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This report, the third update of a previously published living systematic review (1), focuses on treatment (not prophylaxis) of coronavirus disease 2019 (COVID-19) with hydroxychloroquine or chloroquine. The first and second updates covered evidence available through 1 July 2020 (2) and 1 August 2020 (3), respectively. This update evaluates evidence published through 21 September 2020.No new evidence about chloroquine was found. One new randomized trial (4) and 5 new cohort studies (5-9) evaluating hydroxychloroquine were found. None of the studies used zinc; all studies (5-8) except for 1 (9) with a hydroxychloroquine group and an azithromycin group evaluated hydroxychloroquine alone. The trial used a "standard care" control group (4) and had high risk of bias, whereas all of the cohort studies had serious risk of bias (5-9). The trial (4) and 3 of the new cohort studies (6, 7, 9) assessed hospital-initiated hydroxychloroquine, whereas 2 of the new cohort studies (5, 8) assessed prehospital initiation.The Supplement Table displays the following for outcomes of all identified trials (4, 10 -16, 32, 34) and cohort studies (5-9, 17-31, 33, 35) that addressed treatment with hydroxychloroquine: risk-of-bias assessments, unadjusted estimates of effect, and overall ratings of strength of evidence. In trials, when hydroxychloroquine is initiated in the outpatient setting, there is low strength of evidence that it reduces hospitalizations (11, 12); whereas, in cohort studies, there remains insufficient evidence (5, 8, 33). There is now low strength of evidence that hydroxychloroquine has no positive effect on all-cause mortality and need for mechanical ventilation in both trials and cohort studies. Even with 3 new cohort studies assessing intensive care unit admission (5, 6, 8) and 1 trial (4) and 1 cohort study (9) assessing symptom resolution, there is still insufficient evidence for determining hydroxychloroquine's effect on both outcomes. No new trial or studies assessed any other outcome.It is becoming increasingly unlikely that in-hospital use of hydroxychloroquine will yield beneficial effects. The large SOLIDARITY-WHO and ORCHID-NIH trials have been prematurely discontinued, with press releases citing lack of efficacy (36, 37), but preprints or publications of these trials are still not available. However, the outpatient use of hydroxychloroquine is more promising. Trials with some concern of bias (11) and high risk of bias (12) found nonsignificant reductions in hospitalizations, whereas 2 cohort studies with serious risk of bias found significant reductions (5, 8). However, 1 cohort study with critical risk of bias found a significant increase (33). One of these cohort studies (5) found a significant reduction in intensive care unit admission with hydroxychloroquine use, whereas another found a nonsignificant reduction (8), which is in contrast to 2 cohort studies (6, 24) with serious risk of bias assessing inpatient use of hydroxychloroquine where intensive care unit admissions were significantly increased.

Background Efficacy and safety of treatments for hospitalized COVID-19 are uncertain. We systematically reviewed efficacy and safety of remdesivir for the treatment of COVID-19. Methods Studies evaluating remdesivir in adults with hospitalized COVID-19 were searched in several engines until August 21, 2020. Primary outcomes included all-cause mortality, clinical improvement or recovery, need for invasive ventilation, and serious adverse events (SAEs). Inverse variance random effects meta-analyses were performed. Results We included four randomized controlled trials (RCTs) (n = 2296) [two vs. placebo (n = 1299) and two comparing 5-day vs. 10-day regimens (n = 997)], and two case series (n = 88). Studies used intravenous remdesivir 200mg the first day and 100mg for four or nine more days. One RCT (n = 236) was stopped early due to AEs; the other three RCTs reported outcomes between 11 and 15 days. Time to recovery was decreased by 4 days with remdesivir vs. placebo in one RCT (n = 1063), and by 0.8 days with 5-days vs. 10-days of therapy in another RCT (n = 397). Clinical improvement was better for 5-days regimen vs. standard of care in one RCT (n = 600). Remdesivir did not decrease all-cause mortality (RR 0.71, 95%CI 0.39 to 1.28, I2 = 43%) and need for invasive ventilation (RR 0.57, 95%CI 0.23 to 1.42, I2 = 60%) vs. placebo at 14 days but had fewer SAEs; 5-day decreased need for invasive ventilation and SAEs vs. 10-day in one RCT (n = 397). No differences in all-cause mortality or SAEs were seen among 5-day, 10-day and standard of care. There were some concerns of bias to high risk of bias in RCTs. Heterogeneity between studies could be due to different severities of disease, days of therapy before outcome determination, and how ordinal data was analyzed. Conclusions There is paucity of adequately powered and fully reported RCTs evaluating effects of remdesivir in hospitalized COVID-19 patients. Until stronger evidence emerges, we cannot conclude that remdesivir is efficacious for treating COVID-19.

Background There is a paucity of contemporary data estimating the incidence of major adverse cardiovascular events ( MACE ) in patients with established atherosclerotic disease or multiple risk factors managed in routine practice. We estimated 1‐ and 4‐year incidences of MACE and the association between MACE and vascular beds affected in these patients. Methods and Results Using US IBM MarketScan data from January 1, 2013 to December 31, 2017, we identified patients ≥45 years old with established coronary artery disease, cerebrovascular disease, peripheral artery disease, or the presence of ≥3 risk factors for atherosclerosis during 2013 with a minimum of 4 years of follow‐up. We calculated 1‐ and 4‐year incidences of MACE (cardiovascular death or hospitalization for myocardial infarction or ischemic stroke). A Cox proportional hazards regression model adjusted for age and sex was used to evaluate the association between vascular bed number/location(s) affected and MACE . We identified 1 302 856 patients with established atherosclerotic disease or risk factors for atherosclerosis. Coronary artery disease was present in 16.9% of patients, cerebrovascular disease in 7.6%, peripheral artery disease in 13.6%, and risk factors for atherosclerosis only in 66.0%. The 1‐ and 4‐year incidences of MACE were 1.4% and 6.9%, respectively. At 4 years, MACE was more frequent in patients with atherosclerotic disease in a single (hazard ratio=1.51, 95% CI =1.48–1.55), 2‐(hazard ratio=2.35, 95% CI =2.27–2.44), or all 3 vascular beds (hazard ratio=3.30, 95% CI =2.97–3.68) compared with having risk factors for atherosclerosis. Conclusions Patients with established atherosclerotic disease or who have multiple risk factors and are treated in contemporary, routine practice carry a substantial risk for MACE at 1‐ and 4‐ years of follow‐up. MACE risk was shown to vary based on the number and location of vascular beds involved.

This systematic review in obese and overweight individuals showed that regular intermittent dieting decreased lean mass compared to continuous dieting. There were no differences in effects for either intermittent vs continuous interventions across all other outcomes. In contrast to previous systematic reviews, this study suggested that lean mass is better preserved in continuous dieting compared to regular intermittent dieting.

Aims  Vascular calcification is common in diabetic patients. Warfarin has been associated with renovascular calcification and worsening renal function; rivaroxaban may provide renopreservation by decreasing vascular inflammation. We compared the impact of rivaroxaban and warfarin on renal outcomes in diabetic patients with non-valvular atrial fibrillation (NVAF). Methods and results  Using United States IBM MarketScan data from January 2011 to December 2017, we identified adults with both NVAF and diabetes, newly-initiated on rivaroxaban or warfarin with ≥12-month insurance coverage prior to anticoagulation initiation. Patients with Stage 5 chronic kidney disease (CKD) or undergoing haemodialysis at baseline were excluded. Differences in baseline covariates between cohorts were adjusted using inverse probability-of-treatment weighting (IPTW) based on propensity scores (absolute standardized differences <0.1 achieved for all after adjustment). Outcomes included incidence rates of emergency department/hospital admissions for acute kidney injury (AKI) and the composite of the development of Stage 5 CKD or need for haemodialysis. Patients were followed until an event, index anticoagulant discontinuation/switch, insurance disenrollment, or end-of-data availability. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox regression. We assessed 10 017 rivaroxaban (22.6% received a reduced dose) and 11 665 warfarin users. In comparison to warfarin, rivaroxaban was associated with lower risks of AKI (HR = 0.83, 95% CI = 0.74–0.92) and development of Stage 5 CKD or need for haemodialysis (HR = 0.82, 95% CI = 0.70–0.96). Sensitivity and subgroup analyses had similar effects as the base-case analysis. Conclusion  Rivaroxaban appears to be associated with lower risks of undesirable renal outcomes vs. warfarin in diabetic NVAF patients.

Background We systematically assessed benefits and harms of the use of ivermectin (IVM) in COVID-19 patients. Methods Published and preprint randomized controlled trials (RCTs) assessing IVM effects on COVID-19 adult patients were searched until March 22, 2021 in five engines. Primary outcomes were all-cause mortality, length of stay (LOS), and adverse events (AE). Secondary outcomes included viral clearance and severe AEs. Risk of bias (RoB) was evaluated using Cochrane RoB 2·0 tool. Inverse variance random effect meta-analyses were performed. with quality of evidence (QoE) evaluated using GRADE methodology. Results Ten RCTs (n=1173) were included. Controls were standard of care [SOC] in five RCTs and placebo in five RCTs. COVID-19 disease severity was mild in 8 RCTs, moderate in one RCT, and mild and moderate in one RCT. IVM did not reduce all-cause mortality vs. controls (RR 0.37, 95%CI 0.12 to 1.13, very low QoE) or LOS vs. controls (MD 0.72 days, 95%CI −0.86 to 2.29, very low QoE). AEs, severe AE and viral clearance were similar between IVM and controls (all outcomes: low QoE). Subgroups by severity of COVID-19 or RoB were mostly consistent with main analyses; all-cause mortality in three RCTs at high RoB was reduced with IVM. Conclusions In comparison to SOC or placebo, IVM did not reduce all-cause mortality, length of stay or viral clearance in RCTs in COVID-19 patients with mostly mild disease. IVM did not have an effect on AEs or severe AEs. IVM is not a viable option to treat COVID-19 patients.

ObjectiveA systematic review and meta-analysis was conducted to assess the efficacy of low-sodium salt substitutes (LSSS) as a potential intervention to reduce cardiovascular (CV) diseases.MethodsFive engines and ClinicalTrials.gov were searched from inception to May 2018. Randomised controlled trials (RCTs) enrolling adult hypertensive or general populations that compared detected hypertension, systolic blood pressure (SBP), diastolic blood pressure (DBP), overall mortality, stroke and other CV risk factors in those receiving LSSS versus regular salt were included. Effects were expressed as risk ratios or mean differences (MD) and their 95% CIs. Quality of evidence assessment followed GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology.Results21 RCTs (15 in hypertensive (n=2016), 2 in normotensive (n=163) and 4 in mixed populations (n=5224)) were evaluated. LSSS formulations were heterogeneous. Effects were similar across hypertensive, normotensive and mixed populations. LSSS decreased SBP (MD −7.81 mm Hg, 95% CI −9.47 to –6.15, p<0.00001) and DBP (MD −3.96 mm Hg, 95% CI −5.17 to –2.74, p<0.00001) compared with control. Significant increases in urinary potassium (MD 11.46 mmol/day, 95% CI 8.36 to 14.55, p<0.00001) and calcium excretion (MD 2.39 mmol/day, 95% CI 0.52 to 4.26, p=0.01) and decreases in urinary sodium excretion (MD −35.82 mmol/day, 95% CI −57.35 to –14.29, p=0.001) were observed. Differences in detected hypertension, overall mortality, total cholesterol, triglycerides, glucose or BMI were not significant. Quality of evidence was low to very low for most of outcomes.ConclusionsLSSS significantly decreased SBP and DBP. There was no effect for detected hypertension, overall mortality and intermediate outcomes. Large, long-term RCTs are necessary to clarify salt substitute effects on clinical outcomes.