Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data
BMJ 2020; 369 doi: https://doi.org/10.1136/bmj.m1844 (Published 14 May 2020) Cite this as: BMJ 2020;369:m1844Read our latest coverage of the coronavirus pandemic
Linked Editorial
Lack of efficacy of hydroxychloroquine in covid-19
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Dear Editor，
We have read with great interests the research by Matthieu Mahévas and colleagues1 in The BMJ, which assessed the clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who required oxygen. While applauding the author's contribution, we also have some doubts.
Firstly, the dosage of 600 mg per day of hydroxychloroquine in this study was based on another previous study2, which reported treatment experiences in chronic diseases caused by intracellular bacteria. But we think that the dosage of clinical drug should need more reliable data especially on the unknown diseases, such as results of experiments in vitro and in vivo. It has been reported that Yao et al3 figured out a loading dose of 400 mg twice daily given orally, followed by a maintenance dose of 200 mg given twice daily for 4 days as the optimized dosing design of Hydroxychloroquine based on Physiologically-based pharmacokinetic models (PBPK) results,3 but in this study there was not the same design and the main administration route of hydroxychloroquine was not described. Therefore, we consider that further studies about the optimized dosage should be carried out in the future.
Secondly, the vast majority of patients in this study were in mild and moderate conditions. That is to say, most of these patients can recover under the routine supportive treatment in 20 days, which was the median duration of viral shedding revealed by the study of Zhou et al 4. So we doubt that whether the improvement of these patients is due to the efficacy of hydroxychloroquine or not?
Lastly and most importantly, we think that the objective efficacy criteria should reach a consensus. In this study, there were two main outcomes measured to evaluate the efficacy of hydroxychloroquine including the primary outcome which was survival without transfer to the intensive care unit and secondary outcomes that were overall survival, survival without acute respiratory distress syndrome, weaning from oxygen, and discharge from hospital to home or rehabilitation. But in our opinions, the evaluation indicators in this paper could not fully explain whether the drug is effective or not, and other observation features such as changes of clinical signs and symptoms, and the laboratory indicators, such as virological endpoint and the changes of viral loads should also be taken into account.
Reference:
1. Mahévas Matthieu,Tran Viet-Thi,Roumier Mathilde et al. Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data.[J] .BMJ, 2020, 369: m1844. DOI: 10.1136/bmj.m1844.
2. Zhou Fei,Yu Ting,Du Ronghui, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.[J] .Lancet, 2020, 395: 1054-1062. DOI: 10.1016/S0140-6736(20)30566-3.
3. Gautret Philippe,Lagier Jean-Christophe,Parola Philippe et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial.[J] .Int. J. Antimicrob. Agents, 2020, undefined: 105949. DOI: 10.1016/j.ijantimicag.2020.105949.
4. Yao Xueting,Ye Fei,Zhang Miao et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).[J] .Clin. Infect. Dis., 2020, undefined: undefined. DOI: 10.1093/cid/ciaa237.
Competing interests: No competing interests
Dear Editor,
“The decision to use HCQ for COVID-19 should take into account the occasional possibility of cardiac arrhythmia”. A Scientific Statement from the Indian Heart Rhythm Society. [1]
Hydroxychloroquine is a widely used antimalarial drug with a lot of prior experience in countries such as India. We read with great interest two recent publications on hydroxychloroquine (HCQ) use in patients with Covid-19 published in The BMJ. [2 3] The study by Mahevas et al. and several others have cited a high incidence of adverse events with the HCQ. [4-7] Conversely, other reports have indicated that HCQ/CQ is safe and well tolerated in Covid-19 population. [8 9]
We would like to ask several questions of these data from Electrophysiology and Cardiology perspective.
Firstly, what is known about the incidence of cardiac complications with HCQ in the non-Covid population? A recent pre-Covid-19 meta-analysis in > 145,000 real world HCQ recipients did not demonstrate a pronounced increase in cardiac arrhythmias. [10] The incidence of potential complications is low with low teratogenic risk allowing a relatively safe use of the drug even in pregnant women. [11 12]
Cardiac side effects with HCQ and CQ are well known. Mostly, both agents can inhibit IKr resulting in mild QT prolongation and thus rarely cause Torsades De Pointes (TdP). [13] Other cardiac complications, such as biventricular cardiomyopathy, are extremely rare. [14]
The reported incidence of significant QT prolongation in Covid-19 population with the use of HCQ/CQ, and mostly in combination with AZ or other QT prolonging antiviral medications, is in the of range of 0-19% with a weighted average of 8%. [2 4 15] Similarly, a 10% incidence of electrocardiographic changes was reported by Mahevas et al. in 84 patients with Covid-19 pneumonia requiring oxygen. [4] QT interval prolongation was noted in seven patients with only one demonstrating QTC > 500 ms. Two additional patients showed other conduction abnormalities of unclear relationship to HCQ that may not necessarily have prompted its discontinuation. The second paper in BMJ by Tang et al. is a randomized open label study of HCQ in patients with mild to moderate disease. They reported no incidence of QT prolongation despite the use of higher dose HCQ. [2]
These two parallel observations suggest that a sicker patient population may be more predisposed to QT prolongation corresponding to a known much higher incidence of this and related complications in the ICU patients without Covid-19, treated with a number of potentially QT prolonging drugs. [16]
In a recent study of 90 patients treated with HCQ (53 also treated with AZ) admitted to ICU (33% were critically ill and 26% - on mechanical ventilation), a higher incidence of QT prolongation was reported with one patient with multiorgan failure subsequently demonstrating TdP. Concomitant use of diuretics and longer baseline QTc were associated with a higher likelihood of its subsequent prolongation. [5] However, the combination of HCQ and AZ was well tolerated in a large observational study of 1061 patients. [9] Another study of 201 hospitalized patients with ARDS or high risk of it due to Covid-19 (the number in ICU not reported) documented discontinuation of HCQ due to QT interval prolongation only in 7 patients (3.5%) and no incidence of TdP. [8] Interestingly, several patients in this study were noted to have non-sustained or sustained VT without concomitant QT prolongation. This was attributed to viral myocarditis and highlights the fact that HCQ may not be the sole cause of ventricular arrhythmias.
The largest reported observation to date also reports a higher incidence of ventricular arrhythmias but surprisingly presents no data on QT prolongation or development of cardiomyopathy. [7] Knowing that other proarrhythmic mechanisms not related to QT prolongation/drugs are likely to be at play in a sicker patient population one may question the unequivocal attribution of ventricular arrhythmias to HCQ in this study.
HCQ appears to be relatively safe in studies conducted prior to Covid-19 pandemic. Covid-19 populations are highly heterogeneous, and some of the recent reports suggest that in late stages of the disease and in sicker ICU patients HCQ may result in higher incidence of electrocardiographic changes and arrhythmias. Patients at milder stages of the disease are more likely to be similar to non-Covid population in this respect. It is expected that randomized controlled studies will report on efficacy and side effects of all promising treatment strategies such as HCQ and include data on QT interval prolongation and other cardiac abnormalities. Until such studies are available, the same stringent criteria on data reporting should be applied to all observational studies published to date.
References:
1. Kapoor A, Pandurangi U, Arora V, et al. Cardiovascular risks of hydroxychloroquine in treatment and prophylaxis of COVID-19 patients: A scientific statement from the Indian Heart Rhythm Society. Indian Pacing Electrophysiol J 2020;20(3):117-20. doi: 10.1016/j.ipej.2020.04.003 [published Online First: 2020/04/12]
2. Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. Bmj 2020;369:m1849. doi: 10.1136/bmj.m1849 [published Online First: 2020/05/16]
3. Mahévas M, Tran VT, Roumier M, et al. Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data. Bmj 2020;369:m1844. doi: 10.1136/bmj.m1844 [published Online First: 2020/05/16]
4. Mahevas M, Tran VT, Roumier M, et al. Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data. BMJ 2020;369:m1844. doi: 10.1136/bmj.m1844 [published Online First: 2020/05/16]
5. Mercuro NJ, Yen CF, Shim DJ, et al. Risk of QT Interval Prolongation Associated With Use of Hydroxychloroquine With or Without Concomitant Azithromycin Among Hospitalized Patients Testing Positive for Coronavirus Disease 2019 (COVID-19). JAMA Cardiol 2020 doi: 10.1001/jamacardio.2020.1834 [published Online First: 2020/05/02]
6. Geleris J, Sun Y, Platt J, et al. Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19. N Engl J Med 2020 doi: 10.1056/NEJMoa2012410 [published Online First: 2020/05/08]
7. Mehra MR, Desai SS, Ruschitzka F, et al. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. The Lancet 2020 doi: 10.1016/s0140-6736(20)31180-6
8. Saleh M, Gabriels J, Chang D, et al. The Effect of Chloroquine, Hydroxychloroquine and Azithromycin on the Corrected QT Interval in Patients with SARS-CoV-2 Infection. Circ Arrhythm Electrophysiol 2020 doi: 10.1161/CIRCEP.120.008662 [published Online First: 2020/04/30]
9. Million M, Lagier JC, Gautret P, et al. Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: A retrospective analysis of 1061 cases in Marseille, France. Travel Med Infect Dis 2020:101738. doi: 10.1016/j.tmaid.2020.101738 [published Online First: 2020/05/11]
10. Vouri SM, Thai TN, Winterstein AG. An evaluation of co-use of chloroquine or hydroxychloroquine plus azithromycin on cardiac outcomes: A pharmacoepidemiological study to inform use during the COVID19 pandemic. Res Social Adm Pharm 2020 doi: 10.1016/j.sapharm.2020.04.031 [published Online First: 2020/05/16]
11. Costedoat-Chalumeau N, Amoura Z, Duhaut P, et al. Safety of hydroxychloroquine in pregnant patients with connective tissue diseases: a study of one hundred thirty-three cases compared with a control group. Arthritis Rheum 2003;48(11):3207-11. doi: 10.1002/art.11304 [published Online First: 2003/11/13]
12. Sperber K, Hom C, Chao CP, et al. Systematic review of hydroxychloroquine use in pregnant patients with autoimmune diseases. Pediatr Rheumatol Online J 2009;7:9. doi: 10.1186/1546-0096-7-9 [published Online First: 2009/05/15]
13. Simpson T, Kovacs R, Stecker E. Ventricular Arrhythmia Risk Due to Hydroxychloroquine-Azithromycin Treatment For COVID-19 [Website]. 2020 [updated Mar 29, 2020; cited 2020 May 26]. Available from: https://www.acc.org/latest-in-cardiology/articles/2020/03/27/14/00/ventr... accessed May 26 2020.
14. Joyce E, Fabre A, Mahon N. Hydroxychloroquine cardiotoxicity presenting as a rapidly evolving biventricular cardiomyopathy: key diagnostic features and literature review. Eur Heart J Acute Cardiovasc Care 2013;2(1):77-83. doi: 10.1177/2048872612471215 [published Online First: 2013/09/26]
15. Borba MGS, Val FFA, Sampaio VS, et al. Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection. JAMA Network Open 2020;3(4) doi: 10.1001/jamanetworkopen.2020.8857
16. Fernandes FM, Silva EP, Martins RR, et al. QTc interval prolongation in critically ill patients: Prevalence, risk factors and associated medications. PLoS One 2018;13(6):e0199028. doi: 10.1371/journal.pone.0199028 [published Online First: 2018/06/14]
Competing interests: No competing interests
Dear Editor
We read with great interest the recent observational studies of hydroxychloroquine (HCQ) in the treatment of patients with COVID-19 pneumonia [1,2]. While these studies are impressive for their breadth and efforts to control statistically for confounders there remain serious concerns about observational bias and selection for treatment.
In particular, it is clear that prior work has noted a drop in inflammatory markers following the administration of HCQ in trials for the treatment of COVID-19 pneumonia [3]. Few observational trials to date have stratified results using LDH release, C-reactive protein (CRP), or lymphocyte counts following treatment.
LDH levels have been used to assess survival in the setting of cancer for many years, higher levels portending a much worse prognosis [4]. An LDH level greater than 365 U/Liter alone can also predict for death from COVID-19 disease 10-18 days in advance with 90% accuracy [5]. CRP level and percent lymphocytes add another 5% to accurate predictions of mortality. These relatively straightforward measurements can be easily applied to all randomized and observational trials of patients being treated for COVID-19 disease, to more accurately assess the efficacy of therapy in those patients at highest risk.
COVID-19 pathogenesis can be partially explained by infection of the dendritic cell (DC) and endothelial cells through engagement of the ACE2/DC-SIGN/CD209/CD147 receptor complex on these cells as well as infection of the type II pneumocyte through its comparable expression of the ACE2/L-SIGN/CD209/CD147 complex [6]. A critical primary target of viral infection with subsequent destruction and intussusceptive neoangiogenesis is the ACE2/DC-SIGN/CD209/CD147 complex on pulmonary endothelium [7] which can also lead to inflammation with an increased LDH and possibly other inflammatory markers.
HCQ is a modulator of the DC as well as autophagy pathways in these and other cells [8]. Such modulation could be expected to blunt the initial deleterious immune response, limit DC transmission of virus, and reduce levels of LDH and other inflammatory markers.
As the clinical trials data on treatments for COVID-19 mature, models that involve modulation of DCs as well as endothelial cells infected by SARS-CoV-2, guided by use of such inflammatory markers, should be taken into account with stratification of patients being evaluated. It should also be relatively straightforward to re-analyze existing observational trials and control for LDH levels as well as other inflammatory markers if available.
Address correspondence to Adam Brufsky, MD, PhD at brufskyam@upmc.edu
1 Mahévas M, Tran V-T, Roumier M, et al. Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data. BMJ. 2020 May 14;369:m1844. doi: 10.1136/bmj.m1844
2 Mehra MR, Desai SS, Ruschitzka F, Patel AN. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet. 2020 May 24; doi: 10.1016/S0140-6736(20)31180-6
3 Yu B, Wang DW, Li C. Hydroxychloroquine application is associated with a decreased mortality in critically ill patients with COVID-19. medRxiv. 2020 Jan 1;2020.04.27.20073379. doi: 10.1101/2020.04.27.20073379
4 Petrelli F, Cabiddu M, Coinu A, et al. Prognostic role of lactate dehydrogenase in solid tumors: A systematic review and meta-analysis of 76 studies. Acta Oncol (Madr). 2015 Aug 9;54(7):961–70. doi: 10.3109/0284186X.2015.1043026
5 Yan L, Zhang H-T, Goncalves J, et al. An interpretable mortality prediction model for COVID-19 patients. Nat Mach Intell. 2020;2(5):283–8. doi: 10.1038/s42256-020-0180-7
6 Brufsky A, Lotze M. DC/L SIGNs of Hope in the COVID-19 Pandemic. J Med Virol. 2020; doi: 10.1002/jmv.25980
7 Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. N Engl J Med. 2020 May 21; doi: 10.1056/NEJMoa2015432
8 Schrezenmeier E, Dörner T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol. 2020;16(3):155–66. doi: 10.1038/s41584-020-0372-x
Competing interests: No competing interests
Dear Editor
The patients' Covid-19 data detailed in Fig. 1 indicates that 14 patients in the treatment group and 8 patients in the control group evidenced a "percentage of lungs affected on CT scan >50%".
It appears that precisely 8 patients in the control group died, yet there is no indication in the entire study as to whether those 8 patients were those whose lung impairment was greater than 50% on CT scan at inclusion. If that were the case, then the poor result of the number of deaths in the treatment group (9) needs to be reevaluated, in the light that it was obtained in spite of a much higher number of patients in critical lung condition in this group (14), as it might have been expected that all 14 patients have died. That would also shed a different light on the "Survival without ARDS" and "Survival without transfer to ICU" outcomes.
Therefore, a comment from the authors as to whether the "percentage of lungs affected on CT scan >50%" had an impact on the fatal outcome seems highly needed.
Yours faithfully,
LS
Competing interests: No competing interests
Dear Editor:
A lack of evidence for any positive effects of the anti-malarial drug, Hydroxychloroquine (HCQ), in severely ill COVID-19 patients who required oxygen as found in this study or HCQ’s equally unimpressive role to help mild to moderate SARS-CoV-2-infected patients as reported in this issue by Tang et al. [1] coupled with a flurry of other recent studies, as reviewed by Meyerowitz et al. [2], most of which also failed to find useful action of HCQ to combat COVID-19, should send a strong message to the global medical community that “off-label” use of HCQ is not warranted to treat COVID-19 patients. In fact, other studies showing serious adverse effects of HCQ in COVID-19 patients recently prompted the US Food & Drug Administration (FDA) to issue a special warning (“drug safety communication”) that HCQ may trigger abnormal heart rhythms, QT prolongation, ventricular tachycardia, heart failure and death in coronavirus disease [3]. Taken together, it is difficult to see any solid medical rationale to use HCQ in the management of COVID-19 patients.
Unfortunately, the medical dilemma of whether to use HCQ for control of the global COVID-19 pandemic is frequently (mis)guided and decided not on the basais of science but on extraneous political or economic conditions. Earlier in March 2020, during the initial stage of COVID-19 pandemic, the entire world reverberated one day and was compelled to put their focus on HCQ when the sitting US president, Donald Trump, publicly claimed that he knew that HCQ would work like “magic” against COVID-19. A lot of people in the USA and across the world were awestruck with this bold claim by the most powerful man on earth. Prescriptions for HCQ quickly jumped 46-fold as many started to take the drug believing that it may protect them or cure COVID-19 [4].
Trump’s boisterous call to use HCQ to combat COVID-19 crossed the boundaries of the USA as countries around the globe joined in the search for this illusive role of a long-known anti-malaria drug. India, largest manufacturer of HCQ in the world (perhaps due to its widespread incidence of malaria each year), quickly jumped into the fray, seeing a golden opportunity for an economic boost as they started exporting enormous quantities of HCQ to countries around the world [5]. In fact, the Indian Ministry of Health & Family Welfare (MOHFW) published “Revised Guidelines on Clinical Management of COVID-19” on their website on 31st March, 2020 in which they recommended Indian doctors to use a combination of HCQ and a broad-spectrum antibiotic, Azithromycin, for treatment of critically ill COVID-19 patients in ICU patients [6]. Taking this a step further, the Indian Task Force for COVID-19 also recommended using HCQ as a prophylactic measure against COVID-19 for asymptomatic and uninfected individuals [7]. Inspired with the unrestrained and direct recommendation by the Indian medical authorities to use HCQ against SARS-CoV-2 infections, both as treatment and prophylaxis, some major cities in India have also started to distribute HCQ to poor slum dwellers in an attempt to prevent the spread of COVID-19 [8]. We have seen the horrific and unimaginable pictures of corpses, died from COVID-19, piled up in the morgues or dumped in refrigerated trucks. COVID-19 has been the biggest challenge in public health in the past more than 100 years. It is unclear at this moment whether irrational use of HCQ contributed to the ongoing pain, suffering and death of COVID-19 patients.
As the COVID-19 pandemic continues to ravage the globe, the medical community needs to stand firm based solely on the science in this complex threat to public health that in recent months has been palpably influenced by the political powers and extraneous economic pressures. International medical fraternities must not succumb to the temptation and pressure from the political leaders to prescribe HCQ in this battle against COVID-19. As the data from the most recent clinical studies have shown, there is little or no reason to use HCQ as a preventive medicine against COVID-19 and considering the serious risks of increased cardiovascular complications associated with this long-known anti-malarial drug, HCQ also should not be routinely use treat SARS-CoV-2 infections, especially in patients with existing heart conditions.
References:
1. Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: Open label, randomized controlled trial. BMJ 2020; 369:m1849. dx.doi.org/10.1136/bmj.m1849.
2. Meyerowitz EA, Vannier AGL, Friesen MGN, et al. Rethinking the role of Hydroxychloroquine in the treatment of COVID-19. FASEB 2020; 34:6027-37. doi.org/10.1096/fj.202000919.
3. FDA cautions against use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems [cited 2020 April, 24]. Available from: https://www.fda.gov/drugs/drug-safety-and-availability/fda-cautions-agai... Accessed April 25, 2020.
4. Prescriptions surged as Trump praised drugs in coronavirus fight [Internet]. New York Times 2020. [cited 2020 Apr. 25]. Available from: https://www.nytimes.com/2020/04/25/us/coronavirus-trump-chloroquine-hydr...
5. India sending Hydroxychloroquine to 55 coronavirus-hit countries [Internet]. Economic Times. 2020. [cited 2020 Apr. 16]. Available from: https://economictimes.indiatimes.com/news/politics-and-nation/india-send...
6. Revised guidelines on clinical management of COVID-19 – Govt. of India, Ministry of Health & Family Welfare [Internet]. 2020. Available from: https://www.mohfw.gov.in/pdf/RevisedNationalClinicalManagementGuidelinef... (accessed 19 May, 2020)
7. National Task Force for COVID-19. Advisory on the use of Hydroxychloroquine as prophylaxis for SARS-CoV-2 infection. 2020. https://www.mohfw.gov.in/pdf/AdvisoryontheuseofHydroxychloroquinasprophy... (accessed 19 May, 2020).
8. Natnayas E, Gaikwad VE, Jain, Y. Rolling out mass hydroxychloroquine prophylaxis for COVID-19 in India’s slums risks eroding public trust. BMJ Blogs 2020. https://blogs.bmj.com/bmj/2020/05/01/rolling-out-mass-hydroxychloroquine... (accessed 19 May, 2020)
Competing interests: As president of "People for Better Treatment" (PBT), a charitable organization (NGO) working to improve healthcare delivery system in India, we recently filed a public interest litigation (PIL) in Supreme Court of India seeking directions for Indian authority to provide precautionary measures in hospitals to prevent cardiovascular complications, heart failure and sudden death of COVID-19 patients treated with "off-label" Hydroxychloroquine and/or Azithromycin.
Dear Editor: the combination of Azithromycin and Hydroxychloroquine (15 placed on the combination, no ICU admits, no deaths) as compared to their respective monotherapies seems worth a follow up. ARE THERE any studies planned powered to look at the combination therapies' efficacy, and if not, why not?
Competing interests: No competing interests
Dear Editor
There has been much public hype surrounding the use of hydroxychloroquine (HCQ) in COVID-19. The observational comparative study of Mahevas et al in 181 hypoxic patients with COVID-19 pneumonia suggests that when used later on the disease there appears to be no benefit on survival albeit with a relatively limited sample size [1]. This is perhaps not unsurprising given that HCQ primarily works upstream in COVID-19 by preventing viral entry into lung epithelium via ACE2 [2].
In the study of Mahevas et al 85% of patients already had evidence of cytokine mediated hyperinflammatory syndrome in terms of a C reactive protein (CRP) level more than 40mg/l on admission to hospital [1]. In this regard a CRP above 42mg/l at initial presentation is indicative of poor outcomes in COVID-19 [3]. By this stage of the disease it is probably too late for any impact of attenuated entry of SARS-CoV2 into type 2 pneumonocytes, especially when the inflammatory related lung tissue damage has already begun.
Although HCQ also inhibits production of interleukin-6 from T cells and monocytes [4], this putative downstream immunomodulatory effect clearly did not translate into improved outcomes. Indeed the results of Mahevas et al were similar to those of another observational study in 1376 patients with hypoxic severe COVID-19 in New York City, where there was no difference in the primary outcome of death or intubation compared to standard of care [5].
The NIHR RECOVERY randomised controlled trial is evaluating the use of HCQ as monotherapy in the first randomisation phase in large numbers of hospitalised patients with COVID-19. However for sick hypoxic patients with late stage COVID-19 disease the emerging data points to futility in regard to use of HCQ alone. Surely the time has now come to end the hype with regard to use of HCQ in severe COVID-19. Given the adaptive design of RECOVERY perhaps an interim analysis is now indicated to test if using HCQ on its own is pointless. We believe that for such patients perhaps a combined treatment regimen may be required comprising earlier use of antivirals such as remdesivir or interferon-beta-1b [6] together with later use of selective cytokine inhibition as either anti-IL6 [7] or anti-IL1 [8], in order to address both upstream and downstream disease pathways [9].
References
1. Mahévas M, Tran V-T, Roumier M, et al. Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data. BMJ 2020;369:m1844. doi: 10.1136/bmj.m1844
2. Yao X, Ye F, Zhang M, et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis 2020 doi: 10.1093/cid/ciaa237 [published Online First: 2020/03/10]
3. Liu F, Li L, Xu M, et al. Prognostic value of interleukin-6, C-reactive protein, and procalcitonin in patients with COVID-19. J Clin Virol 2020;127:104370. doi: 10.1016/j.jcv.2020.104370 [published Online First: 2020/04/29]
4. Sperber K, Quraishi H, Kalb TH, et al. Selective regulation of cytokine secretion by hydroxychloroquine: inhibition of interleukin 1 alpha (IL-1-alpha) and IL-6 in human monocytes and T cells. J Rheumatol 1993;20(5):803-8. [published Online First: 1993/05/01]
5. Geleris J, Sun Y, Platt J, et al. Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19. New England Journal of Medicine 2020 doi: 10.1056/NEJMoa2012410
6. Hung IF-N, Lung K-C, Tso EY-K, et al. Triple combination of interferon beta-1b, lopinavir–ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. The Lancet doi: 10.1016/S0140-6736(20)31042-4
7. Xu X, Han M, Li T, et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proceedings of the National Academy of Sciences 2020:202005615. doi: 10.1073/pnas.2005615117
8. Cavalli G, De Luca G, Campochiaro C, et al. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. The Lancet Rheumatology doi: 10.1016/S2665-9913(20)30127-2
9. Lipworth B, Chan R, Lipworth S, et al. Weathering the cytokine storm in susceptible patients with severe SARS-CoV-2 infection. J Allergy Clin Immunol Pract 2020 doi: 10.1016/j.jaip.2020.04.014 [published Online First: 2020/04/21]
Competing interests: No competing interests
Re: Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data
Dear Editor,
« Absence of evidence is not evidence of absence »
While it is usually reasonable not to accept a new treatment unless there is positive evidence in its favour, when issues of public health are concerned we must question whether the absencev of evidence is a
valid enough justification for inaction (1).
The study by Mahevas et al. concludes that « In patients admitted to hospital with covid-19 pneumonia who require oxygen, hydroxychloroquine treatment seemed to have no effect on reducing admissions to intensive care or deaths at day 21 after hospital admission » (2).
Using the data in Table 2, survival without transfer to UCI at 21 days is 1-(17/84) or 79.8% in the treated group versus 1-(22/89) or 74.2% in the control group. This absolute difference of 5.6% is not statistically
significant. However, a post-hoc power calculation can be performed (3).
Considering that the alternative hypothesis is true, with a bilateral test and a 5% alpha risk, the power of the study to highlight this difference is calculated to be 16%. If we imagine that hydroxychloroquine would
improve the prognosis by 50%, which would be a phenomenal gain, and for an occurrence of the event in the control group of 25%, the power of this study would be only 58% to highlight this difference.
It therefore appears that the power of this study, given the frequency of occurrence of the event in the control group, is much too low to support its conclusions of absence of effect of the treatment evaluated.
Reference:
1. Altman DG, Bland JM. Absence of evidence is not evidence of absence. BMJ 1995;311: 485.
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Competing interests: No competing interests