Efficacy of early treatment with hydroxychloroquine in people with mild to moderate COVID-19: a systematic review and meta-analysis.

Introduction: No early treatment intervention for COVID-19 has proven effective to date. We systematically reviewed the efficacy of hydroxychloroquine as early treatment for COVID-19. Material and methods: Randomized controlled trials (RCTs) evaluating hydroxychloroquine for early treatment of COVID-19 were searched in five engines and preprint websites until September 14, 2021. Primary outcomes were hospitalization and all-cause mortality. Secondary outcomes included COVID-19 symptom resolution, viral clearance, and adverse events. Inverse variance random-effects meta-analyses were performed and quality of evidence (QoE) per outcome was assessed with GRADE methods. Results: Five RCTs (n = 1848) were included. The comparator was placebo in four RCTs and usual care in one RCT. The RCTs used hydroxychloroquine total doses between 1,600 and 4,400 mg and had follow-up times between 14 and 90 days. Compared to the controls, early treatment with hydroxychloroquine did not reduce hospitalizations (RR = 0.80, 95% CI: 0.47-1.36, I 2 = 2%, 5 RCTs, low QoE), all-cause mortality (RR = 0.77, 95% CI: 0.16-3.68, I 2 = 0%, 5 RCTs, very low QoE), symptom resolution (RR = 0.94, 95% CI: 0.77-1.16, I 2 = 71%, 3 RCTs, low QoE) or viral clearance at 14 days (RR = 1.02, 95% CI: 0.82-1.27, I 2 = 65%, 2 RCTs, low QoE). There was a larger non-significant increase of adverse events with hydroxychloroquine vs. controls (RR = 2.17, 95% CI: 0.86-5.45, I 2 = 92%, 5 RCTs, very low QoE). Conclusions: Hydroxychloroquine was not efficacious as early treatment for COVID-19 infections in RCTs with low to very low quality of evidence for all outcomes. More RCTs are needed to elucidate the efficacy of hydroxychloroquine as early treatment intervention.

Beneficial and Harmful Effects of Monoclonal Antibodies for the Treatment and Prophylaxis of COVID-19: Systematic Review and Meta-Analysis.

BACKGROUND: We systematically assessed beneficial and harmful effects of monoclonal antibodies for coronavirus disease 2019 (COVID-19) treatment, and prophylaxis in individuals exposed to severe acute respiratory syndrome coronavirus 2. METHODS: We searched 5 engines and 3 registries until November 3, 2021 for randomized controlled trials evaluating monoclonal antibodies vs control in hospitalized or non-hospitalized adults with COVID-19, or as prophylaxis. Primary outcomes were all-cause mortality, COVID-19-related death, and serious adverse events; hospitalization for non-hospitalized; and development of symptomatic COVID-19 for prophylaxis. Inverse variance random effects models were used for meta-analyses. Grading of Recommendations, Assessment, Development, and Evaluations methodology was used to assess certainty of evidence. RESULTS: Twenty-seven randomized controlled trials were included: 20 in hospitalized patients (n = 8253), 5 in non-hospitalized patients (n = 2922), and 2 in prophylaxis (n = 2680). In hospitalized patients, monoclonal antibodies slightly reduced mechanical ventilation (relative risk [RR] 0.74; 95% confidence interval [CI], 0.60-0.9; I2 = 20%, low certainty of evidence) and bacteremia (RR 0.77; 95% CI, 0.64-0.92; I2 = 7%, low certainty of evidence); evidence was very uncertain about the effect on adverse events (RR 1.31; 95% CI, 1.02-1.67; I2 = 77%, very low certainty of evidence). In non-hospitalized patients, monoclonal antibodies reduced hospitalizations (RR 0.30; 95% CI, 0.17-0.53; I2 = 0%, high certainty of evidence) and may slightly reduce serious adverse events (RR 0.47; 95% CI, 0.22-1.01; I2 = 33%, low certainty of evidence). In prophylaxis studies, monoclonal antibodies probably reduced viral load slightly (mean difference -0.8 log10; 95% CI, -1.21 to -0.39, moderate certainty of evidence). There were no effects on other outcomes. CONCLUSIONS: Monoclonal antibodies had limited effects on most of the outcomes in COVID-19 patients, and when used as prophylaxis. Additional data are needed to determine their efficacy and safety.

Efficacy and harms of tocilizumab for the treatment of COVID-19 patients: A systematic review and meta-analysis.

INTRODUCTION: We systematically assessed benefits and harms of tocilizumab (TCZ), which is an antibody blocking IL-6 receptors, in hospitalized COVID-19 patients. METHODS: Five electronic databases and two preprint webpages were searched until March 4, 2021. Randomized controlled trials (RCTs) and inverse probability treatment weighting (IPTW) cohorts assessing TCZ effects in hospitalized, COVID-19 adult patients were included. Primary outcomes were all-cause mortality, clinical worsening, clinical improvement, need for mechanical ventilation, and adverse events (AE). Inverse variance random-effects meta-analyses were performed with quality of evidence (QoE) evaluated using GRADE methodology. RESULTS: Nine RCTs (n = 7,021) and nine IPTW cohorts (n = 7,796) were included. TCZ significantly reduced all-cause mortality in RCTs (RR 0.89, 95%CI 0.81-0.98, p = 0.03; moderate QoE) and non-significantly in cohorts (RR 0.67, 95%CI 0.44-1.02, p = 0.08; very low QoE) vs. control (standard of care [SOC] or placebo). TCZ significantly reduced the need for mechanical ventilation (RR 0.80, 95%CI 0.71-0.90, p = 0.001; moderate QoE) and length of stay (MD -1.92 days, 95%CI -3.46 to -0.38, p = 0.01; low QoE) vs. control in RCTs. There was no significant difference in clinical improvement or worsening between treatments. AEs, severe AEs, bleeding and thrombotic events were similar between arms in RCTs, but there was higher neutropenia risk with TCZ (very low QoE). Subgroup analyses by disease severity or risk of bias (RoB) were consistent with main analyses. Quality of evidence was moderate to very low in both RCTs and cohorts. CONCLUSIONS: In comparison to SOC or placebo, TCZ reduced all-cause mortality in all studies and reduced mechanical ventilation and length of stay in RCTs in hospitalized COVID-19 patients. Other clinical outcomes were not significantly impacted. TCZ did not have effect on AEs, except a significant increased neutropenia risk in RCTs. TCZ has a potential role in the treatment of hospitalized COVID-19 patients.

Ivermectin for the Treatment of Coronavirus Disease 2019: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: We systematically assessed benefits and harms of the use of ivermectin (IVM) in patients with coronavirus disease 2019 (COVID-19). METHODS: Published and preprint randomized controlled trials (RCTs) assessing the effects of IVM on adult patients with COVID-19 were searched until 22 March 2021 in 5 engines. Primary outcomes were all-cause mortality rate, length of hospital stay (LOS), and adverse events (AEs). Secondary outcomes included viral clearance and severe AEs (SAEs). The risk of bias (RoB) was evaluated using the Cochrane Risk of Bias 2.0 tool. Inverse variance random effect meta-analyses were performed, with quality of evidence (QoE) evaluated using GRADE methods. RESULTS: Ten RCTs (n = 1173) were included. The controls were the standard of care in 5 RCTs and placebo in 5. COVID-19 disease severity was mild in 8 RCTs, moderate in 1, and mild and moderate in 1. IVM did not reduce all-cause mortality rates compared with controls (relative risk [RR], 0.37 [95% confidence interval, .12-1.13]; very low QoE) or LOS compared with controls (mean difference, 0.72 days [95% confidence interval, -.86 to 2.29 days]; very low QoE). AEs, SAEs, and viral clearance were similar between IVM and control groups (low QoE for all outcomes). Subgroups by severity of COVID-19 or RoB were mostly consistent with main analyses; all-cause mortality rates in 3 RCTs at high RoB were reduced with IVM. CONCLUSIONS: Compared with the standard of care or placebo, IVM did not reduce all-cause mortality, LOS, or viral clearance in RCTs in patients with mostly mild COVID-19. IVM did not have an effect on AEs or SAEs and is not a viable option to treat patients with COVID-19.

Efficacy and harms of convalescent plasma for treatment of hospitalized COVID-19 patients: a systematic review and meta-analysis.

INTRODUCTION: We systematically reviewed benefits and harms of convalescent plasma (CP) in hospitalized COVID-19 patients. MATERIAL AND METHODS: Randomized controlled trials (RCTs) and observational studies assessing CP effects on hospitalized, adult COVID-19 patients were searched until November 24, 2020. We assessed risk of bias (RoB) using Cochrane RoB 2.0 and ROBINS-I tools. Inverse variance random effect meta-analyses were performed. Quality of evidence was evaluated using GRADE methodology. Primary outcomes were all-cause mortality, clinical improvement, and adverse events. RESULTS: Five RCTs (n = 1067) and 6 cohorts (n = 881) were included. Three and 1 RCTs had some concerns and high RoB, respectively; and there was serious RoB in all cohorts. Convalescent plasma did not reduce all-cause mortality in RCTs of severe (RR = 0.60, 95% CI: 0.33-1.10) or moderate (RR = 0.60, 95% CI: 0.09-3.86) COVID-19 vs. standard of care (SOC); CP reduced all-cause mortality vs. SOC in cohorts (RR = 0.66, 95% CI: 0.49-0.91). Convalescent plasma did not reduce invasive ventilation vs. SOC in moderate disease (RR = 0.85, 95% CI: 0.47-1.55). In comparison to placebo + SOC, CP did not affect all-cause mortality (RR = 0.75, 95% CI: 0.48-1.16) or clinical improvement (HR = 1.07, 95% CI: 0.82-1.40) in severe patients. Adverse and serious adverse events were scarce, similar between CP and controls. Quality of evidence was low or very low for most outcomes. CONCLUSIONS: In comparison to SOC or placebo + SOC, CP did not reduce all-cause mortality in RCTs of hospitalized COVID-19 patients. Convalescent plasma did not have an effect on other clinical or safety outcomes. Until now there is no good quality evidence to recommend CP for hospitalized COVID-19 patients.

Efficacy and Safety of Hydroxychloroquine for Hospitalized COVID-19 Patients: A Systematic Review and Meta-Analysis.

We systematically reviewed the efficacy and safety of hydroxychloroquine as treatment for hospitalized COVID-19. Randomized controlled trials (RCTs) evaluating hydroxychloroquine as treatment for hospitalized COVID-19 patients were searched until 2nd of December 2020. Primary outcomes were all-cause mortality, need of mechanical ventilation, need of non-invasive ventilation, ICU admission and oxygen support at 14 and 30 days. Secondary outcomes were clinical recovery and worsening, discharge, radiological progression of pneumonia, virologic clearance, serious adverse events (SAE) and adverse events. Inverse variance random effects meta-analyses were performed. Thirteen RCTs (n=18,540) were included. Hydroxychloroquine total doses ranged between 2000 and 12,400 mg; treatment durations were from 5 to 16 days and follow up times between 5 and 30 days. Compared to controls, hydroxychloroquine non-significantly increased mortality at 14 days (RR 1.07, 95%CI 0.92-1.25) or 30 days (RR 1.08, 95%CI 1.00-1.16). Hydroxychloroquine did not affect other primary or secondary outcomes, except SAEs that were significantly higher than the control (RR 1.24, 95%CI 1.05-1.46). Eleven RCTs had high or some concerns of bias. Subgroup analyses were consistent with main analyses. Hydroxychloroquine was not efficacious for treating hospitalized COVID-19 patients and caused more severe adverse events. Hydroxychloroquine should not be recommended as treatment for hospitalized COVID-19 patients.

Impact of Prophylactic Hydroxychloroquine on People at High Risk of COVID-19: A Systematic Review and Meta-Analysis.

There are no proven prophylactic interventions for COVID-19. We systematically reviewed the efficacy of prophylactic hydroxychloroquine for COVID-19. Studies evaluating hydroxychloroquine for prophylaxis of COVID-19 were searched in several engines until 8 December 2020. Primary outcomes included RT-PCR positivity, COVID-19 infections (positive RT-PCR or compatible COVID-19 symptoms), and all-cause mortality. Random effects meta-analyses were performed for all outcomes. Five randomized controlled trials (RCTs) (n = 5579) and one cohort (n = 106) were included. Placebo was the comparator in four RCTs, and usual care in one RCT. Compared to the controls, five RCTs showed that hydroxychloroquine prophylaxis did not reduce RT-PCR positivity (RR 1.01, 95% CI 0.88-1.16), COVID-19 infection (RR 0.98, 95% CI 0.78-1.22), or all-cause mortality (RR 0.73, 95% CI 0.27-1.99). There were no differences of effects by pre- or post-exposure prophylaxis. Prophylaxis with hydroxychloroquine increased the risk of diarrhea, abdominal pain, or vomiting (RR 4.56, 95% CI 1.58-13.19). There were no effects of hydroxychloroquine on other secondary outcomes. Quality of evidence was low to very low for all outcomes. Hydroxychloroquine was not efficacious as a prophylaxis for COVID-19 infections, defined either as RT-PCR positivity or as a composite of RT-PCR positivity or compatible symptoms. Hydroxychloroquine did not reduce all-cause mortality, clinical worsening, or adverse events.

Renal Denervation for Uncontrolled and Resistant Hypertension: Systematic Review and Network Meta-Analysis of Randomized Trials.

Comparative efficacy and safety of renal denervation (RDN) interventions for uncontrolled (UH) and resistant hypertension (RH) is unknown. We assessed the comparative efficacy and safety of existing RDN interventions for UH and RH. Six search engines were searched up to 1 May 2020. Primary outcomes were mean 24-h ambulatory and office systolic blood pressure (SBP). Secondary outcomes were mean 24-h ambulatory and office diastolic blood pressure (DBP), clinical outcomes, and serious adverse events. Frequentist random-effects network meta-analyses were used to evaluate effects of RDN interventions. Twenty randomized controlled trials (RCTs) (n = 2152) were included, 15 in RH (n = 1544) and five in UH (n = 608). Intervention arms included radiofrequency (RF) in main renal artery (MRA) (n = 10), RF in MRA and branches (n = 4), RF in MRA+ antihypertensive therapy (AHT) (n = 5), ultrasound (US) in MRA (n = 3), sham (n = 8), and AHT (n = 9). RF in MRA and branches ranked as the best treatment to reduce 24-h ambulatory, daytime, and nighttime SBP and DBP versus other interventions (p-scores: 0.83 to 0.97); significant blood pressure effects were found versus sham or AHT. RF in MRA+AHT was the best treatment to reduce office SBP and DBP (p-scores: 0.84 and 0.90, respectively). RF in MRA and branches was the most efficacious versus other interventions to reduce 24-h ambulatory SBP and DBP in UH or RH.

Diagnostic accuracy of Xpert MTB/RIF for tuberculous meningitis: systematic review and meta-analysis.

OBJECTIVE: This systematic review evaluated the diagnostic accuracy of Xpert MTB/RIF to detect tuberculous meningitis (TBM). METHODS: PubMed and five other databases were systematically searched through March 2019. All studies evaluating diagnostic accuracy of Xpert MTB/RIF on cerebrospinal fluid (CSF) samples were included. Reference standards were definitive or definite plus probable TBM. The quality of studies was assessed by the QUADAS-2 tool. We performed bivariate random-effects meta-analysis and calculated summary diagnostic statistics. RESULTS: We identified 30 studies (n = 3972 participants), including 5 cohort studies and 25 cross-sectional studies. Reference standards were definite TB (n = 28 studies) or definite plus probable TBM (n = 6 studies). The pooled Xpert MTB/RIF sensitivity was 85% (95% CI, 70-93%), and specificity was 98% (95% CI, 97-99%) with a negative likelihood ratio of 0.15 (95% CI, 0.04-0.27) for definite TBM. For probable TBM cases, pooled sensitivity was 81% (95% CI, 66-90%), and specificity was 99% (95% CI, 97-99%). For both reference standard types, meta-analyses showed a C-statistic area under the curve of 0.98. The QUADAS-2 tool revealed low risk of bias as well as low concerns regarding applicability. Methodological heterogeneity was high among studies. CONCLUSIONS: Xpert MTB/RIF showed high accuracy for TBM diagnosis, but a negative Xpert MTB/RIF test does not rule out TBM. Repeat Xpert testing may be necessary. In clinical practice, Xpert MTB/RIF adds speed and sensitivity when compared to classic TBM diagnostic methods or previous commercial nucleic acid amplification techniques. More studies and better strategies for rapidly confirming a diagnosis of TBM in children are urgently needed.

OBJECTIF: Cette revue systématique a évalué la précision diagnostique de Xpert MTB/RIF pour détecter la méningite tuberculeuse (MTB). MÉTHODES: PubMed et cinq autres bases de données ont fait l'objet d'une recherche systématique jusqu'en mars 2019. Toutes les études évaluant la précision du diagnostic de Xpert MTB/RIF sur des échantillons de liquide céphalo-rachidien (LCR) ont été incluses. Les étalons de référence étaient des MTB définitives ou définitives et probables. La qualité des études a été évaluée par l'outil QUADAS-2. Nous avons effectué une méta-analyse des effets aléatoires bivariés et calculé des statistiques de résumés diagnostiques. RÉSULTATS: Nous avons identifié 30 études (n = 3.972 participants), dont 5 études de cohorte et 25 études transversales. Les étalons de référence étaient la TB définitive (n = 28 études) ou la MTB définitive et probable (n = 6 études). La sensibilité poolée Xpert MTB/RIF était de 85% (IC95%: 70-93%) et la spécificité était de 98% (IC95%: 97-99%) avec un rapport de vraisemblance négatif de 0,15 (IC95%: 0,04-0,27) pour la MTB définitive. Pour les cas probables de la MTB, la sensibilité poolée était de 81% (IC95%: 66-90%) et la spécificité était de 99% (IC95%: 97-99%). Pour les deux types d'étalons de référence, les méta-analyses ont montré une aire statistique C sous la courbe de 0,98. L'outil QUADAS-2 a révélé un faible risque de biais ainsi que de faibles préoccupations concernant l'applicabilité. L'hétérogénéité méthodologique était élevée parmi les études. CONCLUSIONS: Xpert MTB/RIF a montré une grande précision pour le diagnostic de la MTB, mais un test Xpert MTB/RIF négatif n'exclut pas la MTB. La répétition du tests Xpert peut être nécessaire. Dans la pratique clinique, Xpert MTB/RIF ajoute vitesse et sensibilité par rapport aux méthodes de diagnostic classiques de la MTB ou aux précédentes techniques d'amplification d'acide nucléique commerciales. Des études supplémentaires et de meilleures stratégies pour confirmer rapidement un diagnostic de MTB chez les enfants sont nécessaires d'urgence.

Efficacy and harms of remdesivir for the treatment of COVID-19: A systematic review and meta-analysis.

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.

Developing Criteria and Associated Instructions for Consistent and Useful Quality Improvement Study Data Extraction for Health Systems.

BACKGROUND: The Agency for Healthcare Research and Quality (AHRQ) could devote resources to collate and assess quality improvement studies to support learning health systems (LHS) but there is no reliable data on the consistency of data extraction for important criteria. METHODS: We identified quality improvement studies and evaluated the consistency of data extraction from two experienced independent reviewers at three time points: baseline, first revision (where explicit instructions for each criterion were created), and final revision (where the instructions were revised). Six investigators looked at the data extracted by the two systematic reviewers and determined the extent of similarity on a scale of 0 to 10 (where 0 represented no similarity and 10 perfect similarity). There were 42 assessments for baseline, 42 assessments for the first revision, and 42 assessments for the final revision. We asked two LHS participants to assess the relative value of our criteria. RESULTS: The consistency of extraction improved from 1.17 ± 1.85 at baseline to 6.07 ± 2.76 after revision 1 (P < 0.001) and to 6.81 ± 1.94 out of 10 for the final revision (P < 0.001). However, the final revision was not significantly improved over the first revision (P = 0.14). One key informant rated the difficulty in finding and using quality improvement studies a 6 (moderately difficult) while the other a 4 (moderately difficult). When asked how valuable it would be if AHRQ found and collated the demographic information about the health systems and the interventions used in published quality improvement studies, they rated it a 9 (highly valuable) and a 6 (moderately valuable). CONCLUSION: Creating explicit instructions for extracting data for quality improvement studies helps enhance the consistency of data extraction. This is important because it is difficult for LHS to vet these quality improvement studies on their own and they would value AHRQ's support in that regard.

Meta-Analysis.

When a review is performed following predefined steps (ie, systematically) and its results are quantitatively analyzed, it is called meta-analysis. Publication of meta-analyses has increased exponentially in pubmed.gov; using the key word "meta-analysis," 1,473 titles were yielded in 2007 and 176,704 on January 2020. Well-designed and reported meta-analyses provide valuable information for clinicians, researchers, and policymakers. The aim of this study was to provide CHEST peer reviewers, as well as authors and researchers in training, with tools that can help to improve the quality and timeliness of journal reviews, as well as the quality of the meta-analyses submitted. This article also is intended to be a practical guide to inform authors about the key features of meta-analyses to be considered when producing their review.

The Role of Suppressing Inflammation in the Treatment of Atherosclerotic Cardiovascular Disease.

OBJECTIVE: To review the 3 anti-inflammatory drugs, canakinumab, colchicine, and methotrexate, that have been investigated in major clinical trials for treating patients with atherosclerotic cardiovascular disease (ASCVD). DATA SOURCES: An Ovid MEDLINE literature search (1946 to February 2, 2020) was performed using search strategy [(C-reactive protein OR ASCVD OR cardiac disease OR cardiovascular disease) AND (canakinumab OR methotrexate OR Colchicine)]. Additional references were identified from the citations. STUDY SELECTION AND DATA EXTRACTION: English-language studies assessing the impact of these 3 drugs on inflammation as measured by high-sensitivity C-reactive protein (hs-CRP) or the association with reducing ASCVD events were included. DATA SYNTHESIS: Canakinumab and colchicine significantly reduced ASCVD events in high-risk patients with median baseline hs-CRP levels of ~4.0 mg/L. Methotrexate was ineffective at reducing ASCVD events in high-risk patients, but their baseline hs-CRP concentrations were a median of <2 mg/L. In subgroup analyses of the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS), patients whose baseline hs-CRP was 2 to 4 mg/L had benefits from canakinumab therapy similar to those with baseline levels exceeding 4. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Even with the best current drug therapies, patients with underlying inflammation can benefit from the addition of both colchicine and canakinumab to further lower CV events. Given its cost, colchicine is a more attractive option. CONCLUSIONS: Patients at high risk of recurrent cardiovascular disease events with an hs-CRP of 2 mg/L or greater can reduce the occurrence of ASCVD events with canakinumab or colchicine therapy. Colchicine is the preferable option, in particular for those with myocardial infarction, given its more reasonable cost.

Hydroxychloroquine or Chloroquine for Treatment or Prophylaxis of COVID-19: A Living Systematic Review.

BACKGROUND: Hydroxychloroquine and chloroquine have antiviral effects in vitro against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). PURPOSE: To summarize evidence about the benefits and harms of hydroxychloroquine or chloroquine for the treatment or prophylaxis of coronavirus disease 2019 (COVID-19). DATA SOURCES: PubMed (via MEDLINE), EMBASE (via Ovid), Scopus, Web of Science, Cochrane Library, bioRxiv, Preprints, ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform, and the Chinese Clinical Trials Registry from 1 December 2019 until 8 May 2020. STUDY SELECTION: Studies in any language reporting efficacy or safety outcomes from hydroxychloroquine or chloroquine use in any setting in adults or children with suspected COVID-19 or at risk for SARS-CoV-2 infection. DATA EXTRACTION: Independent, dually performed data extraction and quality assessments. DATA SYNTHESIS: Four randomized controlled trials, 10 cohort studies, and 9 case series assessed treatment effects of the medications, but no studies evaluated prophylaxis. Evidence was conflicting and insufficient regarding the effect of hydroxychloroquine on such outcomes as all-cause mortality, progression to severe disease, clinical symptoms, and upper respiratory virologic clearance with antigen testing. Several studies found that patients receiving hydroxychloroquine developed a QTc interval of 500 ms or greater, but the proportion of patients with this finding varied among the studies. Two studies assessed the efficacy of chloroquine; 1 trial, which compared higher-dose (600 mg twice daily for 10 days) with lower-dose (450 mg twice daily on day 1 and once daily for 4 days) therapy, was stopped owing to concern that the higher dose therapy increased lethality and QTc interval prolongation. An observational study that compared adults with COVID-19 receiving chloroquine phosphate, 500 mg once or twice daily, with patients not receiving chloroquine found minor fever resolution and virologic clearance benefits with chloroquine. LIMITATION: There were few controlled studies, and control for confounding was inadequate in observational studies. CONCLUSION: Evidence on the benefits and harms of using hydroxychloroquine or chloroquine to treat COVID-19 is very weak and conflicting. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

Four-year incidence of major adverse cardiovascular events in patients with atherosclerosis and atrial fibrillation.

BACKGROUND: There is a paucity of contemporary data assessing the implications of atrial fibrillation (AF) on major adverse cardiovascular events (MACE) in patients with or at high-risk for atherosclerotic disease managed in routine practice. HYPOTHESIS: We sought to evaluate the 4-year incidence of MACE in patients with or at risk of atherosclerotic disease in the presence of AF. METHODS: Using US MarketScan data, we identified AF patients ≥45 years old with billing codes indicating established coronary artery disease, cerebrovascular disease, or peripheral artery disease or the presence of ≥3 risk factors for atherosclerotic disease from January 1, 2013 to December 31, 2013 with a minimum of 4-years of available follow-up. We calculated the 4-year incidence of MACE (cardiovascular death or hospitalization with a primary billing code for myocardial infarction or ischemic stroke). Patients were further stratified by CHA2 DS2 -VASc score and oral anticoagulation (OAC) use at baseline. RESULTS: We identified 625,951 patients with 4-years of follow-up, of which 77,752 (12.4%) had comorbid AF. The median (25%, 75% range) CHA2 DS2 -VASc score was 4 (3, 5) and 64% of patients received an OAC at baseline. The incidence of MACE increased as CHA2 DS2 -VASc scores increased (P-interaction<.0001 for all). AF patients receiving an OAC were less likely to experience MACE (8.9% vs 11.6%, P < .0001) including ischemic stroke (5.4% vs 6.7%, P < .0001). CONCLUSION: Comorbid AF carries a substantial risk of MACE in patients with or at risk of atherosclerotic disease. MACE risk increases with higher CHA2 DS2 -VASc scores and is more likely in patients without OAC.

Incidence and Predictors of Major Adverse Cardiovascular Events in Patients With Established Atherosclerotic Disease or Multiple Risk Factors.

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.