Clinical Gastroenterology and Hepatology 2015;13:2023–2028

LETTERS TO THE EDITOR Readers are encouraged to write letters to the editor concerning articles that have been published in Clinical Gastroenterology and Hepatology. Short, general comments are also considered, but use of the Letters to the Editor section for publication of original data in preliminary form is not encouraged. Letters should be typewritten and submitted electronically to http://www. editorialmanager.com/cgh.

Weight Loss Is Truly Effective in Reducing Symptoms and Proton Pump Inhibitor Use in Patients With Gastroesophageal Reflux Disease

important to bear in mind that weight loss management has to be associated with a cognitive-behavior therapeutic approach with a tight scheduled follow-up evaluation to obtain a high percentage of adherence to a weight loss protocol. NICOLA DE BORTOLI, MD Division of Gastroenterology Department of Translational Research and New Technology in Medicine and Surgery University of Pisa Pisa, Italy

Dear Editor: We read with interest the study by Ness-Jensen et al,1 which was a narrative review providing appraisal of data from meta-analyses, systematic reviews, randomized clinical trials, and prospective observational studies (from 1946 to October 2014) on the role of lifestyle interventions in gastroesophageal reflux disease (GERD). The authors concluded that weight loss and tobacco smoking cessation should be recommended to GERD patients who are obese and smoke, respectively. Moreover, they stated that avoiding late evening meals and head of the bed elevation is effective in nocturnal GERD. We congratulate the authors because data on this topic are limited and unclear, and an explanatory review was absolutely necessary. In particular, the relevance of weight loss in overweight/obese patients with reflux symptoms is controversial, although the role of body mass index as a risk factor for GERD has been highlighted in several articles and reviews.2–4 In keeping, we wonder that not all the available studies in literature have been quoted since we recently published data from a comparative, prospective, nonrandomized study analyzing the efficacy of a hypocaloric diet and physical exercise vs a standard-of-care dietetic program without any change in daily caloric intake, in patients with reflux symptoms and an endoscopically proven erosive esophagitis.5 We showed that weight loss, obtained through a tailored dietetic program and increased aerobic exercise (101 patients enrolled), was as follows: (1) associated with a reduction in body mass index, and waist and hip circumference; (2) associated with a higher reduction of GERD-related typical symptoms; and (3) able to obtain a reduction/discontinuation of proton pump inhibitor dosage.5 Showing that reducing weight loss leads patients with GERD to reduce medication intake, we speculated that this kind of intervention may further reduce the National Health System costs as a direct consequence.5 In summary, our data confirm that lifestyle interventions and in particular a 10% weight loss is truly effective in reducing symptoms and PPI use in patients with GERD. This suggestion also has been corroborated by the recent European guideline for management of obesity and overweight in adults.6 However, it is

SALVATORE TOLONE, MD, PhD Division of Surgery, Department of Surgery Second University of Naples Naples, Italy EDOARDO V. SAVARINO, MD, PhD Division of Gastroenterology, Department of Surgery Oncology and Gastroenterology University of Padua Padua, Italy

References 1.

Ness-Jensen E, et al. Clin Gastroenterol Hepatol 2015 Epub ahead of print.

2.

El-Serag H. Dig Dis Sci 2008;53:2307–2312.

3.

Savarino E, et al. Dig Liver Dis 2011;43:940–945.

4.

Savarino E, et al. J Gastroenterol 2012;47:159–168.

5.

de Bortoli N, et al. Dis Esophagus 2014 Epub ahead of print.

6.

Tsigos C, et al. Obes Facts 2008;1:106–116.

Acknowledgments All authors are members of the Gruppo Italiano Studio Esofago. Conflicts of interest The authors disclose no conflicts. Most current article http://dx.doi.org/10.1016/j.cgh.2015.05.034

Risk of Upper and Lower Gastrointestinal Bleeding in Patients Taking Nonsteroidal Anti-Inflammatory Drugs, Antiplatelet Agents, or Anticoagulants Dear Editor: In the otherwise excellent article by Lanas et al,1 as with most other articles examining the putative role of nonsteroidal anti-inflammatory drugs (NSAIDs) in

2024 Letters to the Editor

gastrointestinal (GI) bleeding, I fear that insufficient attention is being paid to the differences among NSAIDs in half-life, and to the actual dosing regimens used in the patients studied. For some effects of NSAIDs, the duration of cyclooxygenase (COX) inhibition over the 24-hour period may be very important. This has been shown for renal function, in which roficoxib has more of an effect than celecoxib, and this has been attributed to COX inhibition around the clock with twice-daily administration of roficoxib (17-hour half-life) compared with incomplete inhibition with twice-daily administration of celecoxib (8- to 12-hour half-life.) With respect to the GI tract, COX-1 inhibition can affect various functions that are important in GI bleeding, from effects on platelets and coagulation to direct mucosal damage (particularly in the case of upper-GI bleeding). It is believed that proton pump inhibitors and H2-receptor antagonists can mitigate the direct toxicity of NSAIDs through their effects on acid secretion, but the effects of those agents on lower-GI bleeding, where gastric acid is not present, is minimal or nonexistent. NSAIDs also differ in their ability to damage the mucosa; for example, nabumetone is a prodrug that does not have a direct effect on gastric mucosa. In contrast to the ability of NSAIDs to cause mucosal damage to the upper-GI tract directly, the known effects of COX-1 inhibition on mucosal repair (epithelial cell regeneration and spreading) may be important in both upper- and lower-GI bleeding. Absent NSAIDs, mucosal repair proceeds rapidly. Therefore, periods of ineffective NSAID concentrations during the day may be of great importance in determining whether lesions persist, with an opportunity for bleeding to develop, or rapidly heal with reconstitution of mucosal integrity. This, then, leads to the importance of the consistency of COX-1 inhibition over the 24-hour period as a potential determinant of GI bleeding. Naproxen, with a half-life of 12 to 17 hours, provides 24-hour COX inhibition with twice-daily dosing, whereas ibuprofen and diclofenac, with half-lives of approximately 1 to 2 hours, provide only intermittent COX inhibition even when given 2 or 3 times a day. Just as important is the problem of dosing. Any NSAID, taken as needed, is unlikely to provide COX inhibition around the clock, and unlikely to have a large effect on causing or maintaining lesions with subsequent bleeding. The data presented by Lanas et al1 point to a wide variation in the amount of NSAIDs taken—possibly owing to unit dosing but also likely owing to frequency of dosing. The mean dose of ibuprofen was 909.8 mg, or approximately 4.5 tablets, but with a SD (apparently) of 465.4 mg; some patients were taking almost 2 g/day whereas others were taking only 1 to 2 tablets/day. Similarly large variations were reported for other NSAIDs in the study (diclofenac, aspirin, and naproxen). Given this large variation in dosing, probably involving both dosing intervals and amounts, and even knowing the

Clinical Gastroenterology and Hepatology Vol. 13, No. 11

half-life of the drugs, it is not possible to know what is really going on, what is contributing to the increase in bleeding, and what the actual jeopardy is from full or incomplete COX suppression. This does not mean that the data presented are not important. It is, rather, a plea for more careful attention to the details on the particular NSAID administered, the dose, and the exact dosing regimen in studies of this important problem. ROBERT H. PALMER, MD

Reference 1.

Lanas A, et al. Clin Gastroenterol Hepatol 2015;13:906–912.

Conflicts of interest The author discloses no conflicts. Most current article http://dx.doi.org/10.1016/j.cgh.2015.05.025

Reply. We greatly appreciate the insightful comments from Dr Palmer concerning our recently published study.1 We agree that the duration of cyclooxygenase (COX) inhibition over the 24hour period is important because it affects various mechanisms of the gastrointestinal (GI) mucosal defense and platelet inhibition and therefore affects the risk of bleeding. This has been reported already elsewhere.2,3 In contrast with clinical trials, in which nonsteroidal anti-inflammatory drug (NSAID) dosing is regular and induces a more constant inhibition of GI mucosal defense mechanisms and platelet inhibition, in our study we reported the association between clinical use of NSAIDs in the general population and GI bleeding. It is likely that in real-life, hospital admissions of patients with GI bleeding are associated with more irregular use and lower doses of NSAIDs than those used commonly in clinical trials. In addition, patients often take nonprescription over-thecounter NSAIDs, which increases the variability of use and makes it difficult to provide the actual dose and time of use, although this also can happen to some extent in clinical trials. In any case, this means that COX-1 inhibition in the GI tract and platelets may not be constant over time with NSAID use in real life, which should have an impact on the association with GI bleeding. Ibuprofen is the most frequent NSAID used and with a daily dose of 1200 mg or less (600 mg tablets twice daily) in more than 75% of cases, COX-1 the GI mucosa and platelets should be inhibited for limited periods of time during the daily 24 hours. Also, intensity of COX inhibition with that dose should be in the low range. In fact, our results are in agreement with these mechanistic hypotheses: adjusted odds ratios (ORs) of GI bleeding among patients on 1200 mg/day dose or less is not statistically significant (OR, 1.13; 95% confidence interval, 0.80–1.62) compared with nonuse, whereas patients on more than a 1200 mg/day dose presented with a significant increase of GI bleeding (adjusted OR, 8.21; 95% CI, 2.7–24.4). In a similar way, regular use of NSAIDs over time should have

Risk of Upper and Lower Gastrointestinal Bleeding in Patients Taking Nonsteroidal Anti-Inflammatory Drugs, Antiplatelet Agents, or Anticoagulants.

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