Systematic review and meta-analysis of ivermectin for treatment of COVID-19: evidence beyond the hype.

BACKGROUND: The role of ivermectin in the treatment of COVID-19 is still under debate, yet the drug has been widely used in some parts of the world, as shown by impressive market data. The available body of evidence may have changed over the last months, as studies have been retracted and "standards of care" (SOC) used in control groups have changed with rapidly evolving knowledge on COVID-19. This review aims to summarize and critically appraise the evidence of randomized controlled trials (RCTs) of ivermectin, assessing clinical outcomes in COVID-19 patients. METHODS: RCTs evaluating the effects of ivermectin in adult patients with COVID-19 were searched through June 22, 2022, in four databases, L.OVE platform, clinical trial registries and pre-prints platforms. Primary endpoints included all-cause mortality and invasive ventilation requirement. Secondary endpoint was the occurrence of adverse events. Risk of bias was evaluated using the Cochrane Risk of Bias 2.0 tool. Meta-analysis included only studies which compared ivermectin to placebo or SOC. Random-effects were used to pool the risk ratios (RRs) of individual trials. The quality of evidence was evaluated using GRADE. The protocol was register in PROSPERO (CRD42021257471). RESULTS: Twenty-five RCTs fulfilled inclusion criteria (n = 6310). Of those, 14 compared ivermectin with placebo, in night ivermectin associated with SOC was compared to SOC and two studies compared ivermectin to an active comparator. Most RCTs had some concerns or high risk of bias, mostly due to lack of concealment of the randomization sequence and allocation, lack of blinding and high number of missing cases. Ivermectin did not show an effect in reducing mortality (RR = 0.76; 95%CI: 0.52-1.11) or mechanical ventilation (RR = 0.74; 95%CI: 0.48-1.16). This effect was consistent when comparing ivermectin vs. placebo, and ivermectin associated with SOC vs. SOC, as well as in sensitivity analysis. Additionally, there was very low quality of evidence regarding adverse effects (RR = 1.07; 95%CI: 0.84-1.35). CONCLUSIONS: The evidence suggests that ivermectin does not reduce mortality risk and the risk of mechanical ventilation requirement. Although we did not observe an increase in the risk of adverse effects, the evidence is very uncertain regarding this endpoint.

Predictors of venous thromboembolism in COVID-19 patients: results of the COVID-19 Brazilian Registry.

Previous studies that assessed risk factors for venous thromboembolism (VTE) in COVID-19 patients have shown inconsistent results. Our aim was to investigate VTE predictors by both logistic regression (LR) and machine learning (ML) approaches, due to their potential complementarity. This cohort study of a large Brazilian COVID-19 Registry included 4120 COVID-19 adult patients from 16 hospitals. Symptomatic VTE was confirmed by objective imaging. LR analysis, tree-based boosting, and bagging were used to investigate the association of variables upon hospital presentation with VTE. Among 4,120 patients (55.5% men, 39.3% critical patients), VTE was confirmed in 6.7%. In multivariate LR analysis, obesity (OR 1.50, 95% CI 1.11-2.02); being an ex-smoker (OR 1.44, 95% CI 1.03-2.01); surgery ≤ 90 days (OR 2.20, 95% CI 1.14-4.23); axillary temperature (OR 1.41, 95% CI 1.22-1.63); D-dimer ≥ 4 times above the upper limit of reference value (OR 2.16, 95% CI 1.26-3.67), lactate (OR 1.10, 95% CI 1.02-1.19), C-reactive protein levels (CRP, OR 1.09, 95% CI 1.01-1.18); and neutrophil count (OR 1.04, 95% CI 1.005-1.075) were independent predictors of VTE. Atrial fibrillation, peripheral oxygen saturation/inspired oxygen fraction (SF) ratio and prophylactic use of anticoagulants were protective. Temperature at admission, SF ratio, neutrophil count, D-dimer, CRP and lactate levels were also identified as predictors by ML methods. By using ML and LR analyses, we showed that D-dimer, axillary temperature, neutrophil count, CRP and lactate levels are risk factors for VTE in COVID-19 patients.

Reasons for discharge delays in teaching hospitals.

OBJECTIVE: To analyze the causes of delay in hospital discharge of patients admitted to internal medicine wards. METHODS: We reviewed 395 medical records of consecutive patients admitted to internal medicine wards of two public teaching hospitals: Hospital das Clínicas of the Universidade Federal de Minas Gerais and Hospital Odilon Behrens. The Appropriateness Evaluation Protocol was used to define the moment at which notes in the medical records indicated hospital stay was no longer appropriate and patients could be discharged. The interval between this estimated time and actual discharge was defined as the total number of days of delay in hospital discharge. An instrument was used to systematically categorize reasons for delay in hospital discharge and frequencies were analyzed. RESULTS: Delays in discharge occurred in 60.0% of 207 hospital admissions in the Hospital das Clínicas and in 58.0% of 188 hospital admissions in the Hospital Odilon Behrens. Mean delay per patient was 4.5 days in the former and 4.1 days in the latter, corresponding to 23.0% and 28.0% of occupancy rates in each hospital, respectively. The main reasons for delay in the two hospitals were, respectively, waiting for complementary tests (30.6% versus 34.7%) or for results of performed tests to be released (22.4% versus 11.9%) and medical-related accountability (36.2% versus 26.1%) which comprised delays in discussing the clinical case and in clinical decision making and difficulties in providing specialized consultation (20.4% versus 9.1%). CONCLUSIONS: Both hospitals showed a high percentage of delay in hospital discharge. The delays were mainly related to processes that could be improved by interventions by care teams and managers. The impact on mean length of stay and hospital occupancy rates was significant and troubling in a scenario of relative shortage of beds and long waiting lists for hospital admission.

Fatores de atraso na alta hospitalar em hospitais de ensino / Reasons for discharge delays in teaching hospitals

OBJETIVO Analisar os motivos de atraso na alta hospitalar de pacientes internados em enfermarias de clínica médica. MÉTODOS Foram analisados 395 prontuários de pacientes consecutivos das enfermarias de clínica médica de dois hospitais públicos de ensino: Hospital das Clínicas da Universidade Federal de Minas Gerais e Hospital Odilon Behrens. Foi utilizado o Appropriateness Evaluation Protocol para definir o momento a partir do qual as anotações do prontuário permitiam concluir que a permanência no hospital não mais era adequada. O intervalo entre esse momento e a data da alta hospitalar efetivada definiu o total de dias de atraso na alta hospitalar. Foi utilizado, sistematicamente, instrumento para categorizar os motivos de atraso da alta hospitalar, tendo sido realizada análise de frequências. RESULTADOS O atraso na alta hospitalar ocorreu em 60,0% das 207 internações do Hospital das Clínicas e em 58,0% das 188 internações do Hospital Odilon Behrens. O atraso por paciente foi em média de 4,5 dias no primeiro e 4,1 dias no segundo, o que corresponde à taxa de ocupação de 23,0% e 28,0% em cada hospital, respectivamente. Os principais motivos de atraso nos dois hospitais foram, respectivamente: espera para realização de exames complementares (30,6% e 34,7%) ou para liberação dos laudos dos exames (22,4% e 11,9%) e os relacionados à responsabilidade médica (36,2% e 26,1%), compreendendo a demora na discussão do caso clínico e na tomada de decisão clínica e dificuldades nas interconsultas, respectivamente (20,4% e 9,1%). CONCLUSÕES Foi constatado percentual elevado de atraso na alta hospitalar nos dois hospitais. O atraso foi devido principalmente a fatores relacionados a processos, que podem ser melhorados por intervenções da equipe assistencial e dos ...

OBJECTIVE To analyze the causes of delay in hospital discharge of patients admitted to internal medicine wards. METHODS We reviewed 395 medical records of consecutive patients admitted to internal medicine wards of two public teaching hospitals: Hospital das Clínicas of the Universidade Federal de Minas Gerais and Hospital Odilon Behrens. The Appropriateness Evaluation Protocol was used to define the moment at which notes in the medical records indicated hospital stay was no longer appropriate and patients could be discharged. The interval between this estimated time and actual discharge was defined as the total number of days of delay in hospital discharge. An instrument was used to systematically categorize reasons for delay in hospital discharge and frequencies were analyzed. RESULTS Delays in discharge occurred in 60.0% of 207 hospital admissions in the Hospital das Clínicas and in 58.0% of 188 hospital admissions in the Hospital Odilon Behrens. Mean delay per patient was 4.5 days in the former and 4.1 days in the latter, corresponding to 23.0% and 28.0% of occupancy rates in each hospital, respectively. The main reasons for delay in the two hospitals were, respectively, waiting for complementary tests (30.6% versus 34.7%) or for results of performed tests to be released (22.4% versus 11.9%) and medical-related accountability (36.2% versus 26.1%) which comprised delays in discussing the clinical case and in clinical decision making and difficulties in providing specialized consultation (20.4% versus 9.1%). CONCLUSIONS Both hospitals showed a high percentage of delay in hospital discharge. The delays were mainly related to processes that could be improved by interventions by care teams and managers. The impact on mean length of stay and hospital occupancy rates was significant and troubling in a scenario of relative shortage of beds and long waiting lists for hospital admission. .

Identifying potential predictors of high-quality oral anticoagulation assessed by time in therapeutic international normalized ratio range: a prospective, long-term, single-center, observational study.

BACKGROUND: The efficacy and risks of oral anticoagulation are largely associated with maintaining the quality of anticoagulation control. Nevertheless, few studies have addressed which factors, if any, are associated with this control. OBJECTIVE: This study aimed to identify predictors of high-quality oral anticoagulation. METHODS: A prospective observational study enrolled all adult patients on intended long-term oral anticoagulation attending a public anticoagulation clinic. Patients with high-quality anticoagulation, defined as percentage of time in therapeutic international normalized ratio (INR) range (TTR) ≥66%, were compared with those with poor anticoagulation control (TTR <66%). Measures included cognitive, psychological, and relevant behavioral factors, in addition to traditionally implicated ones, such as age, comorbidity, and concurrent medications. RESULTS: Participation was requested from all 233 patients followed up at the anticoagulation clinic. Eighty-six did not meet the inclusion criteria (49 due to intended anticoagulation duration <90 days, 37 due to the need for a caregiver responsible for medications). A total of 147 patients were enrolled, of whom 13 (8.8%) were lost to follow-up. Therefore, data were analyzed from 134 patients (mean [SD] age, 55 [14.2] years [range, 19-87 years]), who were followed up for a mean (SD) duration of 272 (87) days. The total mean TTR was 64.7%, which is comparable to values achieved in clinical trials. The good-control group had 61 patients (45.5%) (mean TTR, 77.7% [8.5%]) and the poor-control group had 73 patients (54.5%) (mean TTR, 50.4 [11.7%]). On multivariate logistic regression analysis, high-quality anticoagulation was independently associated with regular vitamin K intake, expressed by its variability in daily dosage (odds ratio [OR] = 0.79; 95% CI, 0.64-0.98); male sex (OR = 2.41; 95% CI, 1.06-5.49); duration of anticoagulation treatment >2 months (OR = 3.23; 95% CI, 1.25-8.36); presence of family support (OR = 3.32; 95% CI, 1.16-9.48); functional and cognitive ability to take medications as prescribed, defined as good medication management capacity (MMC; as assed using the Drug Regimen Unassisted Grading Scale) (OR = 4.18; 95% CI, 1.63-10.68); and no regular use of alcohol (OR = 8.59; 95% CI, 1.45-51.09). CONCLUSIONS: The data suggest that independent predictors of high-quality oral anticoagulation included regular vitamin K intake, male sex, duration of anticoagulation treatment >2 months, presence of family support, good MMC, and no regular alcohol use. These findings may help clinicians to decide whether to start anticoagulation in intermediate-risk patients, to identify patients who will require closer attention on their anticoagulation management, and to direct their efforts to improve the quality of oral anticoagulation.

Quality of management of oral anticoagulation as assessed by time in therapeutic INR range in elderly and younger patients with low mean years of formal education: a prospective cohort study.

BACKGROUND: despite the overwhelming evidence of its effectiveness, oral anticoagulation continues to be underused in the elderly, presumably due to physicians' misconceptions when estimating bleeding risk and ability to comply with treatment. OBJECTIVE: to investigate the quality of anticoagulation control among deprived elderly and younger patients. DESIGN: prospective observational study. SETTING: a public anticoagulation clinic in a developing country. SUBJECTS: all adult patients on intended long-term (>90 days) oral anticoagulation. We studied 171 patients (79 elderly and 92 non-elderly) with a mean follow-up of 273 ± 84.9 days. METHODS: the main outcome measure was the quality of anticoagulation management as measured by the time in therapeutic (TTR) international normalised ratio (INR) range. Elderly patients (≥60 years) were compared with younger patients with respect to the educational level and co-morbidities. RESULTS: the mean number of years of formal education was 4.37 ± 3.2 years. The mean TTR was 62.50 ± 17.9% in non-elderly and 62.10 ± 16.6% in elderly (P = 0.862) subjects, despite the higher prevalence of co-morbidities in the latter group: heart failure (46.3 versus 28.6%, P = 0.042), diabetes mellitus (22.8 versus 8.7%, P = 0.011), renal failure (estimated glomerular filtration rate <50 ml/min: 38.0 versus 7.1%, P < 0.001) and polypharmacy (84.8 versus 58.7%, P < 0.001). Fifty elderly and 84 non-elderly subjects require little or no assistance in taking medications. Among them, the elderly had lower educational levels (3.42 ± 2.5 versus 5.55 ± 3.4 years of formal education, P < 0.001) and higher rates of cognitive impairment (34.0 versus 13.1%, P = 0.004), but a similar mean TTR (62.46 ± 16.1 versus 63.02 ± 17.8%, P = 0.856). The oldest (≥75 years) patients did as well as those aged ≤50 years (mean TTR: 62.54 ± 16.0 versus 62.23 ± 16.4%, respectively, P = 0.98). CONCLUSIONS: good-quality management of oral anticoagulation is achievable in deprived populations attending an anticoagulation clinic. Elderly patients may experience similar quality of anticoagulation despite having higher levels of co-morbidities and polypharmacy. These results add evidence to the safety of such therapeutic interventions in the elderly.