in COVID-19 and suggests that the recent decline in usage could have resulted in excess deaths.Funding:There was no specific funding for this study. AC was supported in part by RO1 HL059842 and R01 AI1520789; MJJ was supported in part by 5R35HL139854. This project has been funded in whole or in part with Federal funds from the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority under Contract No. 75A50120C00096.

In the absence of effective countermeasures, human convalescent plasma has been widely used to treat severe acute respiratory syndrome coronavirus 2, the causative agent of novel coronavirus disease 19 (COVID‐19), including among patients with innate or acquired immunosuppression. However, the association between COVID‐19‐associated mortality in patients with immunosuppression and therapeutic use of convalescent plasma is unknown. We review 75 reports, including one large matched‐control registry study of 143 COVID‐19 patients with hematological malignancies, and 51 case reports and 23 case series representing 238 COVID‐19 patients with immunosuppression. We review clinical features and treatment protocols of COVID‐19 patients with immunosuppression after treatment with human convalescent plasma. We also discuss the time course and clinical features of recovery. The available data from case reports and case series provide evidence suggesting a mortality benefit and rapid clinical improvement in patients with several forms of immunosuppression following COVID‐19 convalescent plasma transfusion. The utility of convalescent plasma or other forms of antibody therapy in immune‐deficient and immune‐suppressed patients with COVID‐19 warrants further investigation.

The US Food and Drug Administration authorized COVID-19 convalescent plasma (CCP) therapy for hospitalized COVID-19 patients via the Expanded Access Program (EAP) and the Emergency Use Authorization (EUA), leading to use in about 500,000 patients during the first year of the pandemic for the USA.We tracked the number of CCP units dispensed to hospitals by blood banking organizations and correlated that usage with hospital admission and mortality data.CCP usage per admission peaked in Fall 2020, with more than 40% of inpatients estimated to have received CCP between late September and early November 2020. However, after randomized controlled trials failed to show a reduction in mortality, CCP usage per admission declined steadily to a nadir of less than 10% in March 2021. We found a strong inverse correlation (r = -0.52, p=0.002) between CCP usage per hospital admission and deaths occurring 2 weeks after admission, and this finding was robust to examination of deaths taking place 1, 2, or 3 weeks after admission. Changes in the number of hospital admissions, SARS-CoV-2 variants, and age of patients could not explain these findings. The retreat from CCP usage might have resulted in as many as 29,000 excess deaths from mid-November 2020 to February 2021.A strong inverse correlation between CCP use and mortality per admission in the USA provides population-level evidence consistent with the notion that CCP reduces mortality in COVID-19 and suggests that the recent decline in usage could have resulted in excess deaths.There was no specific funding for this study. AC was supported in part by RO1 HL059842 and R01 AI1520789; MJJ was supported in part by 5R35HL139854. This project has been funded in whole or in part with Federal funds from the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority under Contract No. 75A50120C00096.

Following the neutral results of the dal-OUTCOMES trial, a genome-wide study identified the rs1967309 variant in the adenylate cyclase type 9 ( ADCY9 ) gene on chromosome 16 as being associated with the risk of future cardiovascular events only in subjects taking dalcetrapib, a CETP (cholesterol ester transfer protein) modulator. Homozygotes for the minor A allele (AA) were protected from recurrent cardiovascular events when treated with dalcetrapib, while homozygotes for the major G allele (GG) had increased risk. Here, we present the current state of knowledge regarding the impact of rs1967309 in ADCY9 on clinical observations and biomarkers in dalcetrapib trials and the effects of mouse ADCY9 gene inactivation on cardiovascular physiology. Finally, we present our current model of the interaction between dalcetrapib and ADCY9 gene variants in the arterial wall macrophage, based on the intracellular role of CETP in the transfer of complex lipids from endoplasmic reticulum membranes to lipid droplets. Briefly, the concept is that dalcetrapib would inhibit CETP-mediated transfer of cholesteryl esters, resulting in a progressive inhibition of cholesteryl ester synthesis and free cholesterol accumulation in the endoplasmic reticulum. Reduced ADCY9 activity, by paradoxically leading to higher cyclic AMP levels and in turn increased cellular cholesterol efflux, could impart cardiovascular protection in rs1967309 AA patients. The ongoing dal-GenE trial recruited 6145 patients with the protective AA genotype and will provide a definitive answer to whether dalcetrapib will be protective in this population.

Background Prior studies have demonstrated that the cardiac intensive care unit (CICU) patient population has evolved over time. We sought to describe the temporal changes in comorbidities, illness severity, diagnoses, procedures and adjusted mortality within our CICU practice in recent years. Methods We retrospectively reviewed unique CICU admissions at the Mayo Clinic from January 2007 to April 2018. Comorbidities, severity of illness scores, discharge diagnosis codes and CICU procedures and therapies were recorded, and temporal trends were assessed using linear regression and Cochran-Armitage trend tests. Trends in adjusted hospital mortality over time were assessed using multivariable logistic regression. Results We included 12,418 patients with a mean age of 67.6 years (including 37.7% females). Temporal trends in the prevalence of several comorbidities and discharge diagnoses were observed, reflecting an increase in the prevalence of non-coronary cardiovascular diseases, critical care diagnoses, and organ failure (all P ≪ .05). The use of several CICU therapies and procedures increased over time, including mechanical ventilation, invasive lines and vasoactive drugs (all P ≪ .05). A temporal decrease in adjusted hospital mortality was observed among the subgroup of patients with (adjusted OR per year 0.97, 95% CI 0.94–0.99, P = .023) and without (adjusted OR per year 0.91, 95% CI 0.85–0.96, P = .002) a critical care discharge diagnosis. Conclusions We observed an increasing prevalence of critical care and organ failure diagnoses as well as increased utilization of critical care therapies in this CICU cohort, associated with a decrease in risk-adjusted hospital mortality over time.

Background: Age, smoking, hypercholesterolemia, and hypertension are major risk factors for atherosclerotic cardiovascular disease. Objective: We examined whether the effects of alirocumab on low-density lipoprotein cholesterol (LDL-C) differed according to age, hypertension, or smoking status. Methods: Data were pooled from 10 Phase 3 ODYSSEY randomized trials (24–104 weeks’ duration) in 4983 people with heterozygous familial hypercholesterolemia (FH) or non–familial hypercholesterolemia (3188 on alirocumab, 1795 on control [620 on ezetimibe and 1175 on placebo]). Most participants received concomitant maximum tolerated statin therapy. In 8 trials, the alirocumab dose was increased from 75 mg every 2 weeks (Q2W) to 150 mg Q2W at Week 12 if predefined risk-based LDL-C goals were not achieved at Week 8 (≥70 mg/dL in very high cardiovascular risk; ≥100 mg/dL in moderate or high cardiovascular risk). Two trials compared alirocumab 150 mg Q2W vs placebo. The efficacy and safety of alirocumab were assessed post hoc in subgroups stratified by age (

The institutional review board (IRB) is a group federally mandated to review and monitor research involving humans to ensure protection of their rights and welfare as research participants. Clinicians engaged in research require IRB approval for all research involving human participants, whether living individuals, data, or specimens. The process for obtaining IRB approval may seem like a daunting task. However, it is critical for clinical researchers to conduct research in a manner that protects human participants, and it is the mission of the IRB to help researchers accomplish this task. The purpose of this article is to review the role and purpose of the IRB, highlight federal and regulatory standards in human research participants protection, and help clinical researchers have a broader understanding of IRB functions that will help them conduct high-quality research with human participants.

Supplemental Digital Content is available in the text., Grateful patients provide substantial philanthropic funding for health care institutions, resulting in important societal benefits. Although grateful patient fundraising (GPFR) is widespread, it raises an array of ethical issues for patients, physicians, development professionals, and institutions. These issues have not been described comprehensively, and there is insufficient guidance to inform the ethical practice of GPFR. Consequently, the authors convened a “Summit on the Ethics of Grateful Patient Fundraising,” with the goal of identifying primary ethical issues in GPFR and offering recommendations regarding how to manage them. Participants were 29 experts from across the United States who represented the perspectives of bioethics, clinical practice, development, law, patients, philanthropy, psychology, and regulatory compliance. Intensive discussions resulted in articulating ethical issues for physicians and other clinicians (discussions with patients about philanthropy; physician-initiated discussions; clinically vulnerable patients; conflicts of obligation and equity regarding physician’s time, attention, and responsiveness and the provision of special services; and transparency and respecting donor intent) as well as for development officers and institutions (transparency in the development professional–donor relationship; impact on clinical care; confidentiality and privacy; conflicts of interest; institution–patient/donor relationship; concierge services for grateful patients; scientific merit and research integrity; transparency in use of philanthropic gifts; and institutional policies and training in responsible GPFR). While these recommendations promise to mitigate some of the ethical issues associated with GPFR, important next steps include conducting research on the ethical issues in GPFR, disseminating these recommendations, developing standardized training for clinicians regarding them, and revising them as warranted.

Background: Inclisiran is a double-stranded small interfering RNA that suppresses proprotein convertase subtilisin–kexin type 9 (PCSK9) translation in the liver, leading to sustained reductions in low-density lipoprotein cholesterol (LDL-C) and other atherogenic lipoproteins with twice-yearly dosing. Objectives: The purpose of this study was to conduct a patient-level pooled analysis from 3 phase 3 studies of inclisiran. Methods: Participants with heterozygous familial hypercholesterolemia (ORION-9 [Trial to Evaluate the Effect of Inclisiran Treatment on Low Density Lipoprotein Cholesterol (LDL-C) in Subjects With Heterozygous Familial Hypercholesterolemia (HeFH)]), atherosclerotic cardiovascular disease (ASCVD) (ORION-10 [Inclisiran for Participants With Atherosclerotic Cardiovascular Disease and Elevated Low-density Lipoprotein Cholesterol]), or ASCVD and ASCVD risk equivalents (ORION-11 [Inclisiran for Subjects With ASCVD or ASCVD-Risk Equivalents and Elevated Low-density Lipoprotein Cholesterol]) taking maximally tolerated statin therapy, with or without other LDL-C–lowering agents, were randomly assigned in a 1:1 ratio to receive either inclisiran or placebo, administered by subcutaneous injection on day 1, day 90, and every 6 months thereafter for 540 days. The coprimary endpoints were the placebo-corrected percentage change in LDL-C level from baseline to day 510 and the time-adjusted percentage change in LDL-C level from baseline after day 90 to day 540. Levels of other atherogenic lipoproteins and treatment-emergent adverse events were also assessed. Results: A total of 3,660 participants (n = 482, n = 1,561, and n = 1,617 from ORION-9, -10, and -11, respectively) underwent randomization. The placebo-corrected change in LDL-C with inclisiran at day 510 was −50.7% (95% confidence interval: −52.9% to −48.4%; p < 0.0001). The corresponding time-adjusted change in LDL-C was −50.5% (95% confidence interval: −52.1% to −48.9%; p < 0.0001). Safety was similar in both groups. Treatment-emergent adverse events at the injection site were more frequent with inclisiran than placebo (5.0% vs. 0.7%), but were predominantly mild, and none were severe or persistent. Liver and kidney function tests, creatine kinase values, and platelet counts did not differ between groups. Conclusions: These pooled safety and efficacy data show that inclisiran, given twice yearly in addition to maximally tolerated statin therapy with or without other LDL-C lowering agents, is an effective, safe, and well-tolerated treatment to lower LDL-C in adults with heterozygous familial hypercholesterolemia, ASCVD, or ASCVD risk equivalents.

Treatment of patients with COVID-19 using convalescent plasma from recently recovered patients has been shown to be safe, but the time course of change in clinical status following plasma transfusion in relation to baseline disease severity has not yet been described. We analyzed short, descriptive daily reports of patient status in 7,180 hospitalized recipients of COVID-19 convalescent plasma in the Mayo Clinic Expanded Access Program. We assessed, from the day following transfusion, whether the patient was categorized by his or her physician as better, worse or unchanged compared to the day before, and whether, on the reporting day, the patient received mechanical ventilation, was in the ICU, had died or had been discharged. Most patients improved following transfusion, but clinical improvement was most notable in mild to moderately ill patients. Patients classified as severely ill upon enrollment improved, but not as rapidly, while patients classified as critically ill/end-stage and patients on ventilators showed worsening of disease status even after treatment with convalescent plasma. Patients age 80 and over showed little or no clinical improvement following transfusion. Clinical status at enrollment and age appear to be the primary factors in determining the therapeutic effectiveness of COVID-19 convalescent plasma among hospitalized patients.

Successful therapeutics and vaccines for coronavirus disease 2019 (COVID-19) have harnessed the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Evidence that SARS-CoV-2 exists as locally evolving variants suggests that immunological differences may impact the effectiveness of antibody-based treatments such as convalescent plasma and vaccines. Considering that near-sourced convalescent plasma likely reflects the antigenic composition of local viral strains, we hypothesize that convalescent plasma has a higher efficacy, as defined by death within 30 days of transfusion, when the convalescent plasma donor and treated patient were in close geographic proximity. Results of a series of modeling techniques applied to approximately 28,000 patients from the Expanded Access to Convalescent Plasma program (ClinicalTrials.gov number: NCT04338360) support this hypothesis. This work has implications for the interpretation of clinical studies, the ability to develop effective COVID-19 treatments, and, potentially, for the effectiveness of COVID-19 vaccines as additional locally-evolving variants continue to emerge., Regional differences in SARS-CoV-2 variants may affect treatment outcome. Here, the authors show that near-sourced convalescent plasma has higher efficacy, as defined by death within 30 days of transfusion, than plasma sourced more than 150 miles away.

Currently available therapies reduce low-density lipoprotein cholesterol (LDL-C) through a variety of mechanisms, with statins being the most widely utilized of all therapies. However, patients who do not respond to statin therapy or other oral agents, or who develop side effects from taking the medications often need novel treatments. Inclisiran is a new and novel small interfering RNA compound which inhibits the translation of mRNA for Proprotein convertase subtilisin-kexin 9 (PCSK9) and thus reduces plasma levels of LDL-C. This chapter will focus on small interfering RNA compound PCSK9 inhibitors, which is currently under active investigation, by discussing pharmacology, clinical trials with a focus on stroke outcomes, and clinical use in practice.

Contains fulltext : 232887.pdf (Publisher’s version ) (Open Access) BACKGROUND: Convalescent plasma has been widely used to treat coronavirus disease 2019 (Covid-19) under the presumption that such plasma contains potentially therapeutic antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that can be passively transferred to the plasma recipient. Whether convalescent plasma with high antibody levels rather than low antibody levels is associated with a lower risk of death is unknown. METHODS: In a retrospective study based on a U.S. national registry, we determined the anti-SARS-CoV-2 IgG antibody levels in convalescent plasma used to treat hospitalized adults with Covid-19. The primary outcome was death within 30 days after plasma transfusion. Patients who were enrolled through July 4, 2020, and for whom data on anti-SARS-CoV-2 antibody levels in plasma transfusions and on 30-day mortality were available were included in the analysis. RESULTS: Of the 3082 patients included in this analysis, death within 30 days after plasma transfusion occurred in 115 of 515 patients (22.3%) in the high-titer group, 549 of 2006 patients (27.4%) in the medium-titer group, and 166 of 561 patients (29.6%) in the low-titer group. The association of anti-SARS-CoV-2 antibody levels with the risk of death from Covid-19 was moderated by mechanical ventilation status. A lower risk of death within 30 days in the high-titer group than in the low-titer group was observed among patients who had not received mechanical ventilation before transfusion (relative risk, 0.66; 95% confidence interval [CI], 0.48 to 0.91), and no effect on the risk of death was observed among patients who had received mechanical ventilation (relative risk, 1.02; 95% CI, 0.78 to 1.32). CONCLUSIONS: Among patients hospitalized with Covid-19 who were not receiving mechanical ventilation, transfusion of plasma with higher anti-SARS-CoV-2 IgG antibody levels was associated with a lower risk of death than transfusion of plasma with lower antibody levels. (Funded by the Department of Health and Human Services and others; ClinicalTrials.gov number, NCT04338360.).

Biospecimen research is a prominent investigative strategy that aims to provide novel insights into coronavirus disease 2019 (COVID-19), inform clinical trials, and develop effective, life-saving treatments. However, COVID-19 biospecimen research raises accompanying ethical concerns and practical challenges for investigators and participants. In this special article, we discuss the ethical issues that are associated with autonomy, beneficence, and justice in COVID-19 biospecimen research and describe strategies to manage the practical challenges, with an emphasis on protecting the rights and welfare of human research participants during a pandemic response. Appropriate institutional review board oversight and bioethics guidance for COVID-19 biospecimen research must maintain their focus on protecting the rights and welfare of research participants, despite the urgent need for more knowledge about the virus and the threat it poses to communities and nations.

Contains fulltext : 234991.pdf (Publisher’s version ) (Open Access) Convalescent plasma has been used worldwide to treat patients hospitalized with coronavirus disease 2019 (COVID-19) and prevent disease progression. Despite global usage, uncertainty remains regarding plasma efficacy, as randomized controlled trials (RCTs) have provided divergent evidence regarding the survival benefit of convalescent plasma. Here, we argue that during a global health emergency, the mosaic of evidence originating from multiple levels of the epistemic hierarchy should inform contemporary policy and healthcare decisions. Indeed, worldwide matched-control studies have generally found convalescent plasma to improve COVID-19 patient survival, and RCTs have demonstrated a survival benefit when transfused early in the disease course but limited or no benefit later in the disease course when patients required greater supportive therapies. RCTs have also revealed that convalescent plasma transfusion contributes to improved symptomatology and viral clearance. To further investigate the effect of convalescent plasma on patient mortality, we performed a meta-analytical approach to pool daily survival data from all controlled studies that reported Kaplan-Meier survival plots. Qualitative inspection of all available Kaplan-Meier survival data and an aggregate Kaplan-Meier survival plot revealed a directionally consistent pattern among studies arising from multiple levels of the epistemic hierarchy, whereby convalescent plasma transfusion was generally associated with greater patient survival. Given that convalescent plasma has a similar safety profile as standard plasma, convalescent plasma should be implemented within weeks of the onset of future infectious disease outbreaks.

Introduction: Despite a later onset in life than males, ASCVD is the leading cause of death in females, additionally mortality is higher compared to males. Disparities in the diagnosis and treatment of CVD risk factors may contribute to this difference. Inclisiran is a novel siRNA that inhibits PCSK9 synthesis and lowers LDL-C. Three Phase III placebo-controlled trials evaluated efficacy and safety of inclisiran in patients with HeFH (ORION-9), ASCVD (ORION-10, -11) and ASCVD risk equivalents (ORION-11). Objective: To assess the impact of sex on the efficacy and safety profile of inclisiran. Methods: Patients from each trial were categorized by sex. The co-primary endpoints were percentage change in LDL-C from baseline to Day 510 and time-adjusted percentage change in LDL-C from baseline after Day 90 up to Day 540. Secondary efficacy and safety parameters were assessed over 18 months. Results: Of a total 3660 patients, 1190 (32.5%) were females and 2470 (67.5%) were males. At baseline, females were less likely to receive statins [high-intensity statins] (90% [70%] vs 93% [76%]), or have ASCVD (73.6% vs 90.3%), were more likely to have ASCVD-risk equivalent (26.4% vs 9.7%) vs males. The efficacy of inclisiran vs placebo in both co-primary endpoints was similar in both sexes. Females had higher LDL-C at baseline (122.9 mg/dL vs 105.8 mg/dL) and (secondary endpoints) placebo-corrected mean absolute reduction in LDL-C at Day 510 (62.6 vs 54.0 mg/dL, P vs 51.5 mg/dL, P vs placebo for both sexes except for injection-site AEs that were higher in the inclisiran arm than placebo (females 9.4% vs 0.2%, males 2.8% vs 0.9%; Table). Conclusions: The efficacy and safety profile of inclisiran was generally similar in both sexes, except for more inclisiran injection-site AEs (mainly mild) vs placebo, which were more frequent in females.

Introduction: The risk of major atherosclerotic CV events increases with age, as do comorbidities, polypharmacy, and greater vulnerability to adverse drug reactions/events, posing challenges in the treatment of dyslipidemia. Three Phase III placebo-controlled trials evaluated the efficacy and safety of inclisiran according to age. Objective: To assess the efficacy and safety of inclisiran in patients across age categories. Methods: Patients were categorized according to age: Results: Of a total 3660 patients, 1737 [47.5%] were not old, 1431 [39.1%] were old, and 492 [13.4%] were very old. At baseline, the prevalence of comorbidities increased with age (not old, old, very old): stage 3 CKD (8.4%, 19.9%, 31.2%), hypertension (72.9%, 85.2%, 88.1%) and diabetes mellitus (32.2%, 40.0%, 38.0%), respectively. The placebo-corrected percentage change in LDL-C with inclisiran was similar across all ages: from baseline to Day 510 [–51.3% (not old), –49.9% (old), –51.0% (very old); P P 5x ULN were more frequently elevated in the not old category (Table). Conclusion: Inclisiran lowered LDL-C similarly across all ages with an acceptable safety profile. Inclisiran added to maximally tolerated statin therapy could be a safe option for older patients with ASCVD who need more intensive lipid-lowering treatment.

0AbstractIn the absence of effective countermeasures, human convalescent plasma has been widely used to treat severe acute respiratory syndrome coronavirus 2 including among patients with innate or acquired immunodeficiency. However, the association between COVID-19-associated mortality in patients with immunodeficiency and therapeutic use of convalescent plasma is unknown. We review clinical features and treatment protocols of COVID-19 patients with immunodeficiency after treatment with human convalescent plasma. We also discuss the time course and clinical features of recovery. These insights provide evidence for the need to develop a clear treatment protocol for COVID-19 patients with immunodeficiency and support the efficacy of convalescent plasma in patients with primary or secondary immunodeficiency.

Biospecimen research is a prominent investigative strategy that aims to provide novel insights into coronavirus disease 2019 (COVID-19), inform clinical trials, and develop effective, life-saving treatments. However, COVID-19 biospecimen research raises accompanying ethical concerns and practical challenges for investigators and participants. In this special article, we discuss the ethical issues that are associated with autonomy, beneficence, and justice in COVID-19 biospecimen research and describe strategies to manage the practical challenges, with an emphasis on protecting the rights and welfare of human research participants during a pandemic response. Appropriate institutional review board oversight and bioethics guidance for COVID-19 biospecimen research must maintain their focus on protecting the rights and welfare of research participants, despite the urgent need for more knowledge about the virus and the threat it poses to communities and nations.