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  • Association of Convalescent Plasma Treatment With Clinical Outcomes in Patients With COVID-19: A Systematic Review and Meta-analysis. JAMA Janiaud, P., Axfors, C., Schmitt, A. M., Gloy, V., Ebrahimi, F., Hepprich, M., Smith, E. R., Haber, N. A., Khanna, N., Moher, D., Goodman, S. N., Ioannidis, J. P., Hemkens, L. G. 2021


    Importance: Convalescent plasma is a proposed treatment for COVID-19.Objective: To assess clinical outcomes with convalescent plasma treatment vs placebo or standard of care in peer-reviewed and preprint publications or press releases of randomized clinical trials (RCTs).Data Sources: PubMed, the Cochrane COVID-19 trial registry, and the Living Overview of Evidence platform were searched until January 29, 2021.Study Selection: The RCTs selected compared any type of convalescent plasma vs placebo or standard of care for patients with confirmed or suspected COVID-19 in any treatment setting.Data Extraction and Synthesis: Two reviewers independently extracted data on relevant clinical outcomes, trial characteristics, and patient characteristics and used the Cochrane Risk of Bias Assessment Tool. The primary analysis included peer-reviewed publications of RCTs only, whereas the secondary analysis included all publicly available RCT data (peer-reviewed publications, preprints, and press releases). Inverse variance-weighted meta-analyses were conducted to summarize the treatment effects. The certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation.Main Outcomes and Measures: All-cause mortality, length of hospital stay, clinical improvement, clinical deterioration, mechanical ventilation use, and serious adverse events.Results: A total of 1060 patients from 4 peer-reviewed RCTs and 10 722 patients from 6 other publicly available RCTs were included. The summary risk ratio (RR) for all-cause mortality with convalescent plasma in the 4 peer-reviewed RCTs was 0.93 (95% CI, 0.63 to 1.38), the absolute risk difference was -1.21% (95% CI, -5.29% to 2.88%), and there was low certainty of the evidence due to imprecision. Across all 10 RCTs, the summary RR was 1.02 (95% CI, 0.92 to 1.12) and there was moderate certainty of the evidence due to inclusion of unpublished data. Among the peer-reviewed RCTs, the summary hazard ratio was 1.17 (95% CI, 0.07 to 20.34) for length of hospital stay, the summary RR was 0.76 (95% CI, 0.20 to 2.87) for mechanical ventilation use (the absolute risk difference for mechanical ventilation use was -2.56% [95% CI, -13.16% to 8.05%]), and there was low certainty of the evidence due to imprecision for both outcomes. Limited data on clinical improvement, clinical deterioration, and serious adverse events showed no significant differences.Conclusions and Relevance: Treatment with convalescent plasma compared with placebo or standard of care was not significantly associated with a decrease in all-cause mortality or with any benefit for other clinical outcomes. The certainty of the evidence was low to moderate for all-cause mortality and low for other outcomes.

    View details for DOI 10.1001/jama.2021.2747

    View details for PubMedID 33635310

  • Second versus first wave of COVID-19 deaths: shifts in age distribution and in nursing home fatalities. Environmental research Ioannidis, J. P., Axfors, C., Contopoulos-Ioannidis, D. G. 2021: 110856


    OBJECTIVE: To examine whether the age distribution of COVID-19 deaths and the share of deaths in nursing homes changed in the second versus the first pandemic wave.ELIGIBLE DATA: We considered all countries that had at least 4000 COVID-19 deaths occurring as of January 14, 2020, at least 200 COVID-19 deaths occurring in each of the two epidemic wave periods; and which had sufficiently detailed information available on the age distribution of these deaths. We also considered countries with data available on COVID-19 deaths of nursing home residents for the two waves.MAIN OUTCOME MEASURES: Change in the second wave versus the first wave in the proportion of COVID-19 deaths occurring in people <50 years ("young deaths") among all COVID-19 deaths and among COVID-19 deaths in people <70 years old; and change in the proportion of COVID-19 deaths in nursing home residents among all COVID-19 deaths.RESULTS: Data on age distribution were available for 14 eligible countries. Individuals <50 years old had small absolute difference in their share of the total COVID-19 deaths in the two waves across 13 high-income countries (absolute differences 0.0-0.4%). Their proportion was higher in Ukraine, but it decreased markedly in the second wave. The odds of young deaths was lower in the second versus the first wave (summary prevalence ratio 0.81, 95% CI 0.71-0.92) with large between-country heterogeneity. The odds of young deaths among deaths <70 years did not differ significantly across the two waves (summary prevalence ratio 0.96, 95% CI 0.86-1.06). Eligible data on nursing home COVID-19 deaths were available for 11 countries. The share of COVID-19 deaths that were accounted by nursing home residents decreased in the second wave significantly and substantially in 8 countries (prevalence ratio estimates: 0.36 to 0.78), remained the same in Denmark and Norway and markedly increased in Australia.CONCLUSIONS: In the examined countries, age distribution of COVID-19 deaths has been fairly similar in the second versus the first wave, but the contribution of COVID-19 deaths in nursing home residents to total fatalities has decreased in most countries in the second wave.

    View details for DOI 10.1016/j.envres.2021.110856

    View details for PubMedID 33581086

  • Recruitment and Results Reporting of COVID-19 Randomized Clinical Trials Registered in the First 100 Days of the Pandemic. JAMA network open Janiaud, P. n., Axfors, C. n., Ioannidis, J. P., Hemkens, L. G. 2021; 4 (3): e210330

    View details for DOI 10.1001/jamanetworkopen.2021.0330

    View details for PubMedID 33646310

  • Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials. Nature communications Axfors, C., Schmitt, A. M., Janiaud, P., Van't Hooft, J., Abd-Elsalam, S., Abdo, E. F., Abella, B. S., Akram, J., Amaravadi, R. K., Angus, D. C., Arabi, Y. M., Azhar, S., Baden, L. R., Baker, A. W., Belkhir, L., Benfield, T., Berrevoets, M. A., Chen, C., Chen, T., Cheng, S., Cheng, C., Chung, W., Cohen, Y. Z., Cowan, L. N., Dalgard, O., de Almeida E Val, F. F., de Lacerda, M. V., de Melo, G. C., Derde, L., Dubee, V., Elfakir, A., Gordon, A. C., Hernandez-Cardenas, C. M., Hills, T., Hoepelman, A. I., Huang, Y., Igau, B., Jin, R., Jurado-Camacho, F., Khan, K. S., Kremsner, P. G., Kreuels, B., Kuo, C., Le, T., Lin, Y., Lin, W., Lin, T., Lyngbakken, M. N., McArthur, C., McVerry, B. J., Meza-Meneses, P., Monteiro, W. M., Morpeth, S. C., Mourad, A., Mulligan, M. J., Murthy, S., Naggie, S., Narayanasamy, S., Nichol, A., Novack, L. A., O'Brien, S. M., Okeke, N. L., Perez, L., Perez-Padilla, R., Perrin, L., Remigio-Luna, A., Rivera-Martinez, N. E., Rockhold, F. W., Rodriguez-Llamazares, S., Rolfe, R., Rosa, R., Rosjo, H., Sampaio, V. S., Seto, T. B., Shehzad, M., Soliman, S., Stout, J. E., Thirion-Romero, I., Troxel, A. B., Tseng, T., Turner, N. A., Ulrich, R. J., Walsh, S. R., Webb, S. A., Weehuizen, J. M., Velinova, M., Wong, H., Wrenn, R., Zampieri, F. G., Zhong, W., Moher, D., Goodman, S. N., Ioannidis, J. P., Hemkens, L. G. 2021; 12 (1): 2349


    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: ). We systematically identified unpublished RCTs (, 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 is1.11 (95% CI: 1.02, 1.20; I=0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I=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.

    View details for DOI 10.1038/s41467-021-22446-z

    View details for PubMedID 33859192

  • Population-level COVID-19 mortality risk for non-elderly individuals overall and for non-elderly individuals without underlying diseases in pandemic epicenters. Environmental research Ioannidis, J. P., Axfors, C., Contopoulos-Ioannidis, D. G. 2020; 188: 109890


    OBJECTIVE: To provide estimates of the relative rate of COVID-19 death in people <65 years old versus older individuals in the general population, the absolute risk of COVID-19 death at the population level during the first epidemic wave, and the proportion of COVID-19 deaths in non-elderly people without underlying diseases in epicenters of the pandemic.ELIGIBLE DATA: Cross-sectional survey of countries and US states with at least 800 COVID-19 deaths as of April 24, 2020 and with information on the number of deaths in people with age <65. Data were available for 14 countries (Belgium, Canada, France, Germany, India, Ireland, Italy, Mexico, Netherlands, Portugal, Spain, Sweden, Switzerland, UK) and 13 US states (California, Connecticut, Florida, Georgia, Illinois, Indiana, Louisiana, Maryland, Massachusetts, Michigan, New Jersey, New York, Pennsylvania). We also examined available data on COVID-19 deaths in people with age <65 and no underlying diseases.MAIN OUTCOME MEASURES: Proportion of COVID-19 deaths in people <65 years old; relative mortality rate of COVID-19 death in people <65 versus ≥65 years old; absolute risk of COVID-19 death in people <65 and in those ≥80 years old in the general population as of June 17, 2020; absolute COVID-19 mortality rate expressed as equivalent of mortality rate from driving a motor vehicle.RESULTS: Individuals with age <65 account for 4.5-11.2% of all COVID-19 deaths in European countries and Canada, 8.3-22.7% in the US locations, and were the majority in India and Mexico. People <65 years old had 30- to 100-fold lower risk of COVID-19 death than those ≥65 years old in 11 European countries and Canada, 16- to 52-fold lower risk in US locations, and less than 10-fold in India and Mexico. The absolute risk of COVID-19 death as of June 17, 2020 for people <65 years old in high-income countries ranged from 10 (Germany) to 349 per million (New Jersey) and it was 5 per million in India and 96 per million in Mexico. The absolute risk of COVID-19 death for people ≥80 years old ranged from 0.6 (Florida) to 17.5 per thousand (Connecticut). The COVID-19 mortality rate in people <65 years old during the period of fatalities from the epidemic was equivalent to the mortality rate from driving between 4 and 82 miles per day for 13 countries and 5 states, and was higher (equivalent to the mortality rate from driving 106-483 miles per day) for 8 other states and the UK. People <65 years old without underlying predisposing conditions accounted for only 0.7-3.6% of all COVID-19 deaths in France, Italy, Netherlands, Sweden, Georgia, and New York City and 17.7% in Mexico.CONCLUSIONS: People <65 years old have very small risks of COVID-19 death even in pandemic epicenters and deaths for people <65 years without underlying predisposing conditions are remarkably uncommon. Strategies focusing specifically on protecting high-risk elderly individuals should be considered in managing the pandemic.

    View details for DOI 10.1016/j.envres.2020.109890

    View details for PubMedID 32846654

  • The worldwide clinical trial research response to the COVID-19 pandemic - the first 100 days. F1000Research Janiaud, P., Axfors, C., Van't Hooft, J., Saccilotto, R., Agarwal, A., Appenzeller-Herzog, C., Contopoulos-Ioannidis, D. G., Danchev, V., Dirnagl, U., Ewald, H., Gartlehner, G., Goodman, S. N., Haber, N. A., Ioannidis, A. D., Ioannidis, J. P., Lythgoe, M. P., Ma, W., Macleod, M., Malicki, M., Meerpohl, J. J., Min, Y., Moher, D., Nagavci, B., Naudet, F., Pauli-Magnus, C., O'Sullivan, J. W., Riedel, N., Roth, J. A., Sauermann, M., Schandelmaier, S., Schmitt, A. M., Speich, B., Williamson, P. R., Hemkens, L. G. 2020; 9: 1193


    Background: Never before have clinical trials drawn as much public attention as those testing interventions for COVID-19. We aimed to describe the worldwide COVID-19 clinical research response and its evolution over the first 100 days of the pandemic. Methods: Descriptive analysis of planned, ongoing or completed trials by April 9, 2020 testing any intervention to treat or prevent COVID-19, systematically identified in trial registries, preprint servers, and literature databases. A survey was conducted of all trials to assess their recruitment status up to July 6, 2020. Results: Most of the 689 trials (overall target sample size 396,366) were small (median sample size 120; interquartile range [IQR] 60-300) but randomized (75.8%; n=522) and were often conducted in China (51.1%; n=352) or the USA (11%; n=76). 525 trials (76.2%) planned to include 155,571 hospitalized patients, and 25 (3.6%) planned to include 96,821 health-care workers. Treatments were evaluated in 607 trials (88.1%), frequently antivirals (n=144) or antimalarials (n=112); 78 trials (11.3%) focused on prevention, including 14 vaccine trials. No trial investigated social distancing. Interventions tested in 11 trials with >5,000 participants were also tested in 169 smaller trials (median sample size 273; IQR 90-700). Hydroxychloroquine alone was investigated in 110 trials. While 414 trials (60.0%) expected completion in 2020, only 35 trials (4.1%; 3,071 participants) were completed by July 6. Of 112 trials with detailed recruitment information, 55 had recruited <20% of the targeted sample; 27 between 20-50%; and 30 over 50% (median 14.8% [IQR 2.0-62.0%]). Conclusions: The size and speed of the COVID-19 clinical trials agenda is unprecedented. However, most trials were small investigating a small fraction of treatment options. The feasibility of this research agenda is questionable, and many trials may end in futility, wasting research resources. Much better coordination is needed to respond to global health threats.

    View details for DOI 10.12688/f1000research.26707.1

    View details for PubMedID 33082937