Alimentary Pharmacology and Therapeutics Letters to the Editors tor to suggest that flare rates are significantly higher in the comparator ‘switched’ group. The artificially low flare rate in the reference group can be explained by major flaws in the design leading to an ascertainment bias. From 10 717 eligible patients, in the full data set, only 40 patients are included in the reference group. Patients have been excluded from the analysis due to switching and simultaneously ‘doubling’ their dose. Asacol 400 mg is only licensed in the UK at a maximum dose of 2.4 g/day. As patients on maintenance therapy are often on 1.6 g/day, and a flare in this audit is determined by a doubling of the mesalazine (mesalamine) dose, physicians are unable to double the dose within the licensed indication. Therefore, Asacol 400 mg (which makes up most of Asacol maintenance therapy in the UK) may be switched to a mesalazine with a higher licensed dose. As such, patients who flared on Asacol were removed from the reference group data. Additionally, GPs can often switch patients’ mesalazine brand when they become symptomatic, as a first course of action, without doubling the dose. These patients would not be deemed to flare in the reference group, but deemed to flare following switching, and included as a flare in the comparison group, further biasing the analysis. The patient disposition has not been adequately discussed in this paper to determine why only 40 patients were included in the reference group. In addition, no baseline demographics are provided for the 2 groups and whether these are balanced for confounding factors such as disease state. The statistical methods used by the authors also lead to a bias in the direction of finding a positive
Letter: switches of 5-aminosalicylates in ulcerative colitis, risk of relapse and ascertainment bias – authors’ reply A. Robinson*, M. Hankins†, G. Wiseman‡ & M. Jones§ *Salford Royal NHS Foundation Trust, Salford, UK. † Faculty of Health Sciences, University of Southampton, Southampton, UK. ‡ Medical Affairs, Warner Chilcott UK Ltd, Weybridge, UK. § Health Informatics Research, Sciensus Ltd, Brighton, UK. E-mail: [email protected] doi:10.1111/apt.12593
Aliment Pharmacol Ther 2014; 39: 340-347 ª 2014 John Wiley & Sons Ltd
association between switching and flare. They are at considerable risk of confounding from two other sources. First, the longer the study, the more likely a patient will experience both a switch of treatment and a flare at some point. Secondly, subjects who have an intrinsically high rate of flare are more likely to switch treatment. Even ignoring the ascertainment bias and statistical methodology, the authors equate a doubling of medication possession ratio (MPR) as evidence of doubling of dose. MPR is a measure of compliance, not flare, as it is based on prescription days. Doubling the prescribed dose would therefore not double the MPR. Evidence of flare from prescription records, such as the prescribing physician increasing the dose, is not adequately discussed or covered by the MPR formulation presented in the paper. The paper does not represent a credible argument to provide evidence that there is an increased risk of relapse on switching and does not adequately address the flaws in the trial design leading to the ascertainment bias.
ACKNOWLEDGEMENT Declaration of personal and funding interests: None. REFERENCES 1. Robinson A, Hankins M, Wiseman G, Jones M. Maintaining stable symptom control in inflammatory bowel disease: a retrospective analysis of adherence, medication switches and the risk of relapse. Aliment Pharmacol Ther 2013; 38: 531–8. 2. Feagan BG, MacDonald JK. Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev 2012; 10: CD000544. 3. D‘Haens G, Sandborn WJ, Barrett K, Hodgson I, Streck P. Oncedaily MMX() mesalamine for endoscopic maintenance of remission of ulcerative colitis. Am J Gastroenterol 2012; 107: 1064–77.
SIRS; We fully respect the opinions of Curtis et al.1 However, extensive acknowledgement of any study limitations can be found within the discussion section of our paper. The methodology used was relevant and appropriate, given the technical challenges of using dispensed drug records, and the study is neither biased nor flawed. It is important to note that the study is not a clinical trial; rather, it relates to a specific population of adherent patients who demonstrated sustained symptom stability prior to inclusion. Thus, it is expected that these patients are intrinsically less likely to experience disease relapse 345
Letters to the Editors when compared with a population with variable disease characteristics. Patients who were switched and their dose simultaneously doubled were excluded, because these actions were considered to be indicative of a naturally caused disease flare, not a medication switch. It is important to exclude these patients to avoid confounding factors. We accept the UK licensed indication for Asacol 400 mg modified release (MR) tablets. In this study, patients receiving Asacol 400 or 800 mg MR tablets during the baseline period were eligible for inclusion in the subgroup analyses. It is at the discretion of gastroenterologists if they wish to prescribe at higher doses to manage a disease relapse. The use of a doubling in medication possession ratio as a proxy index of flare is justified, given that it is unlikely that we would see a pattern of doubling in adherence in the absence of any other changes. In addition, using this proxy measure, we show that non-adherence is strongly linked to risk of relapse, which is consistent with currently available literature.2
Letter: effects of iron therapy after non-variceal acute upper gastrointestinal bleeding E. Bounford* & A. C. Ford*,† *Leeds Gastroenterology Institute, Leeds General Infirmary, Leeds, UK. † Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK. E-mail: [email protected] doi:10.1111/apt.12594
SIRS; We read the paper by Bager and Dahelrup with interest.1 The authors compared the effects of oral and intravenous iron therapy following non-variceal acute upper gastrointestinal haemorrhage (AUGIB) with placebo, and with each other. They demonstrated that both routes of administration of iron were superior to placebo in correcting anaemia post-AUGIB. However, we do not feel the authors’ conclusion that their findings ‘clearly indicate that iron supplementation is essential in anaemic non-variceal AUGIB patients’ are justified by the data. The rationale for iron supplementation in these patients relies on the finding in the study of Rockall et al. that
346
The results indicate an association between disease flare in ulcerative colitis and switch in mesalazine formulation, suggesting that caution should be advocated when considering switches for stable patients. Overall, issues raised emphasise the importance of understanding the complex relationship among treatment switches, adherence and patient self-managing behaviour.
ACKNOWLEDGEMENT The authors’ declarations of personal and financial interests are unchanged from those in the original article.3 REFERENCES 1. Curtis H, Jones S, Treasure P. Letter: switches of 5aminosalicylates in ulcerative colitis, risk of relapse and ascertainment bias. Aliment Pharmacol Ther 2014; 39: 344–5. 2. Kane S, Huo D, Aikens J, Hanauer S. Medication non adherence and the outcomes of patients with quiescent ulcerative colitis. Am J Med 2003; 114: 39–43. 3. Robinson A, Hankins M, Wiseman G, Jones M. Maintaining stable symptom control in inflammatory bowel disease: a retrospective analysis of adherence, medication switches and the risk of relapse. Aliment Pharmacol Ther 2013; 38: 531–8.
anaemic patients had a greater risk of rebleeding and mortality following AUGIB.2 Although the significant effect of iron on post-AUGIB haemoglobin levels in the patients in this trial is not disputed, the authors themselves acknowledge that ‘the exact impact and risk of being anaemic after AUGIB have not been investigated’. It therefore seems that this study has missed a unique opportunity to determine the clinical impact of anaemia in this group of patients. Given that the patients were followed up at 1, 4 and 13 weeks, inclusion of data items such as exercise tolerance, quality of life indicators and the prevalence of symptomatic anaemia would have lent greater support to the authors’ claim that iron treatment is both effective and essential post-AUGIB.
ACKNOWLEDGEMENT Declaration of personal and funding interests: None. REFERENCES 1. Bager P, Dahlerup JF. Randomised clinical trial: oral vs. intravenous iron after upper gastrointestinal haemorrhage – a placebo-controlled study. Aliment Pharmacol Ther 2014; 39: 176–87. 2. Rockall TA, Logan RF, Devlin HB, et al. Risk assessment after acute upper gastrointestinal haemorrhage. Gut 1996; 38: 316–21.
Aliment Pharmacol Ther 2014; 39: 340-347 ª 2014 John Wiley & Sons Ltd
Letter: switches of 5-aminosalicylates in ulcerative colitis, risk of relapse and ascertainment bias – authors’ reply A. Robinson*, M. Hankins†, G. Wiseman‡ & M. Jones§ *Salford Royal NHS Foundation Trust, Salford, UK. † Faculty of Health Sciences, University of Southampton, Southampton, UK. ‡ Medical Affairs, Warner Chilcott UK Ltd, Weybridge, UK. § Health Informatics Research, Sciensus Ltd, Brighton, UK. E-mail: [email protected] doi:10.1111/apt.12593
Aliment Pharmacol Ther 2014; 39: 340-347 ª 2014 John Wiley & Sons Ltd
association between switching and flare. They are at considerable risk of confounding from two other sources. First, the longer the study, the more likely a patient will experience both a switch of treatment and a flare at some point. Secondly, subjects who have an intrinsically high rate of flare are more likely to switch treatment. Even ignoring the ascertainment bias and statistical methodology, the authors equate a doubling of medication possession ratio (MPR) as evidence of doubling of dose. MPR is a measure of compliance, not flare, as it is based on prescription days. Doubling the prescribed dose would therefore not double the MPR. Evidence of flare from prescription records, such as the prescribing physician increasing the dose, is not adequately discussed or covered by the MPR formulation presented in the paper. The paper does not represent a credible argument to provide evidence that there is an increased risk of relapse on switching and does not adequately address the flaws in the trial design leading to the ascertainment bias.
ACKNOWLEDGEMENT Declaration of personal and funding interests: None. REFERENCES 1. Robinson A, Hankins M, Wiseman G, Jones M. Maintaining stable symptom control in inflammatory bowel disease: a retrospective analysis of adherence, medication switches and the risk of relapse. Aliment Pharmacol Ther 2013; 38: 531–8. 2. Feagan BG, MacDonald JK. Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev 2012; 10: CD000544. 3. D‘Haens G, Sandborn WJ, Barrett K, Hodgson I, Streck P. Oncedaily MMX() mesalamine for endoscopic maintenance of remission of ulcerative colitis. Am J Gastroenterol 2012; 107: 1064–77.
SIRS; We fully respect the opinions of Curtis et al.1 However, extensive acknowledgement of any study limitations can be found within the discussion section of our paper. The methodology used was relevant and appropriate, given the technical challenges of using dispensed drug records, and the study is neither biased nor flawed. It is important to note that the study is not a clinical trial; rather, it relates to a specific population of adherent patients who demonstrated sustained symptom stability prior to inclusion. Thus, it is expected that these patients are intrinsically less likely to experience disease relapse 345
Letters to the Editors when compared with a population with variable disease characteristics. Patients who were switched and their dose simultaneously doubled were excluded, because these actions were considered to be indicative of a naturally caused disease flare, not a medication switch. It is important to exclude these patients to avoid confounding factors. We accept the UK licensed indication for Asacol 400 mg modified release (MR) tablets. In this study, patients receiving Asacol 400 or 800 mg MR tablets during the baseline period were eligible for inclusion in the subgroup analyses. It is at the discretion of gastroenterologists if they wish to prescribe at higher doses to manage a disease relapse. The use of a doubling in medication possession ratio as a proxy index of flare is justified, given that it is unlikely that we would see a pattern of doubling in adherence in the absence of any other changes. In addition, using this proxy measure, we show that non-adherence is strongly linked to risk of relapse, which is consistent with currently available literature.2
Letter: effects of iron therapy after non-variceal acute upper gastrointestinal bleeding E. Bounford* & A. C. Ford*,† *Leeds Gastroenterology Institute, Leeds General Infirmary, Leeds, UK. † Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK. E-mail: [email protected] doi:10.1111/apt.12594
SIRS; We read the paper by Bager and Dahelrup with interest.1 The authors compared the effects of oral and intravenous iron therapy following non-variceal acute upper gastrointestinal haemorrhage (AUGIB) with placebo, and with each other. They demonstrated that both routes of administration of iron were superior to placebo in correcting anaemia post-AUGIB. However, we do not feel the authors’ conclusion that their findings ‘clearly indicate that iron supplementation is essential in anaemic non-variceal AUGIB patients’ are justified by the data. The rationale for iron supplementation in these patients relies on the finding in the study of Rockall et al. that
346
The results indicate an association between disease flare in ulcerative colitis and switch in mesalazine formulation, suggesting that caution should be advocated when considering switches for stable patients. Overall, issues raised emphasise the importance of understanding the complex relationship among treatment switches, adherence and patient self-managing behaviour.
ACKNOWLEDGEMENT The authors’ declarations of personal and financial interests are unchanged from those in the original article.3 REFERENCES 1. Curtis H, Jones S, Treasure P. Letter: switches of 5aminosalicylates in ulcerative colitis, risk of relapse and ascertainment bias. Aliment Pharmacol Ther 2014; 39: 344–5. 2. Kane S, Huo D, Aikens J, Hanauer S. Medication non adherence and the outcomes of patients with quiescent ulcerative colitis. Am J Med 2003; 114: 39–43. 3. Robinson A, Hankins M, Wiseman G, Jones M. Maintaining stable symptom control in inflammatory bowel disease: a retrospective analysis of adherence, medication switches and the risk of relapse. Aliment Pharmacol Ther 2013; 38: 531–8.
anaemic patients had a greater risk of rebleeding and mortality following AUGIB.2 Although the significant effect of iron on post-AUGIB haemoglobin levels in the patients in this trial is not disputed, the authors themselves acknowledge that ‘the exact impact and risk of being anaemic after AUGIB have not been investigated’. It therefore seems that this study has missed a unique opportunity to determine the clinical impact of anaemia in this group of patients. Given that the patients were followed up at 1, 4 and 13 weeks, inclusion of data items such as exercise tolerance, quality of life indicators and the prevalence of symptomatic anaemia would have lent greater support to the authors’ claim that iron treatment is both effective and essential post-AUGIB.
ACKNOWLEDGEMENT Declaration of personal and funding interests: None. REFERENCES 1. Bager P, Dahlerup JF. Randomised clinical trial: oral vs. intravenous iron after upper gastrointestinal haemorrhage – a placebo-controlled study. Aliment Pharmacol Ther 2014; 39: 176–87. 2. Rockall TA, Logan RF, Devlin HB, et al. Risk assessment after acute upper gastrointestinal haemorrhage. Gut 1996; 38: 316–21.
Aliment Pharmacol Ther 2014; 39: 340-347 ª 2014 John Wiley & Sons Ltd
