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Management of Acute Appendicitis, Comparative Effectiveness Research, and the Nuances of Study Design

Management of Acute Appendicitis, Comparative Effectiveness Research, and the Nuances of Study... To the Editor I commend Minneci and colleagues1 for taking an efficacious treatment and studying its effectiveness. They developed a unique study design in which patients were not randomly assigned to a treatment but were prospectively enrolled (if they met inclusion criteria) and then allowed to choose which treatment they preferred. This very likely aligns with the “real-world” nonoperative management of appendicitis, and experts have called for such investigations so that we may begin to understand whether outcomes are meaningfully improved when an antibiotics-first approach is compared with a therapy as safe and definitive as laparoscopic appendectomy.2 The difference in the rates of complicated appendicitis between patients who chose nonoperative management and patients who underwent surgery is notable (1 of 37 children [2.7%] vs 8 of 65 children [12.3%], respectively). Although not statistically significant, the difference may be a type II error given the small study size. If so, this difference between study groups may also reflect the study’s nonrandomized design. Some parents, viewing the severity of their child’s illness (even those who met inclusion criteria), may have chosen the more “definitive” therapy, whereas those parents whose children seemed less ill may have preferred a less invasive therapy. Moreover, the clinicians themselves, subtly biased by how sick or benign a child appeared, may have unconsciously swayed parents one way or another as they explained the risks and benefits of each treatment. Markers of clinical severity were similar between groups (fever, leukocytosis, and duration of symptoms), but the study was not powered to detect differences in these variables. One hastens to add that the “gold standard” diagnosis—a pathology specimen—was only available in the operative group, so some nonoperative patients with small perforations (ie, “microperforations”) may have gone undetected, deceptively reducing the number of patients with complicated appendicitis. This is unavoidable in studies of nonoperative management (there is a similar challenge with “negative appendectomies”). It would be interesting to know how many of the 8 surgery patients with complicated appendicitis had a gangrenous appendix or large perforation vs those with a microperforation that may never have become clinically significant. Minneci and colleagues1 discuss why their 1-year success rate of 75.7% exceeded that of Svensson et al,3 which was 66%. They attribute this to more stringent inclusion criteria. An additional possibility is that clinical judgment and parental intuition also played a role (a bias obviated by the randomized design of the study by Svensson et al3). These comments should not be construed as criticism—far from it. This study1 adds important real-world data to the discussion of the nonoperative management of appendicitis. Rather, a simple word of caution: nonrandomized studies, by definition, introduce bias. Although not conclusive, there is compelling circumstantial evidence that good clinical judgment and close consultation with patients and families influenced decision making. This is exactly as it should be, but these aspects of study design must be emphasized as others apply the results in clinical practice. Back to top Article Information Corresponding Author: Frederick Thurston Drake, MD, MPH, Division of Endocrine Surgery, Department of Surgery, University of California–San Francisco, 1600 Divisadero St, Hellman Bldg, Room C347, San Francisco, CA 94115 (frederick.drake@uscsf.edu). Published Online: April 13, 2016. doi:10.1001/jamasurg.2016.0477. Conflict of Interest Disclosures: None reported. References 1. Minneci PCMahida JB, Lodwick DL, et al. Effectiveness of patient choice in nonoperative vs surgical management of pediatric uncomplicated acute appendicitis [published online December 16, 2015]. JAMA Surg. doi:10.1001/jamasurg.2015.4534.Google Scholar 2. Flum DR. Clinical practice: acute appendicitis—appendectomy or the “antibiotics first” strategy. N Engl J Med. 2015;372(20):1937-1943.PubMedGoogle ScholarCrossref 3. Svensson JF, Patkova B, Almström M, et al. Nonoperative treatment with antibiotics versus surgery for acute nonperforated appendicitis in children: a pilot randomized controlled trial. Ann Surg. 2015;261(1):67-71.PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Surgery American Medical Association

Management of Acute Appendicitis, Comparative Effectiveness Research, and the Nuances of Study Design

JAMA Surgery , Volume 151 (8) – Aug 1, 2016

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Publisher
American Medical Association
Copyright
Copyright © 2016 American Medical Association. All Rights Reserved.
ISSN
2168-6254
eISSN
2168-6262
DOI
10.1001/jamasurg.2016.0477
pmid
27074110
Publisher site
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Abstract

To the Editor I commend Minneci and colleagues1 for taking an efficacious treatment and studying its effectiveness. They developed a unique study design in which patients were not randomly assigned to a treatment but were prospectively enrolled (if they met inclusion criteria) and then allowed to choose which treatment they preferred. This very likely aligns with the “real-world” nonoperative management of appendicitis, and experts have called for such investigations so that we may begin to understand whether outcomes are meaningfully improved when an antibiotics-first approach is compared with a therapy as safe and definitive as laparoscopic appendectomy.2 The difference in the rates of complicated appendicitis between patients who chose nonoperative management and patients who underwent surgery is notable (1 of 37 children [2.7%] vs 8 of 65 children [12.3%], respectively). Although not statistically significant, the difference may be a type II error given the small study size. If so, this difference between study groups may also reflect the study’s nonrandomized design. Some parents, viewing the severity of their child’s illness (even those who met inclusion criteria), may have chosen the more “definitive” therapy, whereas those parents whose children seemed less ill may have preferred a less invasive therapy. Moreover, the clinicians themselves, subtly biased by how sick or benign a child appeared, may have unconsciously swayed parents one way or another as they explained the risks and benefits of each treatment. Markers of clinical severity were similar between groups (fever, leukocytosis, and duration of symptoms), but the study was not powered to detect differences in these variables. One hastens to add that the “gold standard” diagnosis—a pathology specimen—was only available in the operative group, so some nonoperative patients with small perforations (ie, “microperforations”) may have gone undetected, deceptively reducing the number of patients with complicated appendicitis. This is unavoidable in studies of nonoperative management (there is a similar challenge with “negative appendectomies”). It would be interesting to know how many of the 8 surgery patients with complicated appendicitis had a gangrenous appendix or large perforation vs those with a microperforation that may never have become clinically significant. Minneci and colleagues1 discuss why their 1-year success rate of 75.7% exceeded that of Svensson et al,3 which was 66%. They attribute this to more stringent inclusion criteria. An additional possibility is that clinical judgment and parental intuition also played a role (a bias obviated by the randomized design of the study by Svensson et al3). These comments should not be construed as criticism—far from it. This study1 adds important real-world data to the discussion of the nonoperative management of appendicitis. Rather, a simple word of caution: nonrandomized studies, by definition, introduce bias. Although not conclusive, there is compelling circumstantial evidence that good clinical judgment and close consultation with patients and families influenced decision making. This is exactly as it should be, but these aspects of study design must be emphasized as others apply the results in clinical practice. Back to top Article Information Corresponding Author: Frederick Thurston Drake, MD, MPH, Division of Endocrine Surgery, Department of Surgery, University of California–San Francisco, 1600 Divisadero St, Hellman Bldg, Room C347, San Francisco, CA 94115 (frederick.drake@uscsf.edu). Published Online: April 13, 2016. doi:10.1001/jamasurg.2016.0477. Conflict of Interest Disclosures: None reported. References 1. Minneci PCMahida JB, Lodwick DL, et al. Effectiveness of patient choice in nonoperative vs surgical management of pediatric uncomplicated acute appendicitis [published online December 16, 2015]. JAMA Surg. doi:10.1001/jamasurg.2015.4534.Google Scholar 2. Flum DR. Clinical practice: acute appendicitis—appendectomy or the “antibiotics first” strategy. N Engl J Med. 2015;372(20):1937-1943.PubMedGoogle ScholarCrossref 3. Svensson JF, Patkova B, Almström M, et al. Nonoperative treatment with antibiotics versus surgery for acute nonperforated appendicitis in children: a pilot randomized controlled trial. Ann Surg. 2015;261(1):67-71.PubMedGoogle ScholarCrossref

Journal

JAMA SurgeryAmerican Medical Association

Published: Aug 1, 2016

References