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Mortality, viral clearance, and other clinical outcomes of hydroxychloroquine in COVID-19 patients: A systematic review and meta-analysis of randomized controlled trials.

ABSTRACT: Many meta-analyses have been published about the efficacy of hydroxychloroquine (HCQ) in coronavirus disease 2019 (COVID-19). Most of them included observational studies, and few have assessed HCQ as a prophylaxis or evaluated its safety profile. We searched multiple databases and preprint servers for randomized controlled trials (RCTs) that assessed HCQ for the treatment or prevention of COVID-19. We summarized the effect of HCQ on mortality, viral clearance, and other clinical outcomes. Out of 768 papers screened, 21 RCTs with a total of 14,138 patients were included. A total of 9 inpatient and 3 outpatient RCTs assessed mortality in 8596 patients with a pooled risk difference of 0.01 (95% confidence interval [CI] 0.00-0.03, I² = 1%, p = 0.07). Six studies assessed viral clearance at 7 days with a pooled risk ratio (RR) of 1.11 (95% CI 0.86-1.42, I² = 61%, p = 0.44) and 5 studies at 14 days with a pooled RR of 0.96 (95% CI 0.89-1.04, I² = 0%, p = 0.34). Several trials showed no significant effect of HCQ on other clinical outcomes and. Five prevention RCTs with 5012 patients found no effect of HCQ on the risk of acquiring COVID-19. Thirteen trials showed that HCQ was associated with increased risk of adverse events. We observed, with high level of certainty of evidence, that HCQ is not effective in reducing mortality in patients with COVID-19. Lower certainty evidence also suggests that HCQ neither improves viral clearance and other clinical outcomes, nor prevents COVID-19 infection in patients with high-risk exposure. HCQ is associated with an increased rate of adverse events.

SUBMITTER: Kashour Z

PROVIDER: S-EPMC8013604 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aim to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We present a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/ ). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality has been extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses include patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total sample size). The combined OR on all-cause mortality for hydroxychloroquine is 1.11 (95% CI: 1.02, 1.20; I² = 0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I² = 0%; 4 trials; 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine is associated with increased mortality in COVID-19 patients, and there is no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.

Project description:Prior studies have reported improvements in population-level risk factor burden and cardiovascular disease (CVD) outcomes using polypills for CVD risk reduction. However, a comprehensive assessment of the impact of polypills on CVD outcomes, mortality, adherence, and side effects across different settings has not previously been reported. We performed a systematic review and meta-analysis of randomized controlled trials examining the association between polypill therapy and CVD outcomes published before February 2021. The primary outcome of interest was the risk of major adverse CVD events (MACE). Risk ratios for dichotomous outcomes were converted to log RR and pooled using a generic inverse variance weighted random-effects model. Data for continuous outcomes were pooled using random-effects modeling and presented as mean differences with 95% CIs. Eight studies representing 25,584 patients were included for analysis. In the overall pooled analysis, the use of polypills was associated with a non-significant reduction in the risk of MACE (RR: 0.85; 95% CI: 0.70-1.02) and significant reductions in the risk of all-cause mortality (RR: 0.90; 95% CI: 0.81-1.00). The reductions in the risk of MACE with polypill use varied by baseline risk and nature of the study population (primary prevention vs. secondary prevention), with the most significant risk reduction among lower-risk cohorts, including within primary prevention populations [RR 0.70 (0.62, 0.79)]. Among measures of CVD risk factors, modest but significant reductions were observed for systolic and diastolic blood pressure [systolic: mean difference 1.99 mmHg (95% CI: -3.07 to -0.91); diastolic: mean difference 1.30 mmHg (95% CI: -2.42 to -0.19), but not for levels of total or low-density lipoprotein-cholesterol. Use of the polypill strategy significantly improved drug adherence (RR: 1.31; 95% CI: 1.11-1.55) with no association between polypill use and rates of adverse events or drug discontinuation. The use of polypill formulations is associated with significant reductions in CVD risk factors and the risk of all-cause mortality and MACE, particularly in the low-risk and primary prevention population.

Project description:BackgroundThe sequential organ failure assessment score (SOFA) is increasingly used as an endpoint in intensive care randomized controlled trials (RCTs). Although serially measured SOFA is independently associated with mortality in observational cohorts, the association between treatment effects on SOFA vs. effects on mortality has not yet been quantified in RCTs. The aim of this study was to quantify the relationship between SOFA and mortality in RCTs and to identify which SOFA derivative best reflects between-group mortality differences.MethodsThe review protocol was prospectively registered (Prospero CRD42016034014). We performed a literature search (up to May 1, 2016) for RCTs reporting both SOFA and mortality, and analyzed between-group differences in these outcomes. Treatment effects on SOFA and mortality were calculated as the between-group SOFA standardized difference and log odds ratio (OR), respectively. We used random-effects meta-regression to (1) quantify the linear relationship between RCT treatment effects on mortality (logOR) and SOFA (i.e. responsiveness) and (2) quantify residual heterogeneity (i.e. consistency, expressed as I 2).ResultsOf 110 eligible RCTs, 87 qualified for analysis. Using all RCTs, SOFA was significantly associated with mortality (slope = 0.49 (95% CI 0.17; 0.82), p = 0.006, I 2 = 5%); the overall mortality effect explained by SOFA score (R 2) was 9%. Fifty-eight RCTs used Fixed-day SOFA as an endpoint (i.e. the score on a fixed day after randomization), 25 studies used Delta SOFA as an endpoint (i.e. the trajectory from baseline score) and 15 studies used other SOFA derivatives as an endpoint. Fixed-day SOFA was not significantly associated with mortality (slope = 0.35 (95% CI -0.04; 0.75), p = 0.08, I 2 = 12%) and explained 3% of the overall mortality effect (R 2). Delta SOFA was significantly associated with mortality (slope = 0.70 (95% CI 0.26; 1.14), p = 0.004, I 2 = 0%) and explained 32% of the overall mortality effect (R 2).ConclusionsTreatment effects on Delta SOFA appear to be reliably and consistently associated with mortality in RCTs. Fixed-day SOFA was the most frequently reported outcome among the reviewed RCTs, but was not significantly associated with mortality. Based on this study, we recommend using Delta SOFA rather than Fixed-day SOFA as an endpoint in future RCTs.

Project description:In 2012, the United States Food and Drug Administration (FDA) issued a warning regarding potential adverse effects of HMG-CoA reductase inhibitors (statins) on cognition, based on the Adverse Events Reporting System and a review of the medical literature. We aimed to synthesize randomized clinical trial (RCTs) evidence on the association between statin therapy and cognitive outcomes.We searched MEDLINE, EMBASE, and Cochrane CENTRAL through December 2012, and reviewed published systematic reviews of statin treatment. We sought RCTs that compared statin treatment versus placebo or standard care, and reported at least one cognitive outcome (frequency of adverse cognitive events or measurements using standard neuropsychological cognitive test scores). Studies reporting sufficient information to calculate effect sizes were included in meta-analyses. Standardized and unstandardized mean differences were calculated for continuous outcomes for global cognition and for pre-specified cognitive domains. The main outcome was change in cognition measured by neuropsychological tests; an outcome of secondary interest was the frequency of adverse cognitive events observed during follow-up.We identified 25 RCTs (all placebo-controlled) reporting cognitive outcomes in 46,836 subjects, of which 23 RCTs reported cognitive test results in 29,012 participants. Adverse cognitive outcomes attributable to statins were rarely reported in trials involving cognitively normal or impaired subjects. Furthermore, meta-analysis of cognitive test data (14 studies; 27,643 participants) failed to show significant adverse effects of statins on all tests of cognition in either cognitively normal subjects (standardized mean difference 0.01, 95% confidence interval, CI, -0.01 to 0.03, p?=?0.42) or Alzheimer's disease subjects (standardized mean difference -0.05, 95% CI -0.19 to 0.10, p?=?0.38).Statin therapy was not associated with cognitive impairment in RCTs. These results raise questions regarding the continued merit of the FDA warning about potential adverse effects of statins on cognition.

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Mortality, viral clearance, and other clinical outcomes of hydroxychloroquine in COVID-19 patients: A systematic review and meta-analysis of randomized controlled trials.

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