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Qianheng Jin

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Tocilizumab for reduction of mortality in severe COVID-19 patients: how should we GRADE it?Vladimir TrkuljaVladimir Trkulja, MD, PhDDepartment of PharmacologyZagreb University School of MedicineŠalata 1110000 Zagreb, Croatiae-mail: vladimir.trkulja@mef.hrNumber of words: 799Number of figures/tables: 1To the Editor,A recent systematic review/meta-analysis 1 of randomized trials (RCTs) of tocilizumab (plus standard of care [SoC] vs. SoC w/wo placebo) in severe COVID-19 patients was a pleasure to read owing to a clear presentation of a thorough approach to data (e.g., sensitivity analyses, accounting for corticosteroid use, need for mechanical ventilation [MV] at baseline). Authors assigned high quality (certainty) GRADE levels to the evidence of efficacy in reduction of mortality overall (10 RCTs) and in patients without MV at baseline (data from 9 RCTs), and reduction of incident MV (10 RCTs). The grading was based on fixed-effect pooling, likely owing to low inconsistency index (I2) and closely similar fixed-effect and random-effects estimates1. It is this point that deserves a few comments. Conceptually, fixed-effect meta-analysis of RCTs in medicine is rarely justified, since the underlying assumption is practically inevitably violated due to variety of elements contributing to clinical heterogeneity2. The authors1 presented a range of differences in trial designs (e.g., one or repeated tocilizumab dose, more or less use of concomitant corticosteroids, differences in proportion of subjects on MV). When variance across trials is low, fixed and random-effects estimates are numerically close/identical, but the conceptual differences remain. Again, conceptually, the random-effects method is a preferred approach2 (regardless of numerical closeness of fixed/random estimates) and the choice (fixed/random) should not be based on the heterogeneity estimates2. At this point, the issue of the choice of the variance (τ2) estimator should be mentioned. A number of estimators have been explored: performance depends on the nature of the outcome, may vary across trial sizes, depends on the differences in size of included trials, and is problematic when the number of studies is lowe.g.,2-5. Variance reflects on the assigned trial weights and measures of uncertainty about the pooled estimate. While no τ2 estimator is ideal 2-5, it has been suggested that the Paule-Mandel (PM) estimator performs better than the common DerSimonian-Laird estimator for binary outcomes3.Another point to consider is the method to calculate confidence intervals (CIs) around the pooled estimate. While not without certain limitations 6, the Hartung-Knapp-Sidik-Jonkman (HKSJ) method has been repeatedly shown (under variety of scenarios) to result in more adequate coverage probability than the standard method4,7. Figure 1A re-creates meta-analysis (data presented by the authors1) on mortality across the 10 RCTs (all subjects) – it is only that it uses PM variance estimator and HKSJ correction: random-effects estimate suggests that the mean of the distribution of the effects is 0.88 (as reported1), but the CIs extend to 1.04, suggesting that it includes also effects that are somewhat above unity. It also provides prediction intervals (wider) - the best illustration of heterogeneity2,8. When viewed from the present standpoint, data indicate a non-trivial level of imprecision and heterogeneity. The authors themselves reported apparent differences (mortality reduction vs. no reduction) between estimates based on RCTs with a high proportion vs. low proportion of patients concomitantly treated with corticosteroids 1(or those generated accounting only for corticosteroid-treated vs. not treated patients, but such data were very scarce1): so, there is apparent inconsistency of the estimates across clinical settings. As re-created in Figure 1B-C, there was a tendency of reduced mortality in trials with a high proportion of patients co-treated with corticosteroids (corticosteroid treatment regimen likely variable), but with quite some imprecision and heterogeneity; and no such tendency with “low corticosteroid use”. Similarly, in patients not on MV at baseline, there was a consistent reduction in mortality risk across trials with a high proportion of steroid co-treated patients, but not in trials with a low proportion of co-treated patients (Figure 1D-E). There was also a consistent reduction of risk of incident MV in trials with a high proportion of corticosteroid co-treated patients (Figure 1F), whereas the estimate in trials with “low steroid use” is burdened with heterogeneity and imprecision (Figure 1G).Considering the above, if one were to assign a GRADE level9 to evidence of benefit of tocilizumab in severe COVID-19 patients based on the 10 RCTs addressed in the published meta-analysis1, then the following seems reasonable: a) considering (indiscriminately) all 10 RCTs (and all patients), certainty about reduced mortality is closer to “low/moderate” then to “high” due to imprecision (CIs 0.75-1.04) and heterogeneity/inconsistency; b) data on the effect of tocilizumab+corticosteroid combination that could be extracted from the 10 RCTs are scarce. Trials with high vs. low concomitant use of corticosteroids could be perceived as a proxy, but this is indirect, suggestive and not conclusive evidence. Therefore, while the effects of tocilizumab on the risk of incident MV and mortality in patients not on MV at baseline in trials with a high proportion of corticosteroid co-treated patients were consistent and reasonably precisely estimated, certainty about the benefit of tocilizumab (on top of corticosteroids; regimen?) in this setting is at best moderate/low.ReferencesVela D, Vela-Gaxha Z, Rexhepi M, Olloni R, Hyseni V, nallbani R. Efficacy and safety of tocilizumab versus standard of care/placebo in patients with COVID-19; a systematic review and meta-analysis of randomized controlled trials. Br J Clin Pharmacol . 2021; doi: 10.1111/bcp.15124.Higgins JPT, Thomson SG, Spiegelhalter DJ. A re-evaluation of random-effects meta-analysis. J R Statist Soc A . 2009; 172(Pt1):137-159.Veroniki AA, Jackson D, Viechtbauer W, Bender R, Bowden J, Knapp G, Kuss O, Higgins JPT, Langan D, Salanti G. Methods to estimate the between-study variance and its uncertainty in meta-analysis. Res Synth Methods . 2016;7(1): 55-79.Langan D, Higgins JPT, Jakson D, Bowden J. Veroniki AA, Kontopantelis E, Viechtbauer W, Simmonds M. A comparison of heterogeneity variance estimators in simulated random-effects meta-analyses. Res Synth Methods. 2019; 10(1):83-98.IntHout J, Ioannidis JPA, Borm GF, Goeman JJ. Small studies are more heterogeneous than large ones: a meta-meta-analysis. J Clin Epidemiol . 2015; 68(8):860-869.Jakson D, Law M, Rucker G, Schwarzer G. The Hartung-Knapp modification for random-effects meta-analysis: a useful refinement but are there any residual concerns? Stat Med . 2017; 36(25):3923-3934.IntHout J, Ioannidis JPA, Borm GF. The Hartung-Knapp-Sidik-Jonkman method for random effects meta-analysis is straightforward and considerably outperforms the standard DerSimonian-Laird method.BMC Med Res Methodol . 2014; 14:25 doi:10.1186/1471-2288-14-25.IntHout J, Ioannidis JPA, Rovers MM, Goeman JJ. Plea for routinely presenting prediction intervals in meta-analysis. BMJ Open . 2016; 6:e010247 doi: 10.1136/bmjopen-2015-010247Guyatt GH, Oxman, AD, Vist GE, Kurz R, Falck-Ytter Y, Schunemann HJ. GRADE: what is “quality of evidence” and why is it important to clinicians. BMJ . 2008;336(7651):995-998.Balduzzi S, Rucker G, Schwarzer G. How to perform a meta-analysis with R: a practical tutorial. Evid Based Ment Health . 2019; 22(4):153-160.Figure 1 . Re-creation of the published meta-analysis1 using data provided in the published figures: the difference is in that the present estimates are generated using the Paule-Mandel variance estimator (Q-profile method for variance estimate confidence intervals) instead of the DerSimonian-Laired method available in the RevMan software used by the authors1, and Hartung Knapp Sidik Jonkman correction for random effects (see text for explanation). Panel A corresponds to published1Figure 1, panels B and C correspond to published1supplemental Figure S4. Published meta-analysis1 does not include figures that would correspond to panels D-G. Panels E and G are reduced to summaries for brevity. Note that in all meta-analyses point-estimates of I2 and τ2 were low, but the upper limits of their confidence intervals were rather high, particularly when only 4 RCTs were included (except in panel F with highly consistent results across trials). “High%” or “low %” steroid use refers to trials (as presented in the published meta-analysis1) in which >50% or <50% of the patients were co-treated with corticosteroids. Meta-analyses were performed using packagemeta 10 in R.MV – mechanical ventilation; RCT – randomized controlled trial; SoC – standard of care

Annakan Navaratnam

and 10 more

Objectives: We aimed to characterise the use of tracheostomy procedures for all COVID-19 critical care patients in England and to understand how patient factors and timing of tracheostomy affected outcomes. Design: A retrospective observational study using exploratory analysis of hospital administrative data. Setting: All 500 National Health Service hospitals in England. Participants: All hospitalised COVID-19 patients aged ≥ 18 years in England between March 1st and October 31st, 2020 were included. Main outcomes and measures: This was a retrospective exploratory analysis using the Hospital Episode Statistics administrative dataset. Multilevel modelling was used to explore the relationship between demographic factors, comorbidity and use of tracheostomy and the association between tracheostomy use, tracheostomy timing and the outcomes. Results: In total, 2,200 hospitalised COVID-19 patients had a tracheostomy. Tracheostomy utilisation varied substantially across the study period, peaking in April-June 2020. In multivariable modelling, for those admitted to critical care, tracheostomy was most common in those aged 40-79 years, in males and in people of Black and Asian ethnic groups and those with a history of cerebrovascular disease. In critical care patients, tracheostomy was associated with lower odds of mortality (OR: 0.514 (95% CI 0.443 to 0.596), but greater length of stay (OR: 41.143 (95% CI 30.979 to 54.642). In patients that survived, earlier timing of tracheostomy (≤ 14 days post admission to critical care) was significantly associated with shorter length of stay. Conclusions: Tracheostomy is safe and advantageous for critical care COVID-19 patients. Early tracheostomy may be associated with better outcomes, such as shorter length of stay, compared to late tracheostomy.

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Aurélie Baliarda

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Ramsey Elsayed

and 2 more

Response to Letter to Editor Regarding: Equivalent outcomes with minimally invasive and sternotomy mitral valve repair for degenerative mitral valve disease. J Card Surg. 2021; 36:2636-43.Authors: Ramsey S. Elsayed, MD MS1, Brittany Abt, MD1, and Michael E. Bowdish, MD MS1,2Institutions and Affiliations: 1Division of Cardiac Surgery, Department of Surgery, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA, USA2Department of Preventive Medicine, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA, USAAddress for Correspondence: Dr. Michael E. Bowdish, Associate Professor of Surgery and Preventive Medicine; Department of Surgery, Keck School of Medicine of USC; University of Southern California; 1520 San Pablo Street, HCC II Suite 4300; Los Angeles, CA 90033; Phone: (323)-442-5849; Email: Michael.Bowdish@med.usc.eduConflicts of Interest/Competing Interests: NoneFunding: Research reported in this publication was supported by the Department of Surgery of the Keck School of Medicine of USC. MEB is partially supported by UM1-HL11794 from the National Heart Lung and Blood Institute of the National Institutes of Health.To the editor,We would like to thank Song et. al. for their letter regarding our recent publication in the Journal of Cardiac Surgery titled “Equivalent outcomes with minimally invasive and sternotomy mitral valve repair for degenerative mitral valve disease”1. They asked some important questions and brought up valuable points that are worthy of discussion.Regarding the selection criteria we use for operative approach for mitral valve repair operations, it is primarily based on collective surgeon-patient decision making. However, patients with a previous history of cardiac surgery or peripheral vascular disease (which would render peripheral cannulation difficult), and those in need of concomitant cardiac procedures such as coronary artery bypass grafting, aortic replacement, or biatrial ablation, are not offered a minimally invasive approach. Regarding the role of artificial chordae (neochordae) in mitral valvuloplasty, we use elongated polytetrafluorethylene made of interrupted GoreTex (Gore-Tex, WL Gore and Associates, Inc., Flagstaff, AZ) sutures placed in a horizontal mattress fashion. These neochordae are routinely used to repair elongated or ruptured chordae causing mitral valve prolapse or regurgitation.2 Typically, the neochordae are used in the anterior leaflet of the mitral valve. The etiologies of degenerative mitral valve disease are comprised of myxomatous degeneration of the MV, fibroelastic deficiency including so called Barlow’s valves, and dystrophic calcification of the mitral annulus.3 While the etiologies are not mutually exclusive and may overlap, myxomatous degeneration and fibroelastic deficiencies resulting in severe, symptomatic MR were the most common indications for operation in our patient population. As mentioned by Song and colleagues, the success and durability of MVr can vary depending on etiology, particularly on how much of the valve apparatus is affected by pathology. While not examined in this paper specifically, previous papers (including Tatum et al. conducted at our institution), have demonstrated that anterior leaflet repair is significantly associated with recurrence and progression of MR after surgery, whereas isolated posterior repair is protective.3,4The operative team was similar in all cases, whereas the senior author (VAS) performed over 85% of the total procedures and nearly 100% of the minimally invasive procedures. The success rate of the minimally invasive cohort was 100% (as defined by the Society of Thoracic Surgeons). There was one conversion to conventional sternotomy in the minimally invasive cohort (.003%) for bleeding control.Finally, Song and colleagues are to be congratulated on their robotic and thoracoscopic mitral valvuloplasty results. Their 10-year total robotic mitral valve valvuloplasty results showing excellent cardiac function with 93% of patients in NYHA classes I and II.5 Furthermore, their early thoracoscopic results were very good with one operative mortality and only two reoperations demonstrating thoracoscopic mitral valvuloplasty is a technically feasible, safe, effective, and reproducible technique.6References:Bowdish ME, Elsayed RS, Tatum JM, Cohen RG, Mack WJ, Abt B, Yin V, Barr ML, Starnes VA. Equivalent outcomes with minimally invasive and sternotomy mitral valve repair for degenerative mitral valve disease. J Card Surg. 2021 Aug;36(8):2636-2643. PMID: 33908645.Bortolotti U, Milano AD, Frater RW. Mitral valve repair with artificial chordae: a review of its history, technical details, long-term results, and pathology. Ann Thorac Surg. 2012 Feb;93(2):684-91. PMID: 22153050.David, Tirone E. ”Durability of mitral valve repair for mitral regurgitation due to degenerative mitral valve disease.” Annals of cardiothoracic surgery 4.5 (2015): 417.Tatum, James M., et al. ”Outcomes after mitral valve repair: a single-center 16-year experience.” The Journal of thoracic and cardiovascular surgery 154.3 (2017): 822-830.Zhao H, Gao C, Yang M, Wang Y, Kang W, Wang R, Zhang H. Surgical effect and long-term clinical outcomes of robotic mitral valve replacement: 10-year follow-up study. J Cardiovasc Surg (Torino). 2021 Apr;62(2):162-168. PMID: 33302613.Cui H, Zhang L, Wei S, Li L, Ren T, Wang Y, Jiang S. Early clinical outcomes of thoracoscopic mitral valvuloplasty: a clinical experience of 100 consecutive cases. Cardiovasc Diagn Ther. 2020 Aug;10(4):841-848. PMCID: PMC7487400.

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