Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Comparing remnant lipoprotein cholesterol measurement methods to evaluate efficacy of ezetimibe/statin vs statin therapy

Background: Elevated remnant lipoprotein cholesterol (RLP-C) levels increase cardiovascular disease risk. However, RLP-C measurement methods are not standardized, leading to variations across studies. Objective: To evaluate the effect of ezetimibe (Eze) + statins vs statin monotherapy on RLP-C using immunoseparation (IM), vertical auto profile (VAP) ultracentrifugation, and calculated RLP-C measurement methods. Methods: This post hoc analysis evaluated data pooled from 3 first-line (all-statin [simvastatin 10/20/40/80 mg] vs Eze + statin [Eze 10 mg + simvastatin]) and 2 second-line (statin [atorvastatin uptitrated to 40/80 mg] vs statin + Eze [atorvastatin 20/40 mg + Eze 10 mg]) studies. Similarity of RLP-C methods was evaluated using Pearson correlation coefficients and Bland-Altman plots. RLP-C changes and percent changes from baseline were measured by all 3 methods in first-line and VAP and calculated methods in second-line studies. Results: Correlations between methods were generally moderate to strong for RLP-C levels, changes, and percent changes across treatment groups (r = 0.29\u20130.79) but with little evidence of agreement by Bland-Altman plots. Baseline RLP-C levels for Eze + statin vs all-statin groups were lower by IM (14.0 vs 14.0) compared with VAP (36.9 vs 35.9) and calculated (32.8 vs 33.3) methods. RLP-C changes (mg/dL) and percent changes from baseline were significantly greater (P < .01) with Eze + statins vs statins by VAP, calculated, and IM methods (between-treatment differences: 125.0 and 1212.0, 122.0 and 125.4, and 121.5 and 1212.1, respectively) in first-line, and VAP and calculated methods (between-treatment differences: 125.0 and 1219.9 and 122.0 and 127.3) in second-line studies. Conclusion: Although the 3 methods showed little agreement, each supported Eze + statins for achieving greater RLP-C reductions vs statin monotherapy; variability of results reinforces urgent need to standardize RLP-C measurements

Rationale and design of the CLEAR-outcomes trial: Evaluating the effect of Bempedoic acid on cardiovascular events in patients with statin intolerance

Background: Although statins play a pivotal role in the prevention of atherosclerotic cardiovascular disease, many patients fail to achieve recommended lipid levels due to statin-associated muscle symptoms. Bempedoic acid is an oral pro-drug that is activated in the liver and inhibits cholesterol synthesis in hepatocytes, but is not activated in skeletal muscle which has the potential to avoid muscle-related adverse events. Accordingly, this agent effectively lowers atherogenic lipoproteins in patients who experience statin-associated muscle symptoms. However, the effects of bempedoic acid on cardiovascular morbidity and mortality have not been studied. Study design: Cholesterol Lowering via Bempedoic acid, an ACL-Inhibiting Regimen (CLEAR) Outcomes is a randomized, double-blind, placebo-controlled clinical trial. Included patients must have all of the following: (i) established atherosclerotic cardiovascular disease or have a high risk of developing atherosclerotic cardiovascular disease, (ii) documented statin intolerance, and (iii) an LDL-C≥100mg/dL on maximally-tolerated lipid-lowering therapy. The study randomized 14,014 patients to treatment with bempedoic acid 180mg daily or matching placebo on a background of guideline-directed medical therapy. The primary outcome is a composite of the time to first cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization. The trial will continue until 1620 patients experience a primary endpoint, with a minimum of 810 hard ischemic events (cardiovascular death, nonfatal myocardial infarction or nonfatal stroke) and minimum treatment duration of 36months and a projected median treatment exposure of 42months. Conclusions: CLEAR Outcomes will determine whether bempedoic acid 180mg daily reduces the incidence of adverse cardiovascular events in high vascular risk patients with documented statin intolerance and elevated LDL-C levels.StephenJ Nicholls, A Michael Lincoff, Harold E Bays, Leslie Cho, Diederick E Grobbee, John JP Kastelein ... et al

Eficácia e toxicidade do pó comercial de Hoodia gordonii (Masson) swet ex decne utilizado no tratamento da obesidade Efficacy and toxicity of Hoodia gordonii commercial powder used to combat obesity

A obesidade é atualmente o principal problema de saúde em países desenvolvidos e em desenvolvimento. Diversos recursos terapêuticos têm sido empregados para o tratamento da obesidade destacando-se os fitoterápicos, consagrados pelo conhecimento popular. Nesse contexto, a planta Hoodia gordonii tem despertado atualmente grande interesse mundial, principalmente pelas recentes descobertas e comprovações científicas da inibição do apetite e da sede pelo glicosídeo ativo P57 isolado de espécies da planta. Apesar disso, tais efeitos ainda não foram avaliados e comprovados em amostras comerciais do pó de H. gordonii (PHG), não existindo evidências científicas que garantam a sua eficácia e segurança. Portanto, o objetivo deste trabalho foi realizar ensaios biológicos com ratos para avaliar a atividade farmacológica e a toxicidade de amostras comerciais do pó de H. gordonii. As amostras foram administradas por gavagem em doses equivalentes a 20 vezes as recomendadas para humanos em ratas Wistar durante 4 semanas sendo avaliados os parâmetros indicadores do efeito terapêutico. Após as 4 semanas, os animais foram sacrificados, e amostras de sangue e órgãos foram coletados e submetidos à avaliação dos indicadores metabólicos, endócrinos, hematológicos e histopatológicos. Os resultados demonstraram que para todos os parâmetros avaliados não houve diferenças significativas entre o grupo controle que recebeu somente solução salina estéril e os grupos tratados com PHG indicando que os mesmos, apesar de não apresentarem quaisquer indícios de toxicidade, são incapazes de produzir os supostos efeitos de inibição de apetite e consequente tratamento da obesidade.<br>Obesity is currently the main health problem in developed and developing countries. Several therapeutic methods have been employed for the treatment of obesity, especially herbal medicines, highlighted by popular knowledge. In this context, the plant Hoodia gordonii has currently aroused great interest worldwide, especially for recent discoveries and scientific proof of inhibition of appetite and thirst by the active glycoside P57 isolated from plant species. Nevertheless, such effects have not been evaluated and proven for commercial samples of H. gordonii powder (PHG), with no scientific evidence to ensure its effectiveness and safety. Therefore, the aim of this study was to conduct biological tests with rats to evaluate the pharmacological activity and toxicity of commercial samples of H. gordonii powder. The samples were administered through gavage, at doses equivalent to 20 times those recommended for humans, in female Wistar rats during 4 weeks for evaluation of the parameters indicative of therapeutic efficacy. After 4 weeks, the animals were sacrificed and blood and organ samples were collected and subjected to the evaluation of metabolic, endocrine, hematological and histopathological indicators. Results showed that for all evaluated parameters, there were no significant differences between the control group that only received sterile saline solution and the groups treated with PHG, indicating that the latter, although presenting no evidence of toxicity, are unable to produce the alleged effects of appetite inhibition and subsequent obesity treatment