Letters
ing medical symptom for claims alleging inadequate indication for esophagogastroduodenoscopy or how many occurred in 2002-2012. There may be legitimate reasons to screen for esophageal cancer in some patients, but our findings suggest that the risk of a medical professional liability claim for failing to screen is not one of them. Physicians need to balance the risk of complications from diagnostic procedures, even if those complications are rare. Megan A. Adams, MD, JD Parul Divya Parikh, MPH Kwon Miller Joel H. Rubenstein, MD, MSc Author Affiliations: Division of Gastroenterology, University of Michigan Medical School, Ann Arbor (Adams); PIAA, Rockville, Maryland (Parikh, Miller); Center for Clinical Management Research, Ann Arbor Veterans Affairs Medical Center, Ann Arbor, Michigan (Rubenstein). Corresponding Author: Megan A. Adams, MD, JD, Division of Gastroenterology, University of Michigan, 1500 E Medical Center Dr, Ann Arbor, MI 48109 ([email protected]). Author Contributions: Dr Rubenstein had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Adams, Rubenstein. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Adams. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Adams. Administrative, technical, or material support: Parikh, Miller. Study supervision: Rubenstein. Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Shaheen NJ, Weinberg DS, Denberg TD, Chou R, Qaseem A, Shekelle P; Clinical Guidelines Committee of the American College of Physicians. Upper endoscopy for gastroesophageal reflux disease: best practice advice from the clinical guidelines committee of the American College of Physicians. Ann Intern Med. 2012;157(11):808-816. 2. Spechler SJ, Sharma P, Souza RF, Inadomi JM, Shaheen NJ; American Gastroenterological Association. American Gastroenterological Association medical position statement on the management of Barrett’s esophagus. Gastroenterology. 2011;140(3):1084-1091. 3. Wang KK, Sampliner RE; Practice Parameters Committee of the American College of Gastroenterology. Updated guidelines 2008 for the diagnosis, surveillance and therapy of Barrett’s esophagus. Am J Gastroenterol. 2008;103 (3):788-797. 4. Rubenstein JH, Saini SD, Kuhn L, et al. Influence of malpractice history on the practice of screening and surveillance for Barrett’s esophagus. Am J Gastroenterol. 2008;103(4):842-849. 5. Ben-Menachem T, Decker GA, Early DS, et al; ASGE Standards of Practice Committee. Adverse events of upper GI endoscopy. Gastrointest Endosc. 2012; 76(4):707-718. 6. Peery AF, Dellon ES, Lund J, et al Burden of gastrointestinal disease in the United States: 2012 update. Gastroenterology 2012;143(5):1179-1187, e1-e3.
Richard Saitz, MD, MPH Author Affiliation: Department of Community Health Sciences, Boston University School of Public Health, Boston, Massachusetts. Corresponding Author: Richard Saitz, MD, MPH, Department of Community Health Sciences, Boston University School of Public Health, 801 Massachusetts Ave, Boston, MA 02118 ([email protected]). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported receiving grants from the National Institutes of Health (NIH) (one NIH grant proposal under review but not yet rewarded is a study of naltrexone and includes a plan for Alkermes to provide the medication); being a consulting editor to BMJ; receiving speaking fees from the Commonwealth of Massachusetts, US Substance Abuse and Mental Health Services Administration, numerous academic institutions, International Network on Early Identification and Brief Intervention for Alcohol and other drugs, NIH via Synergy Enterprises, and other government contractors; and consulting as an expert witness on alcohol and drug topics. 1. Jonas DE, Amick HR, Feltner C, et al. Pharmacotherapy for adults with alcohol use disorders in outpatient settings: a systematic review and meta-analysis. JAMA. 2014;311(18):1889-1900. 2. Gerrein JR, Rosenberg CM, Manohar V. Disulfiram maintenance in outpatient treatment of alcoholism. Arch Gen Psychiatry. 1973;28(6):798-802.
COMMENT & RESPONSE
Medications for Alcohol Use Disorders To the Editor The review by Dr Jonas and colleagues1 of the efficacy of medications to treat alcohol use disorders concluded that “well-controlled trials of disulfiram did not show overall reductions in alcohol consumption.” Although the conjama.com
clusion may be true for the studies included in the review, double-blind randomized clinical trials are not the correct design to test the efficacy of a medication that works because patients know they are taking it and that it will make them sick if they drink alcohol. Participants assigned to receive placebo or active medication are both warned of the disulfiramethanol reaction, and they will act based on that belief and take or not take the medication, and avoid alcohol or not, accordingly. Some may experiment with alcohol to unblind themselves, but the majority will not. More appropriately designed studies to test disulfiram efficacy were performed decades ago and compared monitored (eg, observed or facilitated pill taking) with unmonitored pill taking. Four randomized trials2-5 showed substantial differences in abstinence with durations of 8 weeks (7% vs 40%), 6 months (55% vs 90%), 6 months (47% vs 73%), and 2 years (79% vs 98%). Follow-up in these trials ranged from 78% to 100% except in one study’s unmonitored group, in which it was 39%.2 Medications for alcohol use disorders only work when they are taken. Randomized trials of these medications go to substantial lengths to ensure adherence. But disulfiram is different in that its mechanism of action is closely tied to decisions to take or not take it (it not only has no reinforcing effects, it threatens the patient with severe unpleasantness should they slip and have a drink). The proper trial design is a departure from the traditional placebo-controlled study. Although disulfiram is difficult to use in practice because of risks and efforts needed to ensure it is actually taken, it should not be avoided for lack of efficacy. All efficacious treatments for this often fatal disease for which there are only modestly efficacious treatments need to be used.
3. Azrin NH. Improvements in the community-reinforcement approach to alcoholism. Behav Res Ther. 1976;14(5):339-348. 4. Azrin NH, Sisson RW, Meyers R, Godley M. Alcoholism treatment by disulfiram and community reinforcement therapy. J Behav Ther Exp Psychiatry. 1982;13(2):105-112. 5. Liebson IA, Tommasello A, Bigelow GE. A behavioral treatment of alcoholic methadone patients. Ann Intern Med. 1978;89(3):342-344. JAMA October 1, 2014 Volume 312, Number 13
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To the Editor The meta-analysis by Dr Jonas and colleagues1 of medical treatments for alcohol use disorders and the accompanying Editorial2 left me with a sense of scientific unease. Meta-analyses appear to offer solace in large clinical samples culled from many studies but really provide only approximate data when no definitive answers exist. Meta-analysis of questionable studies does not result in better data to guide clinical decisions. For example, Jonas and colleagues commented on acamprosate’s putative effectiveness in Europe but not in the United States. Close reading of the European trials identifies far lower placebo rates than expected in double-blind studies, resulting in a drug effect that appears statistically significant. Nor does statistical significance mean large clinical effect. Jonas and colleagues cited a multisite study comparing naltrexone with acamprosate, the COMBINE trial,3 that reported statistical significance for placebo vs active treatment without comment on the magnitude of the observed effect sizes, such as with the Cohen d statistic. Jonas and colleagues indicated that while disulfiram studies appear to report no effect, none of the studies they examined were performed in monitored settings. By contrast, comparison data from a court-ordered, clinically monitored program4 indicate a high adherence rate of 61.0% over 15 months relative to 18.2% for voluntary disulfiram treatment, a strong effect size of 48.2%. Such data question the accompanying Editorial’s assumptions about patient-centered care in alcoholism and effective medical treatments being at hand. That patient cooperation and patient choice are both important in treating alcoholism is old news. Drs Bradley and Kivlahan did not consider the social setting in which many other factors may also be at play. They go far from the data in listing 4 questionable medical treatments for alcoholism as effective. The best studied, naltrexone, has only partial support for an inconsistently observed effect after drinking. The others require large-sample replication of clinical effect, including monitored disulfiram. Thomas P. Beresford, MD Author Affiliation: Laboratory for Clinical and Translational Research in Psychiatry, Department of Veterans Affairs Medical Center, Denver, Colorado. Corresponding Author: Thomas P. Beresford, MD, Laboratory for Clinical and Translational Research in Psychiatry, Department of Veterans Affairs Medical Center, 1055 Clermont St, Denver, CO 80220 (thomas.beresford@ucdenver .edu). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported receiving a grant from Bristol-Myers Squibb. 1. Jonas DE, Amick HR, Feltner C, et al. Pharmacotherapy for adults with alcohol use disorders in outpatient settings: a systematic review and meta-analysis. JAMA. 2014;311(18):1889-1900. 2. Bradley KA, Kivlahan DR. Bringing patient-centered care to patients with alcohol use disorders. JAMA. 2014;311(18):1861-1862.
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To the Editor A systematic review and meta-analysis1 highlighted the current pharmacotherapy for outpatients affected by alcohol use disorders. However, regarding off-label drugs, some issues need more discussion, particularly those regarding nalmefene use. Nalmefene is no longer an off-label drug in Europe. Nalmefene was approved in February 2013 by the European Medicines Agency and was granted market authorization in the European Union for the reduction of alcohol consumption in alcohol-dependent patients with a high drinking risk level (defined as >60 g/d for men and >40 g/d for women).2 As cited by Jonas and colleagues, 2 randomized, double-blind, placebocontrolled trials have been published in which patients with alcohol use disorders received nalmefene as needed (ie, in selfidentified risk situations, when drinking is imminent, or as soon as possible after drinking) for 6 months. However, a post hoc analysis of these studies only including patients with at least a high drinking risk level both at screening and randomization showed more interesting results: nalmefene reduced the number of heavy drinking days (treatment difference: −3.2 days; P < .001) and total alcohol consumption (treatment difference: −14.3 g/d; P < .001) at month 6 significantly more than placebo.3 In addition, reduction of alcohol consumption is increasingly accepted as a viable treatment goal.4 In particular, patients with alcohol dependence without symptoms of physical dependence and loss of control on alcohol intake and patients not highly motivated to follow a rehabilitation program aimed at achieving complete abstinence may find a beneficial effect in terms of harm reduction in reducing episodes of heavy drinking by the as-needed use of nalmefene.4 Reduction in consumption could be considered an intermediate step before the achievement of complete abstinence from alcohol, which remains the primary objective of treatment. Therefore, nalmefene is an approved drug to treat alcohol use disorders, is the only drug with the indication of reducing alcohol consumption with as-needed use, and is generally well tolerated. In this clinical field, in which almost 20% of patients with alcohol use disorder remain untreated,5 it may represent a valid pharmacological approach to engage more patients in treatment.4 Fabio Caputo, MD, PhD Marco Domenicali, MD, PhD Mauro Bernardi, MD Author Affiliations: Department of Internal Medicine, SS Annunziata Hospital, Cento, Italy (Caputo); “G. Fontana” Centre for Treatment of Alcohol Addiction, University of Bologna, Bologna, Italy (Domenicali, Bernardi). Corresponding Author: Fabio Caputo, MD, PhD, Internal Medicine Unit, SS Annunziata Hospital, Via Vicini 2, 44042 Cento, Italy ([email protected]).
3. Anton RF, O’Malley SS, Ciraulo DA, et al; COMBINE Study Research Group. Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. JAMA. 2006; 295(17):2003-2017.
Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Caputo reported receiving fees from D&A Pharma, Laboratorio Farmaceutico CT, and Lundbeck. Dr Bernardi reported being a consultant or speaker for CLS Behring, PPTA Europe, and Baxter Healthcare. No other disclosures were reported.
4. Martin BK, Clapp L, Alfers J, Beresford TP. Adherence to court-ordered disulfiram at fifteen months: a naturalistic study. J Subst Abuse Treat. 2004;26 (3):233-236.
1. Jonas DE, Amick HR, Feltner C, et al. Pharmacotherapy for adults with alcohol use disorders in outpatient settings: a systematic review and meta-analysis. JAMA. 2014;311(18):1889-1900.
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Letters
2. European Medicines Agency. European public assessment reports. http://www .ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search .jsp&mid=WC0b01ac058001d125. Accessed May 20, 2014. 3. van den Brink W, Aubin HJ, Bladström A, Torup L, Gual A, Mann K. Efficacy of as-needed nalmefene in alcohol-dependent patients with at least a high drinking risk level: results from a subgroup analysis of two randomized controlled 6-month studies. Alcohol Alcohol. 2013;48(5):570-578. 4. Keating GM. Nalmefene: a review of its use in the treatment of alcohol dependence. CNS Drugs. 2013;27(9):761-772. 5. Kohn R, Saxena S, Levav I, Saraceno B. The treatment gap in mental health care. Bull World Health Organ. 2004;82(11):858-866.
In Reply We agree with Dr Saitz that disulfiram may benefit some patients but not that the trials cited adequately establish disulfiram efficacy. These trials were designed to evaluate closely monitored programs that included disulfiram and additional counseling, social support, coaching, or a combination of these. At best, they might allow a conclusion that the programs work for patients interested in taking disulfiram who adhere to the medication. None of these trials disentangle whether benefits can be attributed to disulfiram (ie, beyond benefits of additional counseling or therapeutic relationships). Differences between groups in motivation and goals may also underlie the findings. Furthermore, these 4 small trials (≤15 disulfiram-treated patients in any group) have significant threats to their internal validity. Most did not report methods of randomization or allocation concealment; outcome assessors were typically not masked and descriptions of ascertainment methods were limited; none reported baseline characteristics by study group to allow assessment of similarity of groups at baseline; and none reported their statistical methods or methods of handling missing data. In contrast, 2 trials in our review were better designed to isolate the potential benefits of disulfiram and had few threats to internal validity.1,2 Both trials randomized patients to receive disulfiram, 250 mg; disulfiram, 1 mg (subtherapeutic); or riboflavin. Neither evaluated monitored disulfiram. Disulfiram groups were informed about the disulfiram-ethanol reaction; the riboflavin group was not. One trial1 (N = 605) found no difference between groups for abstinence in its main analyses but reported fewer drinking days with disulfiram, 250 mg, than in other groups for the subsample who drank and had complete assessments. The other trial2 (N = 128) reported similar rates of abstinence for the disulfiram groups (21% and 25%) but lower rates with riboflavin (12%). Given the findings and limitations of trials, guidelines reasonably recommend “to consider offering disulfiram … for service users who have a goal of abstinence but for whom acamprosate and oral naltrexone are not suitable, or prefer disulfiram and understand the … risks.”3 In response to Dr Beresford, we did not conduct metaanalyses of questionable studies. Instead, we evaluated studies using established methods to assess risk of bias and only included studies with low or medium risk in our main analyses. The claim that European trials had far lower placebo rates is incorrect. The European trials had a mean placebo response of 19.3% (range, 7.1%-40%) compared with 14.6% (range, jama.com
7.7%-18.4%) in the US trials (return to any drinking for acamprosate, Figure F-2 of our larger technical report for the Agency for Healthcare Research and Quality on which the article was based). Regarding statistical and clinical significance, our main meta-analyses focused on clinically significant events (eg, return to any drinking) rather than on continuous or standardized measures. We found clinically and statistically significant improvements for acamprosate and oral naltrexone, with numbers needed to treat (NNTs) from 12 to 20. Regarding partial support for an inconsistently observed effect, the data show that the medications work for some people but not everyone, suggesting heterogeneity of treatment effects. Many medications have NNTs similar to or worse than those for naltrexone and acamprosate (eg, NNTs of 14 over 2.2 years for aspirin after transient ischemic attacks to prevent death or stroke and 96 over 5 years for isoniazid for latent tuberculosis to prevent active tuberculosis).4 In response to Dr Caputo and colleagues, we recognize nalmefene’s European approval. We categorized medications based on Food and Drug Administration (FDA) approval status. Nalmefene is not approved by the FDA. We agree that nalmefene can have an important role because evidence shows improvement in some consumption outcomes (including trials that assessed as-needed dosing5,6). There is controversy about harm reduction because many clinicians believe that abstinence is the only appropriate goal. However, for patients unwilling to consider abstinence, reducing heavy drinking may be a reasonable goal. Daniel E. Jonas, MD, MPH Cynthia Feltner, MD, MPH James C. Garbutt, MD Author Affiliations: Department of Medicine, University of North Carolina, Chapel Hill (Jonas, Feltner); Department of Psychiatry, University of North Carolina, Chapel Hill (Garbutt). Corresponding Author: Daniel E. Jonas, MD, MPH, University of North Carolina at Chapel Hill, Department of Medicine, 5034 Old Clinic Bldg, Chapel Hill, NC 27599 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Fuller RK, Branchey L, Brightwell DR, et al. Disulfiram treatment of alcoholism: a Veterans Administration cooperative study. JAMA. 1986;256(11): 1449-1455. 2. Fuller RK, Roth HP. Disulfiram for the treatment of alcoholism: an evaluation in 128 men. Ann Intern Med. 1979;90(6):901-904. 3. National Institute for Health and Care Excellence. Alcohol-use disorders: diagnosis, assessment and management of harmful drinking and alcohol dependence. http://www.nice.org.uk/guidance/CG115/chapter /1-Guidance#interventions-for-alcohol-misuse. Accessed July 16, 2014. 4. Laupacis A, Sackett DL, Roberts RS. An assessment of clinically useful measures of the consequences of treatment. N Engl J Med. 1988;318(26):17281733. 5. Gual A, He Y, Torup L, van den Brink W, Mann K; ESENSE 2 Study Group. A randomised, double-blind, placebo-controlled, efficacy study of nalmefene, as-needed use, in patients with alcohol dependence. Eur Neuropsychopharmacol. 2013;23(11):1432-1442. 6. Mann K, Bladström A, Torup L, Gual A, van den Brink W. Extending the treatment options in alcohol dependence: a randomized controlled study of as-needed nalmefene. Biol Psychiatry. 2013;73(8):706-713. JAMA October 1, 2014 Volume 312, Number 13
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In Reply We agree with Dr Beresford that patient-centered care with shared decision making is not a new concept in medicine. However, patient-centered care is not currently the routine approach to management of alcohol use disorders in medical settings. Instead, referral to specialty treatment is often recommended for patients diagnosed with alcohol use disorders.1 Therefore, we outlined treatments for alcohol use disorders, supported by randomized clinical trials, that have been recommended in evidence-based clinical practice guidelines developed by the UK National Institute of Clinical Effectiveness, as well as those developed by the US Department of Veterans Affairs and the Department of Defense. 2,3 Currently, only about 8% of US adults with alcohol use disorders receive treatment.4 Offering patients different treatment options could increase the proportion of patients engaged in treatment.
Aref A. Bin Abdulhak, MD Abdur Rahman Khan, MD Alan P. Wimmer, MD
Katharine Bradley, MD, MPH Daniel Kivlahan, PhD Author Affiliations: Group Health Research Institute, Seattle, Washington (Bradley); Department of Veterans Affairs, Seattle, Washington (Kivlahan). Corresponding Author: Katharine Bradley, MD, MPH, Group Health Research Institute, 1730 Minor Ave, Seattle, WA 98101 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Bradley reporting having grants pending from the National Institute on Alcohol Abuse and Alcoholism and owning stock in Johnson and Johnson, AbbVie, and Pfizer. Dr Kivlahan reported no disclosures. 1. Substance Abuse and Mental Health Services Administration. Systems-level implementation of screening, brief intervention, and referral to treatment: Technical Assistance Publication Series. http://store.samhsa.gov/product /TAP-33-Systems-Level-Implementation-of-Screening-Brief-Intervention -and-Referral-to-Treatment-SBIRT-/SMA13-4741. Accessed July 15, 2014. 2. National Institute for Health and Care Excellence. Alcohol-use disorders: diagnosis, assessment and management of harmful drinking and alcohol dependence. http://www.nice.org.uk/guidance/CG115. Accessed July 15, 2014. 3. VA Office of Quality and Performance. VA/DoD clinical practice guideline for management of substance use disorders. http://www.healthquality.va.gov /guidelines/MH/sud/sud_full_601f.pdf. Accessed July 15, 2014. 4. Substance Abuse and Mental Health Services Administration. Results from the 2012 National Survey on Drug Use and Health: summary of national findings and detailed tables. http://www.samhsa.gov/data/NSDUH /2012SummNatFindDetTables/Index.aspx. Accessed July 15, 2014.
Azithromycin for Elderly Patients With Pneumonia To the Editor Dr Mortensen and colleagues1 conducted a retrospective cohort study that evaluated the risk of death with azithromycin use in elderly patients with pneumonia in comparison with other guideline-recommended antibiotics. Azithromycin use was associated with a statistically significant decrease in mortality at 10, 30, and 90 days. However, prior studies in elderly populations have shown an increase in mortality from any cause associated with current use of azithromycin, defined as within 1 to 5 days of therapy.2,3 Mortensen and colleagues did not report the risk of death associated with current use of azithromycin. Ray et al2 found that azithromycin use was not associated with a statistically significant difference in the risk of death during the first 10 days of therapy; however, when their analy1352
sis was limited to current azithromycin use, the risk of death was higher among azithromycin-treated patients. Similarly, Rao et al3 reported a higher risk of death with current azithromycin use, but no significant association was observed during days 6 to 10 of therapy. The mechanism of increased risk is thought to be a proarrhythmic effect of the medication, which would be expected to occur during the first 5 days of therapy when drug levels are at their highest. In addition, Mortensen and colleagues excluded from their analysis deaths that occurred on the day of admission and provided no information on whether the patients who died received azithromycin. Not including early deaths that may have occurred as an adverse effect of the medication on initial exposure in susceptible patients may have biased their results in favor of a longer-term mortality benefit among elderly patients treated with azithromycin.
Author Affiliations: Department of Medicine, University of Missouri, Kansas City (Bin Abdulhak); Department of Medicine, University of Toledo Medical Center, Toledo, Ohio (Khan); Saint Luke’s Mid America Heart Institute, University of Missouri, Kansas City (Wimmer). Corresponding Author: Alan P. Wimmer, MD, Saint Luke’s Mid America Heart Institute, University of Missouri, Kansas City, 4330 Wornall Rd, Kansas City, MO 64111 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Mortensen EM, Halm EA, Pugh MJ, et al. Association of azithromycin with mortality and cardiovascular events among older patients hospitalized with pneumonia. JAMA. 2014;311(21):2199-2208. 2. Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death. N Engl J Med. 2012;366(20):1881-1890. 3. Rao GA, Mann JR, Shoaibi A, et al. Azithromycin and levofloxacin use and increased risk of cardiac arrhythmia and death. Ann Fam Med. 2014;12(2):121-127.
In Reply Regarding the concern of Dr Bin Abdulhak and colleagues about examining shorter periods than 10 days after admission, we consider follow-up durations longer than 5 days to be more clinically relevant and important. Although there may be an increased risk of arrhythmias earlier due to the use of azithromycin, we doubt that clinicians or patients would then avoid this medication when there is a clinically significant survival advantage at 90 days. However, we have repeated our analyses for the outcomes of any cardiovascular events and all-cause mortality within 5 days of admission and found results similar to those at 10 days reported in our article. There was significantly improved mortality (odds ratio, 0.75; 95% CI, 0.69-0.72) and a small but significant increase in any cardiovascular event (odds ratio, 1.06; 95% CI, 1.03-1.09). Therefore, we are confident in our published conclusions. We did not exclude patients who died on the day of admission from all analyses; these patients were only excluded from the Kaplan-Meier graphs because this statistical technique excludes those who exit the cohort on the same day as study entry.1
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ing medical symptom for claims alleging inadequate indication for esophagogastroduodenoscopy or how many occurred in 2002-2012. There may be legitimate reasons to screen for esophageal cancer in some patients, but our findings suggest that the risk of a medical professional liability claim for failing to screen is not one of them. Physicians need to balance the risk of complications from diagnostic procedures, even if those complications are rare. Megan A. Adams, MD, JD Parul Divya Parikh, MPH Kwon Miller Joel H. Rubenstein, MD, MSc Author Affiliations: Division of Gastroenterology, University of Michigan Medical School, Ann Arbor (Adams); PIAA, Rockville, Maryland (Parikh, Miller); Center for Clinical Management Research, Ann Arbor Veterans Affairs Medical Center, Ann Arbor, Michigan (Rubenstein). Corresponding Author: Megan A. Adams, MD, JD, Division of Gastroenterology, University of Michigan, 1500 E Medical Center Dr, Ann Arbor, MI 48109 ([email protected]). Author Contributions: Dr Rubenstein had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Adams, Rubenstein. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Adams. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Adams. Administrative, technical, or material support: Parikh, Miller. Study supervision: Rubenstein. Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Shaheen NJ, Weinberg DS, Denberg TD, Chou R, Qaseem A, Shekelle P; Clinical Guidelines Committee of the American College of Physicians. Upper endoscopy for gastroesophageal reflux disease: best practice advice from the clinical guidelines committee of the American College of Physicians. Ann Intern Med. 2012;157(11):808-816. 2. Spechler SJ, Sharma P, Souza RF, Inadomi JM, Shaheen NJ; American Gastroenterological Association. American Gastroenterological Association medical position statement on the management of Barrett’s esophagus. Gastroenterology. 2011;140(3):1084-1091. 3. Wang KK, Sampliner RE; Practice Parameters Committee of the American College of Gastroenterology. Updated guidelines 2008 for the diagnosis, surveillance and therapy of Barrett’s esophagus. Am J Gastroenterol. 2008;103 (3):788-797. 4. Rubenstein JH, Saini SD, Kuhn L, et al. Influence of malpractice history on the practice of screening and surveillance for Barrett’s esophagus. Am J Gastroenterol. 2008;103(4):842-849. 5. Ben-Menachem T, Decker GA, Early DS, et al; ASGE Standards of Practice Committee. Adverse events of upper GI endoscopy. Gastrointest Endosc. 2012; 76(4):707-718. 6. Peery AF, Dellon ES, Lund J, et al Burden of gastrointestinal disease in the United States: 2012 update. Gastroenterology 2012;143(5):1179-1187, e1-e3.
Richard Saitz, MD, MPH Author Affiliation: Department of Community Health Sciences, Boston University School of Public Health, Boston, Massachusetts. Corresponding Author: Richard Saitz, MD, MPH, Department of Community Health Sciences, Boston University School of Public Health, 801 Massachusetts Ave, Boston, MA 02118 ([email protected]). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported receiving grants from the National Institutes of Health (NIH) (one NIH grant proposal under review but not yet rewarded is a study of naltrexone and includes a plan for Alkermes to provide the medication); being a consulting editor to BMJ; receiving speaking fees from the Commonwealth of Massachusetts, US Substance Abuse and Mental Health Services Administration, numerous academic institutions, International Network on Early Identification and Brief Intervention for Alcohol and other drugs, NIH via Synergy Enterprises, and other government contractors; and consulting as an expert witness on alcohol and drug topics. 1. Jonas DE, Amick HR, Feltner C, et al. Pharmacotherapy for adults with alcohol use disorders in outpatient settings: a systematic review and meta-analysis. JAMA. 2014;311(18):1889-1900. 2. Gerrein JR, Rosenberg CM, Manohar V. Disulfiram maintenance in outpatient treatment of alcoholism. Arch Gen Psychiatry. 1973;28(6):798-802.
COMMENT & RESPONSE
Medications for Alcohol Use Disorders To the Editor The review by Dr Jonas and colleagues1 of the efficacy of medications to treat alcohol use disorders concluded that “well-controlled trials of disulfiram did not show overall reductions in alcohol consumption.” Although the conjama.com
clusion may be true for the studies included in the review, double-blind randomized clinical trials are not the correct design to test the efficacy of a medication that works because patients know they are taking it and that it will make them sick if they drink alcohol. Participants assigned to receive placebo or active medication are both warned of the disulfiramethanol reaction, and they will act based on that belief and take or not take the medication, and avoid alcohol or not, accordingly. Some may experiment with alcohol to unblind themselves, but the majority will not. More appropriately designed studies to test disulfiram efficacy were performed decades ago and compared monitored (eg, observed or facilitated pill taking) with unmonitored pill taking. Four randomized trials2-5 showed substantial differences in abstinence with durations of 8 weeks (7% vs 40%), 6 months (55% vs 90%), 6 months (47% vs 73%), and 2 years (79% vs 98%). Follow-up in these trials ranged from 78% to 100% except in one study’s unmonitored group, in which it was 39%.2 Medications for alcohol use disorders only work when they are taken. Randomized trials of these medications go to substantial lengths to ensure adherence. But disulfiram is different in that its mechanism of action is closely tied to decisions to take or not take it (it not only has no reinforcing effects, it threatens the patient with severe unpleasantness should they slip and have a drink). The proper trial design is a departure from the traditional placebo-controlled study. Although disulfiram is difficult to use in practice because of risks and efforts needed to ensure it is actually taken, it should not be avoided for lack of efficacy. All efficacious treatments for this often fatal disease for which there are only modestly efficacious treatments need to be used.
3. Azrin NH. Improvements in the community-reinforcement approach to alcoholism. Behav Res Ther. 1976;14(5):339-348. 4. Azrin NH, Sisson RW, Meyers R, Godley M. Alcoholism treatment by disulfiram and community reinforcement therapy. J Behav Ther Exp Psychiatry. 1982;13(2):105-112. 5. Liebson IA, Tommasello A, Bigelow GE. A behavioral treatment of alcoholic methadone patients. Ann Intern Med. 1978;89(3):342-344. JAMA October 1, 2014 Volume 312, Number 13
Copyright 2014 American Medical Association. All rights reserved.
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To the Editor The meta-analysis by Dr Jonas and colleagues1 of medical treatments for alcohol use disorders and the accompanying Editorial2 left me with a sense of scientific unease. Meta-analyses appear to offer solace in large clinical samples culled from many studies but really provide only approximate data when no definitive answers exist. Meta-analysis of questionable studies does not result in better data to guide clinical decisions. For example, Jonas and colleagues commented on acamprosate’s putative effectiveness in Europe but not in the United States. Close reading of the European trials identifies far lower placebo rates than expected in double-blind studies, resulting in a drug effect that appears statistically significant. Nor does statistical significance mean large clinical effect. Jonas and colleagues cited a multisite study comparing naltrexone with acamprosate, the COMBINE trial,3 that reported statistical significance for placebo vs active treatment without comment on the magnitude of the observed effect sizes, such as with the Cohen d statistic. Jonas and colleagues indicated that while disulfiram studies appear to report no effect, none of the studies they examined were performed in monitored settings. By contrast, comparison data from a court-ordered, clinically monitored program4 indicate a high adherence rate of 61.0% over 15 months relative to 18.2% for voluntary disulfiram treatment, a strong effect size of 48.2%. Such data question the accompanying Editorial’s assumptions about patient-centered care in alcoholism and effective medical treatments being at hand. That patient cooperation and patient choice are both important in treating alcoholism is old news. Drs Bradley and Kivlahan did not consider the social setting in which many other factors may also be at play. They go far from the data in listing 4 questionable medical treatments for alcoholism as effective. The best studied, naltrexone, has only partial support for an inconsistently observed effect after drinking. The others require large-sample replication of clinical effect, including monitored disulfiram. Thomas P. Beresford, MD Author Affiliation: Laboratory for Clinical and Translational Research in Psychiatry, Department of Veterans Affairs Medical Center, Denver, Colorado. Corresponding Author: Thomas P. Beresford, MD, Laboratory for Clinical and Translational Research in Psychiatry, Department of Veterans Affairs Medical Center, 1055 Clermont St, Denver, CO 80220 (thomas.beresford@ucdenver .edu). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported receiving a grant from Bristol-Myers Squibb. 1. Jonas DE, Amick HR, Feltner C, et al. Pharmacotherapy for adults with alcohol use disorders in outpatient settings: a systematic review and meta-analysis. JAMA. 2014;311(18):1889-1900. 2. Bradley KA, Kivlahan DR. Bringing patient-centered care to patients with alcohol use disorders. JAMA. 2014;311(18):1861-1862.
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To the Editor A systematic review and meta-analysis1 highlighted the current pharmacotherapy for outpatients affected by alcohol use disorders. However, regarding off-label drugs, some issues need more discussion, particularly those regarding nalmefene use. Nalmefene is no longer an off-label drug in Europe. Nalmefene was approved in February 2013 by the European Medicines Agency and was granted market authorization in the European Union for the reduction of alcohol consumption in alcohol-dependent patients with a high drinking risk level (defined as >60 g/d for men and >40 g/d for women).2 As cited by Jonas and colleagues, 2 randomized, double-blind, placebocontrolled trials have been published in which patients with alcohol use disorders received nalmefene as needed (ie, in selfidentified risk situations, when drinking is imminent, or as soon as possible after drinking) for 6 months. However, a post hoc analysis of these studies only including patients with at least a high drinking risk level both at screening and randomization showed more interesting results: nalmefene reduced the number of heavy drinking days (treatment difference: −3.2 days; P < .001) and total alcohol consumption (treatment difference: −14.3 g/d; P < .001) at month 6 significantly more than placebo.3 In addition, reduction of alcohol consumption is increasingly accepted as a viable treatment goal.4 In particular, patients with alcohol dependence without symptoms of physical dependence and loss of control on alcohol intake and patients not highly motivated to follow a rehabilitation program aimed at achieving complete abstinence may find a beneficial effect in terms of harm reduction in reducing episodes of heavy drinking by the as-needed use of nalmefene.4 Reduction in consumption could be considered an intermediate step before the achievement of complete abstinence from alcohol, which remains the primary objective of treatment. Therefore, nalmefene is an approved drug to treat alcohol use disorders, is the only drug with the indication of reducing alcohol consumption with as-needed use, and is generally well tolerated. In this clinical field, in which almost 20% of patients with alcohol use disorder remain untreated,5 it may represent a valid pharmacological approach to engage more patients in treatment.4 Fabio Caputo, MD, PhD Marco Domenicali, MD, PhD Mauro Bernardi, MD Author Affiliations: Department of Internal Medicine, SS Annunziata Hospital, Cento, Italy (Caputo); “G. Fontana” Centre for Treatment of Alcohol Addiction, University of Bologna, Bologna, Italy (Domenicali, Bernardi). Corresponding Author: Fabio Caputo, MD, PhD, Internal Medicine Unit, SS Annunziata Hospital, Via Vicini 2, 44042 Cento, Italy ([email protected]).
3. Anton RF, O’Malley SS, Ciraulo DA, et al; COMBINE Study Research Group. Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. JAMA. 2006; 295(17):2003-2017.
Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Caputo reported receiving fees from D&A Pharma, Laboratorio Farmaceutico CT, and Lundbeck. Dr Bernardi reported being a consultant or speaker for CLS Behring, PPTA Europe, and Baxter Healthcare. No other disclosures were reported.
4. Martin BK, Clapp L, Alfers J, Beresford TP. Adherence to court-ordered disulfiram at fifteen months: a naturalistic study. J Subst Abuse Treat. 2004;26 (3):233-236.
1. Jonas DE, Amick HR, Feltner C, et al. Pharmacotherapy for adults with alcohol use disorders in outpatient settings: a systematic review and meta-analysis. JAMA. 2014;311(18):1889-1900.
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Letters
2. European Medicines Agency. European public assessment reports. http://www .ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search .jsp&mid=WC0b01ac058001d125. Accessed May 20, 2014. 3. van den Brink W, Aubin HJ, Bladström A, Torup L, Gual A, Mann K. Efficacy of as-needed nalmefene in alcohol-dependent patients with at least a high drinking risk level: results from a subgroup analysis of two randomized controlled 6-month studies. Alcohol Alcohol. 2013;48(5):570-578. 4. Keating GM. Nalmefene: a review of its use in the treatment of alcohol dependence. CNS Drugs. 2013;27(9):761-772. 5. Kohn R, Saxena S, Levav I, Saraceno B. The treatment gap in mental health care. Bull World Health Organ. 2004;82(11):858-866.
In Reply We agree with Dr Saitz that disulfiram may benefit some patients but not that the trials cited adequately establish disulfiram efficacy. These trials were designed to evaluate closely monitored programs that included disulfiram and additional counseling, social support, coaching, or a combination of these. At best, they might allow a conclusion that the programs work for patients interested in taking disulfiram who adhere to the medication. None of these trials disentangle whether benefits can be attributed to disulfiram (ie, beyond benefits of additional counseling or therapeutic relationships). Differences between groups in motivation and goals may also underlie the findings. Furthermore, these 4 small trials (≤15 disulfiram-treated patients in any group) have significant threats to their internal validity. Most did not report methods of randomization or allocation concealment; outcome assessors were typically not masked and descriptions of ascertainment methods were limited; none reported baseline characteristics by study group to allow assessment of similarity of groups at baseline; and none reported their statistical methods or methods of handling missing data. In contrast, 2 trials in our review were better designed to isolate the potential benefits of disulfiram and had few threats to internal validity.1,2 Both trials randomized patients to receive disulfiram, 250 mg; disulfiram, 1 mg (subtherapeutic); or riboflavin. Neither evaluated monitored disulfiram. Disulfiram groups were informed about the disulfiram-ethanol reaction; the riboflavin group was not. One trial1 (N = 605) found no difference between groups for abstinence in its main analyses but reported fewer drinking days with disulfiram, 250 mg, than in other groups for the subsample who drank and had complete assessments. The other trial2 (N = 128) reported similar rates of abstinence for the disulfiram groups (21% and 25%) but lower rates with riboflavin (12%). Given the findings and limitations of trials, guidelines reasonably recommend “to consider offering disulfiram … for service users who have a goal of abstinence but for whom acamprosate and oral naltrexone are not suitable, or prefer disulfiram and understand the … risks.”3 In response to Dr Beresford, we did not conduct metaanalyses of questionable studies. Instead, we evaluated studies using established methods to assess risk of bias and only included studies with low or medium risk in our main analyses. The claim that European trials had far lower placebo rates is incorrect. The European trials had a mean placebo response of 19.3% (range, 7.1%-40%) compared with 14.6% (range, jama.com
7.7%-18.4%) in the US trials (return to any drinking for acamprosate, Figure F-2 of our larger technical report for the Agency for Healthcare Research and Quality on which the article was based). Regarding statistical and clinical significance, our main meta-analyses focused on clinically significant events (eg, return to any drinking) rather than on continuous or standardized measures. We found clinically and statistically significant improvements for acamprosate and oral naltrexone, with numbers needed to treat (NNTs) from 12 to 20. Regarding partial support for an inconsistently observed effect, the data show that the medications work for some people but not everyone, suggesting heterogeneity of treatment effects. Many medications have NNTs similar to or worse than those for naltrexone and acamprosate (eg, NNTs of 14 over 2.2 years for aspirin after transient ischemic attacks to prevent death or stroke and 96 over 5 years for isoniazid for latent tuberculosis to prevent active tuberculosis).4 In response to Dr Caputo and colleagues, we recognize nalmefene’s European approval. We categorized medications based on Food and Drug Administration (FDA) approval status. Nalmefene is not approved by the FDA. We agree that nalmefene can have an important role because evidence shows improvement in some consumption outcomes (including trials that assessed as-needed dosing5,6). There is controversy about harm reduction because many clinicians believe that abstinence is the only appropriate goal. However, for patients unwilling to consider abstinence, reducing heavy drinking may be a reasonable goal. Daniel E. Jonas, MD, MPH Cynthia Feltner, MD, MPH James C. Garbutt, MD Author Affiliations: Department of Medicine, University of North Carolina, Chapel Hill (Jonas, Feltner); Department of Psychiatry, University of North Carolina, Chapel Hill (Garbutt). Corresponding Author: Daniel E. Jonas, MD, MPH, University of North Carolina at Chapel Hill, Department of Medicine, 5034 Old Clinic Bldg, Chapel Hill, NC 27599 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Fuller RK, Branchey L, Brightwell DR, et al. Disulfiram treatment of alcoholism: a Veterans Administration cooperative study. JAMA. 1986;256(11): 1449-1455. 2. Fuller RK, Roth HP. Disulfiram for the treatment of alcoholism: an evaluation in 128 men. Ann Intern Med. 1979;90(6):901-904. 3. National Institute for Health and Care Excellence. Alcohol-use disorders: diagnosis, assessment and management of harmful drinking and alcohol dependence. http://www.nice.org.uk/guidance/CG115/chapter /1-Guidance#interventions-for-alcohol-misuse. Accessed July 16, 2014. 4. Laupacis A, Sackett DL, Roberts RS. An assessment of clinically useful measures of the consequences of treatment. N Engl J Med. 1988;318(26):17281733. 5. Gual A, He Y, Torup L, van den Brink W, Mann K; ESENSE 2 Study Group. A randomised, double-blind, placebo-controlled, efficacy study of nalmefene, as-needed use, in patients with alcohol dependence. Eur Neuropsychopharmacol. 2013;23(11):1432-1442. 6. Mann K, Bladström A, Torup L, Gual A, van den Brink W. Extending the treatment options in alcohol dependence: a randomized controlled study of as-needed nalmefene. Biol Psychiatry. 2013;73(8):706-713. JAMA October 1, 2014 Volume 312, Number 13
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In Reply We agree with Dr Beresford that patient-centered care with shared decision making is not a new concept in medicine. However, patient-centered care is not currently the routine approach to management of alcohol use disorders in medical settings. Instead, referral to specialty treatment is often recommended for patients diagnosed with alcohol use disorders.1 Therefore, we outlined treatments for alcohol use disorders, supported by randomized clinical trials, that have been recommended in evidence-based clinical practice guidelines developed by the UK National Institute of Clinical Effectiveness, as well as those developed by the US Department of Veterans Affairs and the Department of Defense. 2,3 Currently, only about 8% of US adults with alcohol use disorders receive treatment.4 Offering patients different treatment options could increase the proportion of patients engaged in treatment.
Aref A. Bin Abdulhak, MD Abdur Rahman Khan, MD Alan P. Wimmer, MD
Katharine Bradley, MD, MPH Daniel Kivlahan, PhD Author Affiliations: Group Health Research Institute, Seattle, Washington (Bradley); Department of Veterans Affairs, Seattle, Washington (Kivlahan). Corresponding Author: Katharine Bradley, MD, MPH, Group Health Research Institute, 1730 Minor Ave, Seattle, WA 98101 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Bradley reporting having grants pending from the National Institute on Alcohol Abuse and Alcoholism and owning stock in Johnson and Johnson, AbbVie, and Pfizer. Dr Kivlahan reported no disclosures. 1. Substance Abuse and Mental Health Services Administration. Systems-level implementation of screening, brief intervention, and referral to treatment: Technical Assistance Publication Series. http://store.samhsa.gov/product /TAP-33-Systems-Level-Implementation-of-Screening-Brief-Intervention -and-Referral-to-Treatment-SBIRT-/SMA13-4741. Accessed July 15, 2014. 2. National Institute for Health and Care Excellence. Alcohol-use disorders: diagnosis, assessment and management of harmful drinking and alcohol dependence. http://www.nice.org.uk/guidance/CG115. Accessed July 15, 2014. 3. VA Office of Quality and Performance. VA/DoD clinical practice guideline for management of substance use disorders. http://www.healthquality.va.gov /guidelines/MH/sud/sud_full_601f.pdf. Accessed July 15, 2014. 4. Substance Abuse and Mental Health Services Administration. Results from the 2012 National Survey on Drug Use and Health: summary of national findings and detailed tables. http://www.samhsa.gov/data/NSDUH /2012SummNatFindDetTables/Index.aspx. Accessed July 15, 2014.
Azithromycin for Elderly Patients With Pneumonia To the Editor Dr Mortensen and colleagues1 conducted a retrospective cohort study that evaluated the risk of death with azithromycin use in elderly patients with pneumonia in comparison with other guideline-recommended antibiotics. Azithromycin use was associated with a statistically significant decrease in mortality at 10, 30, and 90 days. However, prior studies in elderly populations have shown an increase in mortality from any cause associated with current use of azithromycin, defined as within 1 to 5 days of therapy.2,3 Mortensen and colleagues did not report the risk of death associated with current use of azithromycin. Ray et al2 found that azithromycin use was not associated with a statistically significant difference in the risk of death during the first 10 days of therapy; however, when their analy1352
sis was limited to current azithromycin use, the risk of death was higher among azithromycin-treated patients. Similarly, Rao et al3 reported a higher risk of death with current azithromycin use, but no significant association was observed during days 6 to 10 of therapy. The mechanism of increased risk is thought to be a proarrhythmic effect of the medication, which would be expected to occur during the first 5 days of therapy when drug levels are at their highest. In addition, Mortensen and colleagues excluded from their analysis deaths that occurred on the day of admission and provided no information on whether the patients who died received azithromycin. Not including early deaths that may have occurred as an adverse effect of the medication on initial exposure in susceptible patients may have biased their results in favor of a longer-term mortality benefit among elderly patients treated with azithromycin.
Author Affiliations: Department of Medicine, University of Missouri, Kansas City (Bin Abdulhak); Department of Medicine, University of Toledo Medical Center, Toledo, Ohio (Khan); Saint Luke’s Mid America Heart Institute, University of Missouri, Kansas City (Wimmer). Corresponding Author: Alan P. Wimmer, MD, Saint Luke’s Mid America Heart Institute, University of Missouri, Kansas City, 4330 Wornall Rd, Kansas City, MO 64111 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Mortensen EM, Halm EA, Pugh MJ, et al. Association of azithromycin with mortality and cardiovascular events among older patients hospitalized with pneumonia. JAMA. 2014;311(21):2199-2208. 2. Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death. N Engl J Med. 2012;366(20):1881-1890. 3. Rao GA, Mann JR, Shoaibi A, et al. Azithromycin and levofloxacin use and increased risk of cardiac arrhythmia and death. Ann Fam Med. 2014;12(2):121-127.
In Reply Regarding the concern of Dr Bin Abdulhak and colleagues about examining shorter periods than 10 days after admission, we consider follow-up durations longer than 5 days to be more clinically relevant and important. Although there may be an increased risk of arrhythmias earlier due to the use of azithromycin, we doubt that clinicians or patients would then avoid this medication when there is a clinically significant survival advantage at 90 days. However, we have repeated our analyses for the outcomes of any cardiovascular events and all-cause mortality within 5 days of admission and found results similar to those at 10 days reported in our article. There was significantly improved mortality (odds ratio, 0.75; 95% CI, 0.69-0.72) and a small but significant increase in any cardiovascular event (odds ratio, 1.06; 95% CI, 1.03-1.09). Therefore, we are confident in our published conclusions. We did not exclude patients who died on the day of admission from all analyses; these patients were only excluded from the Kaplan-Meier graphs because this statistical technique excludes those who exit the cohort on the same day as study entry.1
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