Hemila, Harri

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Helsingin yliopiston digitaalinen arkisto

Copyright 2015 American Medical Association. All rights reserved.3. Laporte S, Mismetti P, Décousus H, et al; RIETE Investigators. Clinicalpredictors for fatal pulmonary embolism in 15,520 patients with venousthromboembolism: findings from the Registro Informatizado de la EnfermedadTromboEmbolica venosa (RIETE) Registry. Circulation. 2008;117(13):1711-1716.Common Cold Treatment Using ZincTo the Editor The JAMA Clinical Evidence Synopsis on zinc forthe common cold by Drs Das and Singh1 was a summary of theirCochrane review.2 I noticed inconsistencies in the synopsis andso attempted to replicate their data.In the Evidence Profile section of the synopsis, the au-thors stated that the number of randomized clinical trials in-cluded was “14 therapeutic (lozenges: low-dose = 5, high-dose = 7, syrup = 2) … and 2 prophylactic …,” which implies thatthe reported findings are purely based on randomized com-parisons. However, their estimate of 3.43-day shorter colds forhigh-dose vs low-dose zinc lozenge users appears not to bebased on a comparison of randomized groups but rather on anarbitrary selection of 5 high-dose zinc groups from 7 trials com-pared with 5 low-dose zinc groups from different trials.There have not been 5 published randomized clinical trialsthat directly compared high-dose and low-dose zinc lozenges.2,3The pairing of the selected high-dose and low-dose zinc groupsalso appeared arbitrary.Furthermore, 3 of the 5 low-dose zinc trials had problemsin the formulation of their zinc lozenges so that zinc was notreleased freely,3 and therefore, the low dosage of zinc was notthe only problem in the low-dose studies.Das and Singh1 stated: “Zinc lozenges were associated witha higher incidence of adverse events compared with placebo(46.5% for lozenges vs 36.4% for placebo; number needed toharm [NNH], 10).” This calculation was based on Analysis 2.12of their Cochrane review.2However, that analysis table counted the placebo groupfrom the study by Turner and Cetnarowski4 3 times. A meta-analysis should not count the same randomized participantsmore than once. The lower rate of adverse events in the pla-cebo group may have been a statistical artifact caused by thetriple-counting of a single placebo group.The negative findings for the low-dose zinc lozenge trialsmay be caused by the low doses or problems in the lozenge for-mulations. Therefore, the estimation of zinc lozenge effectsshould focus on high-dose zinc lozenge studies. Three high-dose zinc acetate lozenge trials found that colds were 42% (95%CI, 35%-48%) shorter in the zinc groups.3Harri Hemilä, MD, PhDAuthor Affiliation: Department of Public Health, University of Helsinki,Helsinki, Finland.Corresponding Author: Harri Hemilä, MD, PhD, Department of Public Health,University of Helsinki, PO Box 41, Helsinki, Finland FIN-00014(harri.hemila@helsinki.fi).Conflict of Interest Disclosures: The author has completed and submitted theICMJE Form for Disclosure of Potential Conflicts of Interest and none werereported.1. Das RR, Singh M. Oral zinc for the common cold. JAMA. 2014;311(14):1440-1441.2. Singh M, Das RR. Zinc for the common cold. Cochrane Database Syst Rev. 2013;6:CD001364.3. Hemilä H. Zinc lozenges may shorten the duration of colds: a systematicreview. Open Respir Med J. 2011;5:51-58.4. Turner RB, Cetnarowski WE. Effect of treatment with zinc gluconate or zincacetate on experimental and natural colds. Clin Infect Dis. 2000;31(5):1202-1208.In Reply The findings reported in the JAMA Clinical EvidenceSynopsis were based on randomized clinical trials, as was ourCochrane review.1 The comparison of the 2 doses (≥75 mg/d vs<75 mg/d) of zinc was performed as a part of a network meta-analysis, which is a valid technique to assess the comparativeeffectiveness of interventions among similar study popula-tions that have not been compared directly in randomized clini-cal trials.2The prerequisite of a network meta-analysis is that the trialsshould have used the same intervention in the same popula-tion and setting, for the same health problem, and measuredthe same outcome. We therefore selected trials using zinc loz-enges that were conducted in the same country (United States),in the same setting (outpatient setting), in the same popula-tion (mostly adults), for the same health problem (naturallyacquired cold), and for the same outcome (duration of cold).This analysis was not included in the Cochrane review.We agree with Dr Hemilä’s point that 3 of the 5 low-dosezinc trials had problems in the formulation of their zinc loz-enges (were nonacetate lozenges) so that zinc was notreleased freely. However, similar kinds of formulations thatreleased more and less ionic zinc were included in both low-dose and high-dose groups.There are many possible analytic approaches in a meta-analysis, and we originally chose to triple count adverse eventdata for 1 study.3 A more commonly used method is to com-bine all relevant intervention groups into a single group, andto combine all relevant control groups into a single controlgroup.4We reanalyzed the data in this way and found a minimalbut insignificant difference from the previous calculation(60.2% for lozenges vs 48.4% for placebo; number needed toharm [NNH], 9). The conclusion remains the same: “zinc loz-enges were associated with a higher incidence of adverse eventscompared with placebo.” This is consistent with findings frompublished clinical trials on zinc lozenges for the common cold.5Moreover, regarding the study in question,3 the authorsreported adverse events to be more common in the lozengesgroup (13%-19%; mean, 16%) than in the placebo group (10%).We agree with Hemilä that the negative findings for thelow-dose (<75 mg/d) zinc lozenge trials may be related to thelow dose or problems in formulations, and the estimation ofzinc lozenge effects should focus on trials using high doses(≥75 mg/d) of zinc.Rashmi Ranjan Das, MD, FCCPMeenu Singh, MD, FCCPAuthor Affiliations: Department of Pediatrics, All India Institute of MedicalSciences, Bhubaneswar, India (Das); Department of Pediatrics, Post-GraduateInstitute of Medical Education and Research, Chandigarh, India (Singh).Corresponding Author: Meenu Singh, MD, FCCP, Department of Pediatrics,Post-Graduate Institute of Medical Education and Research,Chandigarh-160012, India (meenusingh4@gmail.com).Letters730 JAMA August 18, 2015 Volume 314, Number 7 (Reprinted) jama.comDownloaded From: http://jama.jamanetwork.com/ by a UNIVERSITY OF HELSINKI User  on 08/24/2015Copyright 2015 American Medical Association. All rights reserved.Conflict of Interest Disclosures: The authors have completed and submittedthe ICMJE Form for Disclosure of Potential Conflicts of Interest and none werereported.1. Singh M, Das RR. Zinc for the common cold. Cochrane Database Syst Rev.2013;6(6):CD001364.2. Chambers JD, Naci H, Wouters OJ, et al. An assessment of themethodological quality of published network meta-analyses: a systematicreview. PLoS One. 2015;10(4):e0121715.3. Turner RB, Cetnarowski WE. Effect of treatment with zinc gluconate or zincacetate on experimental and natural colds. Clin Infect Dis. 2000;31(5):1202-1208.4. Higgins JPT, Deeks JJ, Altman DG, eds. How to include multiple groups from1 study. In: Higgins JPT, Green S, eds. Cochrane Handbook for SystematicReviews of Interventions. London, England: Cochrane Collaboration; 2011:chap16.5.4.5. Macknin ML, Piedmonte M, Calendine C, Janosky J, Wald E. Zinc gluconatelozenges for treating the common cold in children: a randomized controlledtrial. JAMA. 1998;279(24):1962-1967.CORRECTIONIncorrect Dose in Figure: In the Original Contribution entitled “Effect ofPatiromer on Serum Potassium Level in Patients With Hyperkalemia and DiabeticKidney Disease: The AMETHYST-DN Randomized Clinical Trial” published in the July14, 2015, issue of JAMA,1 an incorrect study drug dose appeared in a figure. InFigure 2, the starting patiromer dose reported as 16.2 in the x-axis for both stra-tum 1 and stratum 2 in both the left and the right plots should have appeared as16.8. This article was corrected online.1. Bakris GL, Pitt B, Weir MR, et al; AMETHYST-DN Investigators. Effect ofpatiromer on serum potassium level in patients with hyperkalemia and diabetickidney disease: the AMETHYST-DN randomized clinical trial. JAMA. 2015;314(2):151-161.Wording Errors in the Text: In the Viewpoint entitled “Innovations of the Ameri-cans With Disabilities Act: Confronting Disability Discrimination in Employment”published in the June 9, 2015, issue of JAMA,1 the article should have stated moreclearly that the pre–Americans with Disabilities Act Amendments Act (ADAAA) re-quirements for establishing coverage under the “regarded as” part of the defini-tion are no longer required under the ADAAA. Under the ADAAA, an individual isregarded as having a disability if he or she has been subject to discrimination “be-cause of an actual or perceived physical or mental impairment whether or not theimpairment limits or is perceived to limit a major life activity.” This article was cor-rected online.1. Rothstein MA. Innovations of the Americans with Disabilities Act: confrontingdisability discrimination in employment. JAMA. 2015;313(22):2221-2222.Guidelines for LettersLetters discussing a recent JAMA article should be submitted within 4weeks of the article's publication in print. Letters received after 4 weekswill rarely be considered. Letters should not exceed 400 words of textand 5 references and may have no more than 3 authors. Letters report-ing original research should not exceed 600 words of text and 6 refer-ences and may have no more than 7 authors. They may include up to 2tables or figures but online supplementary material is not allowed. Allletters should include a word count. Letters must not duplicate other ma-terial published or submitted for publication. Letters not meeting thesespecifications are generally not considered. Letters being considered forpublication ordinarily will be sent to the authors of the JAMA article, whowill be given the opportunity to reply. Letters will be published at thediscretion of the editors and are subject to abridgement and editing. Fur-ther instruc tions can be found at http:// jama.com/public/InstructionsForAuthors.aspx. A signed statement for authorship crite-ria and responsibility, financial disclosure, copyright transfer, andacknowledgment and the ICMJE Form for Disclosure of Potential Con-flicts of Interest are required before publication. Letters should be sub-mitted via the JAMA online submission and review system at http://manuscripts.jama.com. For technical assistance, please contactjama-letters@jamanetwork.org.Section Editor: Jody W. Zylke, MD, Deputy Editor.Lettersjama.com (Reprinted) JAMA August 18, 2015 Volume 314, Number 7 731Downloaded From: http://jama.jamanetwork.com/ by a UNIVERSITY OF HELSINKI User  on 08/24/2015

Common Cold Treatment Using Zinc

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