Drug treatments for covid-19: living systematic review and network meta-analysisBMJ 2020; 370 doi: https://doi.org/10.1136/bmj.m2980 (Published 30 July 2020) Cite this as: BMJ 2020;370:m2980
All rapid responses
Nicely presented review, but surely this team knew about the living NMA work that has been updating searches and treatment comparisons every 3 days for the last few months? https://covid-nma.com/ . The authors mention that they were aware of this work (reference 88 in the publication), but that they decided to proceed independently for reasons that I found unconvincing. A good example of avoidable research waste.
Competing interests: No competing interests
Re: Drug treatments for covid-19: living systematic review and network meta-analysis, the collateral effect on musculoskeletal research
We read with interest the systematic review focussing on drug treatments for Covid-19. We note with interest the plethora of studies and articles currently focussing on Covid-19. The National Institute for Health Research (NIHR) has also led a rapid implementation of research into COVID-19 [1,2,3]. Whilst COVID-19 studies have received swift review and approval, the consequences of focussing on COVID-19 studies on non-COVID-19 trials cannot be under-estimated. Many of these trials were paused by local trusts during the initial peak of the pandemic in the UK .
Whilst this policy may have been the correct response, the ‘collateral damage’ to musculoskeletal research cannot be under-estimated. Arthritis and musculoskeletal (MSK) conditions affect over 17 million people in the UK, with 20% of the population each year consulting their GP and 30 million working days lost each year due to MSK conditions . Arthritis is the most prevalent condition in the population without a cure, and osteoarthritis (OA) has no disease modifying drugs.
Trial infrastructure: the NIHR produced a framework to guide the restart of research activities. Local trusts have begun to review their research portfolios, to determine which studies will be able to resume and when. Priority was given to COVID-19 studies. It is likely that studies involving group interventions or significant face-to-face contact will not be deliverable and may not resume.
Any change to a study’s design, such as virtual instead of a face-to-face follow up necessitates a protocol amendment, Ethics Committee approval, and local research approval. This is challenging with further delays for Health Research England (HRA) sign off as COVID-19 studies are prioritised .
Hospital restructuring: Trusts seeking to limit risk of contracting COVID-19 have reduced foot-fall. Masks have made communication difficult and more time consuming. Additionally most physiotherapy and other interventions are being delivered virtually which impacts on some musculoskeletal pathways and the ability to include physiotherapy interventions as part of a study. Patients now express additional anxiety in attending hospitals and may refuse to come for a face-to-face appointment, reducing the potential to recruit into studies .
Surgical pathways: The Royal College of Surgeons guidelines on prioritisation  has also affected treatment pathways with some patients likely to wait in excess of 3 months for their surgery, significantly delaying studies with a surgical intervention. This will impact on commercial device studies which risk early closure. Global predictive modelling has estimated that 72.3% of all operations will be cancelled during the pandemic with highest cancellation rates for benign diseases affecting recruitment .
Basic science studies: Basic science studies rely on access to university laboratories. Access in most has been reduced, with studies involving cell cultures affected.
Rheumatology studies: Further complexity for rheumatology research is due to many patients on immunosuppressants. In order to identify vulnerable patients that need protection from COVID-19, some rheumatology interventional studies that included immunosuppressants were unblinded, so that patients were aware of their risk. Guidance from the British Society of Rheumatology advised virtual appointments, delaying new DMARDs because of the potential risk with COVID-19, and only giving steroid injections if a patient has failed first-line measures and whose symptoms have a significantly negative effect on their health. Therefore, there will be a profound impact on trial delivery for any orthopaedic or rheumatology study requiring new drug therapies, steroids, imaging or pathology as part of the planned trial activity .
In summary, the profound effect of Covid-19 and a change in national prioritisation of clinical activity and clinical research, has resulted in a significant reduction of patients recruited to musculoskeletal research. The economic, societal and personal patient impact of the current shift in research prioritisation will not be fully determined for many years.
1. Wang L, Wang Y, Ye D, Liu Q. Review of the 2019 novel coronavirus (SARS-CoV-2) based on current evidence. International Journal of Antimicrobial Agents 2020;https://doi.org/10.1016/j.ijantimicag.2020.105948
4. Thornton J. Clinical trials suspended in UK to prioritise covid-19 studies and free up staff. BMJ 2020;368 doi:https//doi.org/10.1136/bmj.m1172
5. Michael Ly, Justine Fitzpatrick, Benjamin Ellis and Tracey Loftis. Why are musculoskeletal conditions the biggest contributors to mortality? 2019. Health Profile for England
8. Royal College of Surgeons. Specialty guides for patient management during the coronavirus pandemic. 11th April 2020
9. CovidSurg Collaborative, Nepogodiev D, Bhangu A. Elective surgery cancellations due to the COVID-19 pandemic: global predictive modelling to inform surgical recovery plans. British Journal of Surgery 2020;https//doi.org/10.1002/bjs.11746
10. Favalli EG, Ingegnoli F, De Lucia OD, Cincinelli G, Cimaz R, Caporali R. COVID-19 infection and rheumatoid arthritis: Faraway, so close! Autoimmunity reviews 2020;19:5:https://doi.org/10.1016/j.autrev.2020.102523
Competing interests: No competing interests
The article fulfills the pressure for a comprehensive review of the present state of all available treatment options for CoVID-19.
For the present it should be a beacon in the darkness of confusion.
I found it noteworthy that, in conclusion, the article has neither labled Hydroxychlroroquine as useless nor put any treatment on a high pedestal of infallibility.
This is just my conjecture:
1) The world population of 7.8 billion has numerous genotypes and phenotypes. Probably each person is a unique entity.
2) There are numerous strains of SARS-CoV-2.
3) The viral load in each person shall differ.
4) There are numerous combinations of co-morbidities and sometimes Co-infections, likely to be present.
6) The climatic conditions will differ from place to place.
7) The finer nuances of the treatment may differ from center to center.
8) For a given person in a given situation, the response of one treating doctor may differ from what another doctor may do.
9) Clinical Medicine is as much or even more an art than it is a science.
There could be many other factors involved than what I or anybody else may envisage.
Thus, although the well connected trials are at the core of the scientific approach to the management of healthcare, decision making and the response to treatment will always be individualized and unique.
Arvind Joshi, MBBS, MD; FCGP, FAMS, FICP;
Founder Convener and President:
Our Own Discussion Group;
Mumbai, Maharashtra State, INDIA;
Competing interests: No competing interests
Re: Drug treatments for covid-19: living systematic review and network meta-analysis; THE “SEX GAP” IN COVID-19 TRIALS:
We read with great interest and little concern Siemieniuk et al. `Drug treatments for covid-19: living systematic review and network meta-analysis`.1 This living systematic review and network meta-analysis provides a comprehensive overview of the evidence for drug treatments of coronavirus disease of 2019 (COVID-19) up to 20 July 2020. We applaud the authors for assessing studies quality using both “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” (PRISMA) and “Grading of Recommendations Assessment, Development and Evaluation” (GRADE).2 3 The authors report that the certainty of the evidence for most of the drug comparisons was very low. The only intervention that probably reduces mortality and the requirement of mechanical ventilation is glucocorticoids, a result entirely driven by the RECOVERY trial.4
The concern that we have relates to the lack of consideration on potential heterogeneity in therapy response between men and women. There is growing evidence that sex differences play a role in the immunological, hormonal, and cardiovascular pathophysiological responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).5 6 Furthermore, COVID-19 appears to affect men more severely than women.5 Also, comorbidities, with a worldwide higher prevalence among men than women, such as chronic lung disease, hypertension, and cardiovascular disease, are associated with more severe COVID-19 infection.5 7 8 These differences, are expected to affect the severity of the virus infection, disease course, and (side)-effects of initiated therapy differentially in men and women.6 9
Historically, in medical research, women were underrepresented in clinical trials, and data were rarely reported separately for men and women.5 6 9 Consequently, differences in disease presentation and progression between men and women have been understudied for decades and system-biological differences in (side-)effects of pharmacological therapy remained undetected.
The rigorous work by Siemieniuk et al., very elegantly reports the results of 20 clinical trials investigating potential effects of pharmacologic therapy on disease outcome. A sex specific meta-regression analysis would help to overcome the historic pitfalls of understudying sex differences. However, the lack of sex-sensitive analysis in the current manuscript is not surprising as only two out of the twenty clinical trials (Beigel et al. and Horby et al.)10 4 investigated sex-effect modification or showed stratified results by sex. Nevertheless, for several reasons we think that reporting the lack of sex-sensitivity analysis in current clinical trials on COVID-19 in the current manuscript is crucial. A large body of evidence shows that responses regarding pharmacokinetics of antiviral drugs differ between men and women and that women encounter adverse drug reactions to antiviral treatment more often than men, as shown for lopinavir/ritonavir.11 In fact, for the same dose administered, higher plasma concentrations of ritonavir have been reported in women. On the other hand, an atazanavir plus ritonavir regimen was associated with a higher risk of virologic failure in women than men.12
Moreover, chloroquine and hydroxychloroquine are known to trigger life-threatening polymorphic ventricular tachycardia (torsades de pointes) by prolonging the heart rate-corrected QT (QTc) interval.13 14 Previous reports indicate that women are more prone to develop drug-induced torsades de pointes than men, with 65–75% of drug-induced torsades de pointes occurring in women.15 Substantial sex differences in the electrocardiographic pattern of ventricular repolarization can be observed, with a longer QTc interval at baseline in women.16 17 Protective effects of testosterone have been suggested to account for the shorter QTc interval and the reduced incidence of drug-induced torsades de pointes in men. Also immune modulating drugs are expected to yield differences in outcome between sexes. Both the number and activity of innate immune cells, including monocytes, macrophages, and dendritic cells as well as downstream inflammatory immune responses in general, are higher in women than men.18 19 Moreover, when vaccinated, women develop higher antibody titres (i.e., a primary indicator of protection) and report more adverse reactions to vaccines than men.20 Both basal levels of immunoglobulin and antibody responses, are consistently higher in women than men.21 22 Data from inactivated influenza vaccines indicate that adult women (18–45 years of age) develop higher IL-6 and antibody responses than adult men, with less pronounced differences between the sexes among aged individuals (65+ years of age).23 In contrast, immunotherapies that suppress the immune response (cytokine or checkpoint inhibitors) are reportedly more efficacious in men.24 Therefore, a one-size-fits-all approach to immunotherapies is not expected to be effective, and sex may contribute to variable treatment success in clinical settings, also for COVID-19, as shown in the past for other diseases.
We expect that the lack of consideration of sex-biases in drug efficacy and reactivity for COVID-19 may lead to disparities in (side-) effects between men and women. To allow more personalized patient care, we call investigators developing and testing therapeutic and prophylactic approaches for COVID-19 to design studies that include sex-specific analyses and for already published studies to perform post-hoc sex-specific analysis. As for the study of Siemieniuk et al., the nature of their study allows future updates to report on the lack of sex-stratified data in current COVID-19 trials.
1. Siemieniuk RA, Bartoszko JJ, Ge L, et al. Drug treatments for covid-19: living systematic review and network meta-analysis. BMJ 2020;370:m2980. doi: 10.1136/bmj.m2980 [published Online First: 2020/08/01]
2. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009;6(7):e1000097. doi: 10.1371/journal.pmed.1000097 [published Online First: 2009/07/22]
3. Puhan MA, Schunemann HJ, Murad MH, et al. A GRADE Working Group approach for rating the quality of treatment effect estimates from network meta-analysis. BMJ 2014;349:g5630. doi: 10.1136/bmj.g5630 [published Online First: 2014/09/26]
4. Group RC, Horby P, Lim WS, et al. Dexamethasone in Hospitalized Patients with Covid-19 - Preliminary Report. N Engl J Med 2020 doi: 10.1056/NEJMoa2021436 [published Online First: 2020/07/18]
5. Gebhard C, Regitz-Zagrosek V, Neuhauser HK, et al. Impact of sex and gender on COVID-19 outcomes in Europe. Biol Sex Differ 2020;11(1):29. doi: 10.1186/s13293-020-00304-9 [published Online First: 2020/05/27]
6. Bischof E, Wolfe J, Klein SL. Clinical trials for COVID-19 should include sex as a variable. J Clin Invest 2020 doi: 10.1172/JCI139306 [published Online First: 2020/05/12]
7. Leung C. Clinical features of deaths in the novel coronavirus epidemic in China. Rev Med Virol 2020;30(3):e2103. doi: 10.1002/rmv.2103 [published Online First: 2020/03/17]
8. Disease GBD, Injury I, Prevalence C. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 2018;392(10159):1789-858. doi: 10.1016/S0140-6736(18)32279-7 [published Online First: 2018/11/30]
9. Bischof E, Oertelt-Prigione S, Morgan R, et al. Towards Precision Medicine: Inclusion of Sex and Gender Aspects in COVID-19 Clinical Studies-Acting Now before It Is Too Late-A Joint Call for Action. Int J Environ Res Public Health 2020;17(10) doi: 10.3390/ijerph17103715 [published Online First: 2020/05/30]
10. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the Treatment of Covid-19 - Preliminary Report. N Engl J Med 2020 doi: 10.1056/NEJMoa2007764 [published Online First: 2020/05/24]
11. Shiau S, Kuhn L, Strehlau R, et al. Sex differences in responses to antiretroviral treatment in South African HIV-infected children on ritonavir-boosted lopinavir- and nevirapine-based treatment. BMC Pediatr 2014;14:39. doi: 10.1186/1471-2431-14-39 [published Online First: 2014/02/14]
12. Smith KY, Tierney C, Mollan K, et al. Outcomes by sex following treatment initiation with atazanavir plus ritonavir or efavirenz with abacavir/lamivudine or tenofovir/emtricitabine. Clin Infect Dis 2014;58(4):555-63. doi: 10.1093/cid/cit747 [published Online First: 2013/11/21]
13. Giudicessi JR, Noseworthy PA, Friedman PA, et al. Urgent Guidance for Navigating and Circumventing the QTc-Prolonging and Torsadogenic Potential of Possible Pharmacotherapies for Coronavirus Disease 19 (COVID-19). Mayo Clin Proc 2020 doi: 10.1016/j.mayocp.2020.03.024 [published Online First: 2020/05/04]
14. Chen CY, Wang FL, Lin CC. Chronic hydroxychloroquine use associated with QT prolongation and refractory ventricular arrhythmia. Clin Toxicol (Phila) 2006;44(2):173-5. doi: 10.1080/15563650500514558 [published Online First: 2006/04/18]
15. Abi-Gerges N, Philp K, Pollard C, et al. Sex differences in ventricular repolarization: from cardiac electrophysiology to Torsades de Pointes. Fundam Clin Pharmacol 2004;18(2):139-51. doi: 10.1111/j.1472-8206.2004.00230.x [published Online First: 2004/04/07]
16. Regitz-Zagrosek V. Therapeutic implications of the gender-specific aspects of cardiovascular disease. Nat Rev Drug Discov 2006;5(5):425-38. doi: 10.1038/nrd2032 [published Online First: 2006/05/05]
17. Group EUCCS, Regitz-Zagrosek V, Oertelt-Prigione S, et al. Gender in cardiovascular diseases: impact on clinical manifestations, management, and outcomes. Eur Heart J 2016;37(1):24-34. doi: 10.1093/eurheartj/ehv598 [published Online First: 2015/11/05]
18. Boissier J, Chlichlia K, Digon Y, et al. Preliminary study on sex-related inflammatory reactions in mice infected with Schistosoma mansoni. Parasitol Res 2003;91(2):144-50. doi: 10.1007/s00436-003-0943-1 [published Online First: 2003/08/12]
19. Melgert BN, Oriss TB, Qi Z, et al. Macrophages: regulators of sex differences in asthma? Am J Respir Cell Mol Biol 2010;42(5):595-603. doi: 10.1165/rcmb.2009-0016OC [published Online First: 2009/07/04]
20. Klein SL, Jedlicka A, Pekosz A. The Xs and Y of immune responses to viral vaccines. Lancet Infect Dis 2010;10(5):338-49. doi: 10.1016/S1473-3099(10)70049-9 [published Online First: 2010/04/27]
21. Butterworth M, McClellan B, Allansmith M. Influence of sex in immunoglobulin levels. Nature 1967;214(5094):1224-5. doi: 10.1038/2141224a0 [published Online First: 1967/06/17]
22. Cook IF. Sexual dimorphism of humoral immunity with human vaccines. Vaccine 2008;26(29-30):3551-5. doi: 10.1016/j.vaccine.2008.04.054 [published Online First: 2008/06/06]
23. Potluri T, Fink AL, Sylvia KE, et al. Age-associated changes in the impact of sex steroids on influenza vaccine responses in males and females. NPJ Vaccines 2019;4:29. doi: 10.1038/s41541-019-0124-6 [published Online First: 2019/07/18]
24. Jawaheer D, Messing S, Reed G, et al. Significance of sex in achieving sustained remission in the consortium of rheumatology researchers of North America cohort of rheumatoid arthritis patients. Arthritis Care Res (Hoboken) 2012;64(12):1811-8. doi: 10.1002/acr.21762 [published Online First: 2012/06/26]
Competing interests: No competing interests
I think several aspects of the way this living systematic review/meta-analysis is reported are highly problematic. The highly positive conclusion and presentation of hydroxychloroquine brings these particular aspects into sharp focus.
The infographic, abstract, and readers' note are sure to be the most-read part of this review: and from them, you would get the impression that the analyses were up-to-date with emerging evidence, as of 21 July. In fact, the evidence in the analyses is a month older and that's a lot in Covid-19 trial time.
The only clue at the top level of this review this it is missing the very large trial on hydroxychloroquine (and one of the only very large trials overall) known to the public since June , is if you examine the infographic closely enough to pick up on what "Upcoming" data sources means. That should be clearer to non-experts, not just in the fine-print and on a hover note. As that infographic isn't in the PDF, there is no clue in the highly-skimmed part of that version that the conclusions on hydroxychloroquine are known to have been affected by the bias of including atypical early results. That such a large volume of data is missing from this version isn't even listed as a limitation of the study.
The way 21 July is often chosen throughout this document instead of the date that really reflects the age of the evidence is problematic beyond the infographic as well. As too, is the design choice for the summary table, giving such a bright green "most beneficial" colour-coding to findings with low/very low certainty.
The message being sent by that colour-coded table is deeply misleading, even apart from the fact that it is so out-of-date on hydroxychloroquine. A strength of network meta-analysis is identifying superior treatments, but it can't do that when there isn't enough data to be even mildly certain: in that circumstance, a report should not give the impression to non-methodological experts that it has done so. That's even more critical when it's known only a small fraction of the evidence on an intervention is included in the analysis.
This is a design/methodological problem. That's demonstrated, I believe, in the risk that the next update may not entirely solve this problem, given that the report of the RECOVERY trial  doesn't include the outcome given a bright green "most beneficial" rating. There is something inherently absurd in a system that could potentially highlight an intervention shown in a dominating large trial to be "associated with an increased length of hospital stay and increased risk of progressing to invasive mechanical ventilation or death"  with a bright green "most beneficial" signal for "time to symptom resolution" based on some small outlier trials.
In a situation like this, either the entire analysis should have been held off, or at least analyses on hydroxychloroquine clearly flagged as out-of-date and not included in the summary table, with no statement about its benefits highlighted in the abstract.
Given how few large and/or high quality trials there are for treatments of this disease, the benefit of a network meta-analysis based on data published in journals or preprints from June 2020 was likely to be of marginal benefit anyway, so fast-tracking wasn't likely to be of great benefit. As it's reported, I think this review is a misleading addition to the debate over treatment for Covid-19 at the end of July 2020.
Competing interests: No competing interests