Macrolides for the Treatment of COVID-19: A Systematic Review, Esquemas y mapas conceptuales de Medicina

¡Descarga Macrolides for the Treatment of COVID-19: A Systematic Review y más Esquemas y mapas conceptuales en PDF de Medicina solo en Docsity! 1 / 11 Research Macrolides for the treatment of COVID-19: a living, systematic review Catalina Verdejoa , Laura Vergara-Merinob , Nicolás Mezab , Javier Pérez-Bracchiglionec , Natalia Carvajal-Juliáa , Eva Madridb , Gabriel Radad , María Ximena Rojas Reyese a School of Medicine, Cochrane Chile Associated Centre, Universidad de Valparaíso, Chile b Interdisciplinary Centre for Health Studies (CIESAL), Universidad de Valparaíso, Cochrane Chile Associated Centre, Valparaíso, Chile c Interdisciplinary Centre for Health Studies (CIESAL), Universidad de Valparaíso, Cochrane Chile Associated Centre, Viña del Mar, Chile d Fundación Epistemonikos, Santiago, Chile e Department of Research, Fundación Cardioinfantil, Cochrane Colombia Affiliate Centre, Bogotá, Colombia Abstract Objective This living, systematic review aims to provide a timely, rigorous, and continuously updated summary of the evidence available on the role of macrolides for treating patients with COVID-19. Design A living, systematic review. Database We conducted searches in the centralized repository L·OVE (Living OVerview of Evidence). L·OVE is a platform that maps PICO questions to evidence from the Epistemonikos database. In response to the COVID-19 emergency, L·OVE was adapted to expand the range of evidence it covers and customized to group all COVID-19 evidence in one place. Today it is maintained through regular searches in 39 databases. Methods We included randomized trials evaluating the effect of macrolides — as monother- apy or in combination with other drugs — versus placebo or no treatment in pa- tients with COVID-19. Randomized trials evaluating macrolides in infections caused by other coronaviruses, such as MERS-CoV and SARS-CoV, and non-ran- domized studies in COVID-19 were searched in case we found no direct evidence from randomized trials. Two reviewers independently screened each study for eli- gibility, extracted data, and assessed the risk of bias. Measures included all-cause mortality; the need for invasive mechanical ventilation; extracorporeal membrane oxygenation, length of hospital stay, respiratory failure, serious adverse events, time to SARS-CoV-2 RT-PCR negativity. We applied the GRADE approach to assess the certainty of the evidence for each outcome. A living, web-based version of this review will be openly available during the COVID-19 pandemic. We will resubmit it every time the conclusions change or whenever there are substantial updates. Results The search in the L·OVE platform retrieved 424 references. We considered 260 as potentially eligible and were reviewed in full texts. We included one randomized clinical trial that evaluated the use of azithromycin in combination with hydroxychloroquine compared to hydroxychloroquine alone in hospitalized patients with COVID 19. The estimates for all outcomes evaluated resulted in insufficient power to draw conclusions. The quality of the evidence for the main outcomes was low to very low. * Corresponding author mxrojas@cardioinfantil.org Citation Verdejo C, Vergara-Merino L, Meza N, Pérez- Bracchiglione J, Carvajal-Juliá N, Madrid E, et al. Macrolides for the treatment of COVID-19: a living, systematic review. Medwave 2020;20(11):e8073 Doi 10.5867/medwave.2020.11.8073 Submission date 13/8/2020 Acceptance date 26/10/2020 Publication date 14/12/2020 Origin Not commissioned Type of review Externally peer-reviewed by three reviewers, double-blind Keywords COVID-19, severe acute respiratory syndrome coronavirus 2, coronavirus infections, systematic review, macrolides, azithromycin, anti-bacterial agents, coronavirus disease 2 / 11 Conclusions Macrolides in the management of patients with COVID 19 showed no beneficial effects compared to standard of care. The evidence for all outcomes is inconclusive. Larger trials are needed to determine the effects of macrolides on pulmonary and other outcomes in COVID-19 patients. Systematic review registration PROSPERO Registration number: CRD42020181032 Protocol preprint DOI: 10.31219/osf.io/rvp59 Introduction COVID-19 is an infection caused by the SARS-CoV-2 coronavirus1. It was first identified in Wuhan, China, on December 31, 20192. On March 11, 2020, the WHO characterized the COVID-19 outbreak as a pandemic1. In July 2020, more than fifteen million cases of con- tagion had been identified worldwide3. While the majority of cases result in mild symptoms, some might progress to pneumonia, acute respiratory distress syndrome, and death4-6. The case fatality rate reported across countries, settings, and age groups is highly variable, but it ranges from about 0.8% to 18%7. Multiple drugs have been proposed as a possible treatment for pa- tients with moderate to severe COVID-19. Azithromycin, and other macrolides, have been suggested due to their alleged role in prevent- ing bacterial superinfection and their immunomodulatory and anti- inflammatory effects8,9. However, clinical studies evaluating the use of macrolides in the treatment of adult or pediatric patients with dif- ferent respiratory infections, such as influenza or respiratory syncyt- ial virus, have shown contradictory results10-17. Despite these results, macrolides have been empirically prescribed in patients with pneumonia caused by novel coronaviruses such as SARS and MERS, and, more recently, SARS-CoV-2. Azithromycin attracted attention after the release of a non-randomized study— with considerable methodological limitations—and an observational study, claiming that hydroxychloroquine with azithromycin achieved a higher level of SARS-CoV-2 clearance in respiratory secretions18,19. Using innovative and agile processes, taking advantage of technolog- ical tools, and resorting to several research groups’ collective effort, this living, systematic review aims to provide a timely, rigorous, and continuously updated summary of the evidence available on patients with COVID-19. Methods Protocol and registration This manuscript complies with the ‘Preferred Reporting Items for Systematic reviews and Meta-Analyses’ (PRISMA) guidelines20. Ap- pendix 1 - PRISMA checklist. A protocol stating the shared objectives and methodology of multi- ple evidence syntheses (systematic reviews and overviews of system- atic reviews) to be conducted in parallel for different questions rele- vant to COVID-19 was published elsewhere21. This systematic re- view protocol was adapted to the specificities of the question22 and submitted to PROSPERO CRD42020181032. Search strategies Electronic searches Our literature search was devised by the team maintaining the L·OVE platform (https://app.iloveevidence.com), using the follow- ing approach: 1. Identification of terms relevant to the population and interven- tion components of the search strategy, using Word2vec technol- ogy23 to the corpus of documents available in Epistemonikos Da- tabase. 2. Discussion of terms with content and methods experts to identify relevant, irrelevant and missing terms. 3. Creation of a sensitive boolean strategy encompassing all the rel- evant terms. 4. Iterative analysis of articles missed by the boolean strategy, and refinement of the strategy accordingly. We conducted searches using the L·OVE (Living OVerview of Ev- idence) platform (https://app.iloveevidence.com) for COVID-19. This system maps PICO questions to a repository and is maintained through regular searches in 31 databases, preprint servers, trial reg- istries, and websites relevant to COVID-19. The list of sources is regularly updated on our website. All the searches covered the period until August 6, 2020. No date, language, study design, publication status, or language restriction was applied to the searches in the Epistemonikos or the additional searches. All the platform information comes from a repository developed and maintained by Epistemonikos Foundation through the screening of different sources relevant to COVID-1924. At the time of releasing this article, this repository included more than 65 000 articles perti- nent to the coronavirus disease, coming from the following data- bases, trial registries, preprint servers and websites relevant to COVID-19: Epistemonikos database, Pubmed/medline, EMBASE, CINAHL, PsycINFO, ICTRP Search Portal, Clinicaltrials.gov, ISRCTN registry, Chinese Clinical Trial Registry, IRCT - Iranian Main messages • Multiple drugs have been proposed as possible treatments for patients with moderate to severe COVID-19. • In patients with COVID-19, there is not enough evidence to conclude any difference between the use of macrolides and standard of care. • Larger trials are needed to determine the effects of macrolides on pulmonary and other outcomes in COVID-19 patients. 5 / 11 Description of the included studies We included one randomized clinical trial33, which included a total of 665 patients, but only 438 of them were randomized to the inter- vention and comparison groups of this systematic review’s interest. In this trial, adult patients with suspected or confirmed COVID-19 were randomly assigned to one of three groups: standard care; hy- droxychloroquine (400 milligrams twice daily for seven days) plus standard care; or azithromycin (400 milligrams twice daily for seven days) plus hydroxychloroquine (400 milligrams twice daily for seven days) plus standard care. For this systematic review, we extracted data from the latter two groups, which compares the isolated effect of azithromycin. Measured outcomes of our interest were: all-cause mortality, invasive mechanical ventilation, length of hospital stay, respiratory failure, serious adverse events, and total adverse events. Table 1 presents the inclusion criteria of the included study, and ta- ble 2 shows the main characteristics and baseline characteristics of the participants. We describe the details of the study in Appendix 2. Table 1. Inclusion criteria of the study. Age Type of disease Clinical or severity parameters Cavalcanti 2020 Adults (18 years and older) Suspected or confirmed Covid-19 with 14 or fewer days since symptom onset Inpatient setting. Mild or moderate disease (no need for oxygen sup- plementation > 4 L/min via nasal cannula or ≥ 40% via Venturi mask or oxygen supplementation via high-flow nasal cannula or need for non-inva- sive ventilation or for invasive mechanical ventila- tion) Prepared by the authors from the study data. Table 2. Main characteristics of the included study and baseline characteristics of the participants. Cavalcanti 2020 Number randomised 438 (AZT/HXQ = 217, HXQ = 221) Geographic location and setting Brazil, inpatient setting Funder Supported by institutions participating in the Coalition COVID-19 Brazil and by EMS Pharma, which provided partial funding, the trial drugs, and logistic support Females in study, % 39.5 Time from onset to treatment, days 7 Amount of supplemental oxygen, % 41.3 Current or former smoker, % 6.6 Underlying chronic diseases, % Hypertension 40.0 Diabetes 9.9, Obesity 15.1, Cancer 2.5, Heart failure 1.6, COPD 1.8, AIDS 0.2, Chronic renal disease 0.7, Asthma 5.7 Baseline medications, % Glucocorticoid 1.1, ACE inhibitor 8.0, Angiotensin II–receptor antagonist 17.1, NSAID 4.6 Prepared by the authors from the study data. AZT/HXQ: azithromycin plus hydroxychloroquine. HXQ: hydroxychloroquine. *Data extracted only from azithromycin plus hydroxychloroquine group and hydroxychloroquine group. * See more details in appendix 2. Ongoing studies We identified 78 ongoing studies (71 randomized trials and seven non-randomized studies). See Appendix 2 - List of included, ex- cluded, and ongoing studies. Excluded studies We excluded 165 studies that did not fulfill our eligibility criteria. A detailed list of excluded studies with reasons for exclusion is pre- sented in Appendix 2 - List of included, excluded, and ongoing stud- ies. Risk of bias of the included study The overall risk of bias was high, mainly due to deviations from the intended interventions. The other four domains (randomization pro- cess, missing outcomes, measurement of the outcome, and selection of reported results) were assessed as low risk of bias. Appendix 2 presents the main reasons for this assessment. Effects of interventions Of the outcomes of interest for this review, the included study did not report on “Extracorporeal membrane oxygenation” and “Time 6 / 11 to SARS-CoV-2 RT-PCR negativity”. The results for all other out- comes are presented in Table 3 and our interactive Summary of Findings table. Table 3. Summary of findings of macrolides for the treatment of COVID-19. Macrolides for the treatment of COVID-19 Patient or population Hospitalized adults with COVID-19 (confirmed or suspected) Setting Inpatient (mild or moderate) Intervention Azithromycin plus hydroxychloroquine plus standard care) Comparison Hydroxychloroquine plus standard care) Outcomes Anticipated absolute effects* (95% CI) Relative effect (95% CI) № of participants (studies) Certainty of the evidence (GRADE) Risk with No macrolides Risk with Macro- lides All-cause mortality 4 per 1000 2 per 1000 (1 to 7) RR 0.57 (0.19 to 1.66) 438 (1 RCT) ⨁⨁◯◯ LOW a,b Invasive mechanical ventilation follow up: 15 days 72 per 1000 92 per 1000 (49 to 173) RR 1.27 (0.68 to 2.39) 438 (1 RCT) ⨁⨁◯◯ LOW a,b Respiratory failure ** follow up: 15 days 158 per 1000 171 per 1000 (112 to 260) RR 1.08 (0.71 to 1.64) 438 (1 RCT) ⨁⨁◯◯ LOW a,b Serious adverse events follow up: 15 days 10 per 1000 21 per 1000 (4 to 107) RR 2.08 (0.41 to 10.61) 438 (1 RCT) ⨁◯◯◯ VERY LOW a,c Length of hospital stay The mean length of hospi- tal stay was 8.9 days MD 0.5 days more (0.82 less days to 1.82 more days) - 438 (1 RCT) ⨁◯◯◯ VERY LOW a,c Total adverse events follow up: 15 days 347 per 1000 413 per 1000 RR 1.17 (0.91 to 1.50) 438 (1 RCT) ⨁◯◯◯ VERY LOWa,c Prepared by the authors from the study data. CI: Confidence interval; HR: Hazard Ratio; RR: Risk ratio; MD: Mean difference, RCT: randomised clinical trial. *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). GRADE Working Group grades of evidence: • High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. • Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. • Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect. • Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect. **Respiratory failure was defined as: participants that needed high flow nasal cannula, non invasive ventilation or invasive mechanical ventilation. a. Downgraded two levels of certainty due to imprecision (confidence interval includes harm, benefit and no effect; is based in less than 300 events; OIS not met). b. Not downgraded because of risk of bias (lack of blinding of participants, personnel and outcome assessors did not affect this outcome). c. Downgraded one level of certainty due to risk of bias (lack of blinding of participants, personnel and outcome assessors). Primary outcome: All-cause mortality The included study reported the effect of interventions on in-hospi- tal death; we extracted this outcome as “All-cause mortality”33. The analysis showed a non-statistically significant difference in the risk of all-cause mortality between intervention groups (risk ratio: 0.57; 95% confidence interval: 0.19 to 1.66; 438 patients; 13 events) (Fig- ure 2). 7 / 11 Figure 2. Relative risk for dichotomous outcomes for azithromycin plus hydroxychloroquine versus hydroxychloroquine. Prepared by the authors from the study data. AZT: Azithromycin. HXQ: Hydroxychloroquine. Secondary outcomes: 1. Mechanical ventilation The included study reported the effect of interventions on the need for invasive mechanical ventilation within fifteen days. Out of the 217 patients in the intervention group, twenty needed mechanical ventilation within fifteen days compared to the sixteen of 221 pa- tients in the control group. Results did not show statistically signifi- cant differences between compared interventions on the need for mechanical ventilation (risk ratio: 1.27; 95% confidence interval: 0.68 to 2.39; 438 patients; 36 events). These results are shown in Figure 2. 2. Extracorporeal membrane oxygenation The included study did not assess this outcome. 3. Length of hospital stay The included study reported the length of hospital stay, and these results are shown in Figure 3. The mean duration of hospital stay for the 217 patients in the intervention group was 9.4 days (standard deviation of 7.8). In comparison, the mean duration of hospital stay for the 221 patients in the control group was 8.9 days (standard de- viation of 6.2). The mean difference between groups showed very imprecise results from which to draw conclusions (mean difference 0.5; 95% confidence interval: -0.82 to 1.82; 438 patients). Figure 3. Mean difference for length of hospital stay for azithromycin plus hydroxychloroquine versus hydroxychloroquine. 4. Respiratory failure The included study reported the need for high flow nasal cannula, non-invasive ventilation, and invasive mechanical ventilation within fifteen days. We extracted these outcomes as “Respiratory failure,” and the results are shown in Figure 3. Out of 217 patients in the intervention group, 37 had respiratory failure, compared to 35 of 221 patients in the control group. The comparative analysis did not show statistically significant differences between compared interventions in the effect on respiratory failure (risk ratio: 1.08; 95% confidence interval: 0.71 to 1.64; 438 patients; 72 events). 5. Serious adverse events The per-protocol analysis showed very imprecise results and did not show any trend regarding the risk of adverse events associated with the compared interventions (risk ratio: 2.08; 95% confidence inter- val: 0.41 to 10.61; 438 patients; 239 in the intervention group; 199 in the control group; seven events). This outcome is presented in Fig- ure 3. 6. Time to SARS-CoV-2 RT-PCR negativity The included study did not assess this outcome. 7. Total adverse events The included study reported serious adverse events, and for any other adverse events, we extracted these two outcomes as “Total ad- verse events.” The per-protocol analysis results did not show statis- tically significant differences between compared interventions in terms of adverse events (risk ratio: 1.19; 95% confidence interval: 0.94 to 1.52; 438 patients; 239 in the intervention group; 199 in the control group; 168 events). Discussion This living, systematic review included only one randomized con- trolled trial that evaluated using azithromycin associated with hy- droxychloroquine compared to hydroxychloroquine alone for COVID-1933. Its results show that there is not enough evidence to conclude any difference between the intervention and control groups. All assessed outcomes had a wide confidence interval and 10 / 11 absence of bacterial co-infection in critically ill H1N1 patients with primary viral pneumonia. 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