- Email: [email protected]
Factors that modify therapy adherence in patients with inflammatory bowel disease
Journal of Crohn's and Colitis (2010) 4, 422–426
available at www.sciencedirect.com
Factors that modify therapy adherence in patients with inflammatory bowel disease☆ Fernando Bermejo a,⁎, Antonio López-San Román b , Alicia Algaba a , Iván Guerra a , Paz Valer a , Silvia García-Garzón a , Belén Piqueras a , Carlos Villa a , Andrea Bermejo a , José L. Rodríguez-Agulló a a b
Department of Gastroenterology, Hospital Universitario de Fuenlabrada, Fuenlabrada, Madrid, Spain Department of Gastroenterology, Hospital Universitario Ramón y Cajal, Madrid, Spain
Received 1 November 2009; received in revised form 4 January 2010; accepted 18 January 2010 KEYWORDS Inflammatory bowel disease; Adherence; Therapy; Crohn's disease; Ulcerative colitis
Abstract Objectives: Inflammatory bowel disease is associated with a high risk of deficient adherence to therapy. Our study was designed to analyze the adherence to treatment in a specialized inflammatory bowel disease clinic, and to study which factors could influence it. Methods: 107 consecutive patients (64% Crohn's disease, 36% ulcerative colitis) filled up an anonymous survey with data on demography, disease, therapy and a self-applied adherence declaration. Results: A 69% (95%CI: 60–77%) showed some type of non-adherence. A 66% (95CI%: 57–75%) acknowledged some involuntary non-adherence: either forgetting to take their dose (63%) or being careless about having taken it (27%). A 16% (95CI%: 9–22%) showed some voluntary nonadherence: interrupting the therapy when feeling better (13%) or when feeling worse (6%). A 25% forgot at least a dose a week in the last 12 months. Multivariate analysis identified as risk factors for a lower adherence the dosing in three or more takes a day (OR 3; 95%CI: 1.1–8.4; p = 0.03) and feeling little informed about their disease (OR 4.9; 95%CI: 1.1–23.8; p = 0.04). Immunomodulator therapy predicted better adherence (OR 0.29; 95%CI: 0.11–0.74; p = 0.01). Conclusions: Adherence to therapy in inflammatory bowel disease patients is not satisfactory, and worse in patients treated with mesalazine. Optimizing the information on the disease and giving the medication in one or two daily doses could enhance therapeutic adherence. © 2010 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.
☆ Data presented previously at 4th Congress of ECCO, Hamburg, 2009 and Digestive Disease Week, 2009, Chicago and published as abstract in Journal of Crohn & Colitis 2009; 3: S49 and Gastroenterology 2009; 136 Supplement 1: A-680. ⁎ Corresponding author. Ríos Rosas 17, 28003 Madrid, Spain. Tel./fax: +34 916006175. E-mail address: [email protected] (F. Bermejo).
1. Introduction Adherence to therapy is a key aspect in determining the efficacy of a given drug in the clinical practice. The concept of adherence implies the active and informed participation of patients in any therapy-related decision, all of which should
1873-9946/$ - see front matter © 2010 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.crohns.2010.01.005
Adherence to therapy in inflammatory bowel disease
423
ensure an optimal follow-up.1,2 Thus, adherence is not the non-informed obedience to the physician's prescription, and a good adherence implies that both patient and physician work together to achieve a common goal, with the patient's opinion always being taken into account. A good adherence positively influences the results of a prescribed therapy. Adherence not only implies that the patient takes the correct dose at the correct times, but also that it is taken as directed, and it also encompasses other aspects (diet, lifestyle, substance abuse, etc.) that help to achieve a better quality of life. In diverse diseases, like essential hypertension, hypercholesterolemia or hepatitis C, a good adherence is key to the success of therapy, which makes it desirable to include some type of control in the follow-up of a given patient.3–5 Inflammatory bowel disease (IBD) is a clinical condition with a high risk of therapeutic non-adherence.6 Some of the factors that determine such a risk are its chronic nature, the frequency with which it attains young patients, the need for prolonged drug administration and the fact that its clinical course includes both symptomatic and asymptomatic periods.1 The aim of our study was to quantify the degree of therapeutic adherence in patients with IBD seen in a specialist clinic, and detect any factors that could modify it.
2. Methods To achieve our aim, we designed a prospective study, set in a specialized IBD Clinic in a University Hospital. During three months, we interviewed 107 patients diagnosed with IBD following the accepted criteria.7 The study was approved by the Ethical Committee of our centre. We excluded patients seen for the first time, patients seen urgently and those unable to understand or fill up the questionnaires. After informed consent was obtained, a structured written interview was done, anonymously and without the presence of any of the treating physicians. This interview included 1) Demographic data: age, gender, studies, working status, and marital status, 2) Data on the disease: type of IBD, year of diagnosis, number of hospital admissions, and number of IBD-related surgical procedures, 3) Data on their treatment: drugs, doses, and intervals, 4) Self-administered test on adherence to treatment (Table 1),1 5) Number of doses usually forgotten every week during the year preceding the survey, and reason for forgetting them, and 6) Self-medication. When relevant, data were
confirmed by consulting the Clinical Records. Additionally, the treating physician filled up a data sheet, containing all the relevant information about the patient's therapy, calculated the clinical activity index (Harvey–Bradshaw's for Crohn disease and Truelove–Witts' for ulcerative colitis).8,9 Data were analyzed with SPSS 15.0 (SPSS Inc., Chicago, IL, USA). For continuous variables, mean and standard deviation were calculated whenever the sample followed a normal distribution; in other cases, the median and the interquartile range (IQR) were used. For categorical variables, percentages and corresponding 95% confidence intervals (95% CI) were provided. A p value b0.05 was considered statistically significant. Continuous variables were compared with the ttest whenever the sample followed a normal distribution; in other cases, the Mann–Whitney U-test was used. Categorical variables were compared with chi-squared test, or Fisher's exact test in comparisons in which less than five registers were expected.
3. Results Main clinical characteristics of the study group are shown in Table 2. The test was correctly filled up by 100% of patients. A 66% of them (95CI%: 57–75%) acknowledged some degree of non-voluntary non-adherence. More specifically, a 63% agreed to the statement “I sometimes forget to take my medication”, whereas a 27% agreed to “I am sometimes careless about whether I have taken my medication”.
Table 2 Characteristics of inflammatory bowel disease patients who completed the survey. Number of patients Type of disease Age (mean ± standard deviation) Gender Duration of the IBD Activity of the IBD
Treatment for the IBD
Table 1 True/false questions used to explore adherence to treatment. 1 2 3 4
Did you sometimes forget to take your medication? Were you careless at times about taking your medication? When you felt better, did you sometimes stop taking your medication? If you felt worse when you took your medication, did you sometimes stop taking your medication?
True
False
True
False
True
False
True
False
Rectal therapy IBD-related hospital admission in the past IBD-related surgical procedure in the past Long term stable partnership Work outside the home Level of education
107 63.5% Crohn's disease, 35.5% ulcerative colitis 41.3 ± 11 years 60% female 6 years (IQR: 3–10) Crohn's disease: 70.5% inactive, 29.5% active Ulcerative colitis: 69% inactive, 31% active 66% aminosalicylates 51% azathioprine/mercaptopurine 8% glucocorticoids 13% mesalazine 66% with some hospital admission 17% with some surgical procedure 80% of patients 58% 18% 45% 27% 10%
of patients without studies primary studies medium studies university degree
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On the other hand, 16% of patients (95CI%: 9–22%) acknowledged some degree of voluntary non-adherence; more specifically, a 13% agreed to “sometimes I stopped my medication because I was feeling better”, and a 6% agreed to the statement “I sometimes stopped my medication because I was feeling worse”. Globally, a 69% of patients (95CI%: 60– 77%) showed some type of non-adherence. When we asked about the frequency and causes of nonadherence in the last 12 months (Table 3), we found a 25% (95CI%: 17–33%) of patients forgot at least one dose a week (median forgotten doses 1.6 per week, range 1–4). The percentage of these weekly medication omissions was higher with mesalazine (30%) than with azathioprine (17%) (n.s.). Different factors such as gender, time since diagnosis of IBD, previous IBD-related admissions or surgeries, or being in a stable affective relationship, did not correlate with the degree of adherence. There was also no association between non-adherence and disease type (p = 0.6), and clinical activity of disease (p = 0.56). On the other hand, patients treated with azathioprine showed better adherence that those receiving mesalazine (p = 0.005). In the multivariate analysis, risk factors for a lower adherence were medication scheduled in three or more daily doses (OR 3; 95CI% 1.1–8.4; p = 0.03) and patients who felt insufficiently informed about the disease (OR 4.9; 95CI% 1.1–23.8; p = 0.04); on the contrary, therapy with immunomodulators predicted a better degree of adherence (OR 0.29; 95CI% 0.11–0.74; p = 0.01). When analyzing factors specifically and independently associated with the type of non-adherence, therapy with immunomodulators was a protective factor against both voluntary and involuntary non-adherence. Administration of the medication in three or more daily doses was a risk factor for involuntary non-adherence (Table 4). Patient's and physician's enumeration of the prescribed drugs and doses were concordant in 86% of cases; in 10.3% they did not agree in the prescribed doses and in the remaining 3.7% there were differences between the actual therapy and the patient's recall. A 9% acknowledged selfmedication during flares (4% with mesalazine, 4% with steroids, and 1% with alternative therapies).
4. Discussion Treatment compliance in clinical trials on IBD varies between 70 and 95%10,11; however, trials are an ideal situation, in which patient and therapy supervision is way more intense than usual. Treatment adherence in real life is noticeably lower, with the percentage of non-adherent patients ranging
Table 3 Frequency and causes of forgetting medication in the last 12 months. Frequency
Causes
75.7 % less than one dose a week 14% one dose a week 6.5% two doses a week 2.8% three doses a week 1% four doses a week
39% 27% 19% 15%
being out of home simple forgetfulness being at work being a weekend
Table 4 Multivariate analysis of the risk factors related with the adherence to therapy. Factors: odds ratio; 95CI%; p Some type of non-adherence
Involuntary non-adherence
Voluntary non-adherence
Therapy with immunomodulators: OR 0.29; 0.11–0.74; p = 0.01 Medication scheduled in 3 or more daily doses: OR 3; 1.1–8.4; p = 0.03 Patients insufficiently informed: OR 4.9; 1.1–23.8; p = 0.04 Therapy with immunomodulators: OR 0.41; 0.17–0.98; p = 0.04 Medication scheduled in 3 or more daily doses: OR 2.8; 1.05–7.4; p = 0.03 Patients insufficiently informed: OR 2.9; 0.7–11; p = 0.11 Therapy with immunomodulators: OR 0.28; 0.09–0.91; p = 0.03 Medication scheduled in 3 or more daily doses: OR 0.66; 0.2–2.1; p = 0.48 Patients insufficiently informed: OR 2.6; 0.7–9.3; p = 0.12
from 35 to 87%.1,10–18 Thus, a significant percentage of patients do not experience the whole potential benefit of their therapy2,6 and we can mistakenly label as “nonresponder” a patient who, in reality, is not taking the correct amount of medication in a proper way. Non-adherence is significant whenever it determines a change in the therapeutic effect intended when prescribing the drug. The significant level of non-adherence is thus different from drug to drug, and even from disease to disease. A very strict adherence is advisable in drugs with a short halflife and exerting their actions through narrowly regulated plasmatic levels. Practical examples would be antiepileptic or antiarrhytmic drugs. The action of other drugs is less strictly regulated, and depend more on biological than on chemical effects. Adherence is still important, but not as determining. Examples could be antibiotics, hypolipemiants or immunomodulators. A limit of 80% of the prescribed dose has been agreed upon as a convention in clinical trials, but it is far to be applicable to every drug and every situation. The only true exponent of the adequacy of a certain level of adherence is the observation of its effect (or lack of it) in the attempted therapeutic goals. Differentiating voluntary non-adherence (after own conscious decision) and involuntary non-adherence (due to forgetfulness or carelessness) is useful to be able to lay out a strategy aiming at the correction of the problem. Sewitch and co-workers describe a prevalence of non-adherence reaching 41%, involuntary in two thirds of cases.1 D'Inca and co-workers communicate a similar prevalence of nonadherence (39%), involuntary in 61% of cases.16 The magnitude of involuntary non-adherence described by these authors is similar to what we have observed (66%). Different strategies could address this involuntary nonadherence,19 such as medication reminders that can use newer technologies such as short mobile phone messages, mechanical alarms (phone, watch, etc.) and e-mail, or
Adherence to therapy in inflammatory bowel disease simply employ traditional reminders (storing medication close to objects used on a daily basis, like the breakfast mug or the toothbrush. More sophisticated options are calendar blisters and pill boxes that can hold supplies for up to one month.6 All these possibilities can be employed in the group of patients in which therapy non-adherence is just involuntary (27% in our series), or related to situations such as being away from home (39%), being at work (19%) or simply weekends (15%). Voluntary non-adherence is less frequent, but its significance is greater, due to the implication of an active decision by the patient. In our series, 16% of patients presented voluntary non-adherence, slightly less than what has been described by other authors.1,13,16 Patient education and empowering19 could reverse this situation, through the optimization of the information made available to the patient, ongoing medical education20 and highlighting potential benefit of therapy, for instance colorectal cancer prevention through mesalazine.21,22 In our patients, immunomodulator therapy predicted a better adherence to treatment; we also described a tendency of a more likely forgetfulness in patients treated with mesalazine than with azathioprine, (30 vs. 17%), as described by Bernal and co-workers (45 vs. 25%).14 It has been postulated, that the quantification of drug or metabolite levels in blood (6-tioguanine nucleotides for thiopurines) or urine (salicylates) could be useful in asserting adherence to treatment.13,15,23 In a survey on 65 Crohn's disease patients treated with azathioprine or mercaptopurine, only 9.2% showed levels of metabolites indicative of non-adherence.24 The reason for a better adherence in patients taking immunomodulators could be determined either by the more severe disease that these patients suffer, or by the patients' impression that this treatment should be handled more carefully, because of its potential toxicity. Also, these patients are subject to a closer medical control due to follow-up and monitoring visits, which could exert a positive effect on adherence. Different possible risk factors for non-adherence have been described in IBD patients.1,13,16,18,19,23 Some of them depend on the disease itself (inactive disease, longer duration of disease, recently diagnosed cases, patients treated with multiple drugs, three daily dose schedules, and rectal administration of the drug). Others depend on the patient himself or herself: persons who are not in a stable affective relationship, male, full time employees, patients who do not trust their physician, patients who have been insufficiently informed. The identification of at-risk patients is in no doubt interesting to concentrate surveying in the subset of cases that are exposed to a higher non-compliance risk. In our series, factors predicting a lower adherence were the distribution of the drug in three or more daily doses (that made the risk three fold higher) and feeling insufficiently informed about the disease (with an almost five-fold increase of non-adherence risk). A fundamental aspect that could ameliorate compliance in any therapy is the simplification of treatment administration. Schedules every 24 or 12 h result in a higher adherence.23,25 A review of studies measuring therapy compliance confirmed that the number of daily doses inversely correlates to compliance.25 In IBD patients, the full dose of thiopurine immunomodulators can be administered in a single dose; several recent contribu-
425 tions have shown that a single daily dose of mesalazine has a similar effectiveness to fractioned doses, on a short26 as well as on a long term.27 Similar results have been described with Multimatrix®, a new mesalazine formulation.28 As to the importance of the information the patient gets about his or her disease, to optimize its accuracy and understandability is a key aspect to enhance adherence to therapy.6 Ideally, the patient should be provided both with verbal and written information, and the allowance of a relaxed and unhurried interview with the caring physician is desirable. The participation in talks and meetings, the contact with patient organizations and a proper use of Internet resources, should be always encouraged. In our patients, the patient–physician concordance was quite high, regarding the administered therapy. The treatment-related behaviour is influenced, among others, by the knowledge the patient possesses about the disease, the acceptance of therapy, fears about the treatment and the patient–physician relationship.29 All these factors influence concordance and condition the degree of adherence to therapy. Self-medication during a flare-up was acknowledged by 9% of our patients. An informed reaction can empower the patient to react against a flare, probably shortening its duration and consequences. It has been shown in controlled studies, that when patients were instructed on how to act if a flare developed, this resulted in less and shorter medical visits, and a more limited duration of the symptoms.30,31 These instructions to follow when confronted with a worsening disease are better established in ulcerative colitis, and almost absent in Crohn's disease. Increasing the dose of salicylates is an effective measure that should be encouraged, but self-adjustment of glucocorticoid therapy is not recommendable and usually leads to a higher exposure and increased adverse effects. In conclusion, adherence to therapy in IBD patients is not satisfactory in our setting. Our results are in agreement with previous observations in a number of aspects. We confirm that involuntary non-adherence is higher than voluntary nonadherence, and the figures observed by us are similar to other experiences.1,16 We are also able to reaffirm that immunomodulator therapy predicts a better adherence14 and a lower rate of forgotten doses, possibly influenced by the patient's perception of this being a “more powerful” therapy. Our study suggests that we should make a closer control of patients treated with salicylates. There are two predictors of non-adherence, namely the prescription of three or more daily doses, and insufficient information, that are of utmost importance, because they can be easily targeted and modified, presumably leading to a better compliance. Optimizing the information on the disease and giving the medication in one or two daily doses could enhance therapeutic adherence in IBD patients.
Acknowledgement Alicia Algaba benefited from a grant by Schering-Plough Spain. Statement of authorship: study conception and design: FB, AL. Data collection: FB, AA, IG. Statistical analysis: FB, AA. Drafting of article: FB, AL. Clinical revision: IG, PV, SG, BP, CV, AB, JR. All authors read and approved the final manuscript.
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References 18. 1. Sewitch MJ, Abrahamowicz M, Barkun A, Bitton A, Wild GE, Cohen A, et al. Patient nonadherence to medication in inflammatory bowel disease. Am J Gastroenterol 2003;98:1535–44. 2. Kane S, Huo D, Aikens J, Hanauer S. Medication nonadherence and the outcomes of patients with quiescent ulcerative colitis. Am J Medicine 2003;114:39–43. 3. Schroeder K, Fahey T, Ebrahim S. How can we improve adherence to blood pressure-lowering medication in ambulatory care? Systematic review of randomized controlled trials. Arch Intern Med 2004;164:722–32. 4. Pasternak RC. Report of the Adult Treatment Panel III: the 2001 National Cholesterol Education Program guidelines on the detection, evaluation and treatment of elevated cholesterol in adults. Cardiol Clin 2003;21:393–8. 5. Levy RL, Feld AD. Increasing patient adherence to gastroenterology treatment and prevention regimens. Am J Gastroenterol 1999;94:1733–42. 6. Robinson A. Review article: improving adherence to medication in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2008;27(Suppl 1):9–14. 7. Lennard-Jones JE. Classification of inflammatory bowel disease. Scand J Gastroenterol 1989;170(Suppl):2–6. 8. Harvey RF, Bradshaw JM. A simple index of Crohn's-disease activity. Lancet 1980 Mar 8;1:514. 9. Truelove SC, Witts LJ. Cortisone in ulcerative colitis. Final report on a therapeutic trial. Br Med J 1955;2:1041–8. 10. Kane SV, Cohen RD, Aikens JE, Hanauer SB. Prevalence of nonadherence with maintenance mesalamine in quiescent ulcerative colitis. Am J Gastroenterol 2001;96:2929–33. 11. Kane SV. Systematic review: adherent issues in the treatment of ulcerative colitis. Aliment Pharmacol Ther 2006;23:577–85. 12. Rubin G, Hungin AP, Chinn D, Dwarakanath AD, Green L, Bates J. Long-term aminosalicylate therapy is under-used in patients with ulcerative colitis: a cross-sectional survey. Aliment Pharmacol Ther 2002;16:1889–93. 13. López-Sanromán, Bermejo F, Carrera E, Pérez-Abad M, Boixeda D. Adherence to treatment in inflammatory bowel disease. Rev Esp Enferm Dig 2005;97:249–57. 14. Bernal I, Domènech E, Garcia-Planella E, Marín L, Mañosa M, Navarro M, et al. Medication-taking behaviour in a cohort of patients with inflammatory bowel disease. Dig Dis Sci 2006;51: 2165–9. 15. Shale MJ, Riley SA. Studies of compliance with delayed-release mesalazine therapy in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2003;18:191–8. 16. D'Incà R, Bertomoro P, Mazzocco K, Vettorato MG, Rumiati R, Sturniolo GC. Risk factors for non-adherence to medication in inflammatory bowel disease patients. Aliment Pharmacol Ther 2008;27:166–72. 17. Nguyen GC, Laveist TA, Harris ML, Datta LW, Bayless TM, Brant SR. Patient trust-in-physician and race are predictors of adherence to
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medical management in inflammatory bowel disease. Inflamm Bowel Dis 2009;15:1233–9. Baars JE, Zelinkova Z, Mensink PB, Markus T, Looman CW, Kuipers EJ, et al. High therapy adherence but substantial limitations to daily activities amongst members of the Dutch inflammatory bowel disease patient organization: a patient empowerment study. Aliment Pharmacol Ther 2009;30:864–72. Hawthorne AB, Rubin G, Ghosh S. Review article: medication non-adherence in ulcerative colitis—strategies to improve adherence with mesalazine and other maintenance therapies. Aliment Pharmacol Ther 2008;27:1157–66. Waters BM, Jensen L, Fedorak R. Effects of formal education for patients with inflammatory bowel disease: a randomized controlled trial. Can J Gastroenterol 2005;19:235–44. Velayos FS, Terdiman JP, Walsh JM. Effect of 5-aminosalicylate use on colorectal cancer and dysplasia risk: a systematic review and meta-analysis of observational studies. Am J Gastroenterol 2005;100:1345–53. Van Staa TP, Card T, Logan RF, Leufkens HG. Aminosalicylate use and colorectal cancer risk in inflammatory bowel disease: a large epidemiological study. Gut 2005;54:1573–8. López-Sanroman A, Bermejo F. Review article: how to control and improve adherence to therapy in inflammatory bowel disease. Aliment Pharmacol Ther 2006;24(Suppl 3):45–9. Bokemeyer B, Teml A, Roggel C, Hartmann P, Fischer C, Schaeffeler E, et al. Adherence to thiopurine treatment in outpatients with Crohn's disease. Aliment Pharmacol Ther 2007;26: 217–25. Claxton AJ, Cramer J, Pierce C. A systematic review of the associations between dose regimens and medication compliance. Clin Ther 2001;23:1296–310. Kruis W, Kiudelis G, Rácz I, Gorelov IA, Pokrotnieks J, Horynski M, et al. Once daily versus three times daily mesalazine granules in active ulcerative colitis: a double-blind, double-dummy, randomised, non-inferiority trial. Gut 2009;58:233–40. Dignass AU, Bokemeyer B, Adamek H, Mross M, Vinter-Jensen L, Börner N, et al. Mesalamine once daily is more effective than twice daily in patients with quiescent ulcerative colitis. Clin Gastroenterol Hepatol 2009;7:762–9. Kamm MA, Lichtenstein GR, Sandborn WJ, Schreiber S, Lees K, Barrett K, et al. Randomised trial of once- or twice-daily MMX mesalazine for maintenance of remission in ulcerative colitis. Gut 2008;57:893–902. Hall NJ, Rubin GP, Hungin AP, Dougall A. Medication beliefs among patients with inflammatory bowel disease who report low quality of life: a qualitative study. BMC Gastroenterol 2007;7:20. Robinson A, Thompson DG, Wilkin D, Roberts C, Northwest Gastrointestinal Research Group. Guided self-management and patient-directed follow-up of ulcerative colitis: a randomised trial. Lancet 2001;358:976–81. Kennedy AP, Nelson E, Reeves D, Richardson G, Roberts C, Robinson A, et al. A randomised controlled trial to assess the effectiveness and cost of a patient orientated self management approach to chronic inflammatory bowel disease. Gut 2004;53:1639–45.
available at www.sciencedirect.com
Factors that modify therapy adherence in patients with inflammatory bowel disease☆ Fernando Bermejo a,⁎, Antonio López-San Román b , Alicia Algaba a , Iván Guerra a , Paz Valer a , Silvia García-Garzón a , Belén Piqueras a , Carlos Villa a , Andrea Bermejo a , José L. Rodríguez-Agulló a a b
Department of Gastroenterology, Hospital Universitario de Fuenlabrada, Fuenlabrada, Madrid, Spain Department of Gastroenterology, Hospital Universitario Ramón y Cajal, Madrid, Spain
Received 1 November 2009; received in revised form 4 January 2010; accepted 18 January 2010 KEYWORDS Inflammatory bowel disease; Adherence; Therapy; Crohn's disease; Ulcerative colitis
Abstract Objectives: Inflammatory bowel disease is associated with a high risk of deficient adherence to therapy. Our study was designed to analyze the adherence to treatment in a specialized inflammatory bowel disease clinic, and to study which factors could influence it. Methods: 107 consecutive patients (64% Crohn's disease, 36% ulcerative colitis) filled up an anonymous survey with data on demography, disease, therapy and a self-applied adherence declaration. Results: A 69% (95%CI: 60–77%) showed some type of non-adherence. A 66% (95CI%: 57–75%) acknowledged some involuntary non-adherence: either forgetting to take their dose (63%) or being careless about having taken it (27%). A 16% (95CI%: 9–22%) showed some voluntary nonadherence: interrupting the therapy when feeling better (13%) or when feeling worse (6%). A 25% forgot at least a dose a week in the last 12 months. Multivariate analysis identified as risk factors for a lower adherence the dosing in three or more takes a day (OR 3; 95%CI: 1.1–8.4; p = 0.03) and feeling little informed about their disease (OR 4.9; 95%CI: 1.1–23.8; p = 0.04). Immunomodulator therapy predicted better adherence (OR 0.29; 95%CI: 0.11–0.74; p = 0.01). Conclusions: Adherence to therapy in inflammatory bowel disease patients is not satisfactory, and worse in patients treated with mesalazine. Optimizing the information on the disease and giving the medication in one or two daily doses could enhance therapeutic adherence. © 2010 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.
☆ Data presented previously at 4th Congress of ECCO, Hamburg, 2009 and Digestive Disease Week, 2009, Chicago and published as abstract in Journal of Crohn & Colitis 2009; 3: S49 and Gastroenterology 2009; 136 Supplement 1: A-680. ⁎ Corresponding author. Ríos Rosas 17, 28003 Madrid, Spain. Tel./fax: +34 916006175. E-mail address: [email protected] (F. Bermejo).
1. Introduction Adherence to therapy is a key aspect in determining the efficacy of a given drug in the clinical practice. The concept of adherence implies the active and informed participation of patients in any therapy-related decision, all of which should
1873-9946/$ - see front matter © 2010 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.crohns.2010.01.005
Adherence to therapy in inflammatory bowel disease
423
ensure an optimal follow-up.1,2 Thus, adherence is not the non-informed obedience to the physician's prescription, and a good adherence implies that both patient and physician work together to achieve a common goal, with the patient's opinion always being taken into account. A good adherence positively influences the results of a prescribed therapy. Adherence not only implies that the patient takes the correct dose at the correct times, but also that it is taken as directed, and it also encompasses other aspects (diet, lifestyle, substance abuse, etc.) that help to achieve a better quality of life. In diverse diseases, like essential hypertension, hypercholesterolemia or hepatitis C, a good adherence is key to the success of therapy, which makes it desirable to include some type of control in the follow-up of a given patient.3–5 Inflammatory bowel disease (IBD) is a clinical condition with a high risk of therapeutic non-adherence.6 Some of the factors that determine such a risk are its chronic nature, the frequency with which it attains young patients, the need for prolonged drug administration and the fact that its clinical course includes both symptomatic and asymptomatic periods.1 The aim of our study was to quantify the degree of therapeutic adherence in patients with IBD seen in a specialist clinic, and detect any factors that could modify it.
2. Methods To achieve our aim, we designed a prospective study, set in a specialized IBD Clinic in a University Hospital. During three months, we interviewed 107 patients diagnosed with IBD following the accepted criteria.7 The study was approved by the Ethical Committee of our centre. We excluded patients seen for the first time, patients seen urgently and those unable to understand or fill up the questionnaires. After informed consent was obtained, a structured written interview was done, anonymously and without the presence of any of the treating physicians. This interview included 1) Demographic data: age, gender, studies, working status, and marital status, 2) Data on the disease: type of IBD, year of diagnosis, number of hospital admissions, and number of IBD-related surgical procedures, 3) Data on their treatment: drugs, doses, and intervals, 4) Self-administered test on adherence to treatment (Table 1),1 5) Number of doses usually forgotten every week during the year preceding the survey, and reason for forgetting them, and 6) Self-medication. When relevant, data were
confirmed by consulting the Clinical Records. Additionally, the treating physician filled up a data sheet, containing all the relevant information about the patient's therapy, calculated the clinical activity index (Harvey–Bradshaw's for Crohn disease and Truelove–Witts' for ulcerative colitis).8,9 Data were analyzed with SPSS 15.0 (SPSS Inc., Chicago, IL, USA). For continuous variables, mean and standard deviation were calculated whenever the sample followed a normal distribution; in other cases, the median and the interquartile range (IQR) were used. For categorical variables, percentages and corresponding 95% confidence intervals (95% CI) were provided. A p value b0.05 was considered statistically significant. Continuous variables were compared with the ttest whenever the sample followed a normal distribution; in other cases, the Mann–Whitney U-test was used. Categorical variables were compared with chi-squared test, or Fisher's exact test in comparisons in which less than five registers were expected.
3. Results Main clinical characteristics of the study group are shown in Table 2. The test was correctly filled up by 100% of patients. A 66% of them (95CI%: 57–75%) acknowledged some degree of non-voluntary non-adherence. More specifically, a 63% agreed to the statement “I sometimes forget to take my medication”, whereas a 27% agreed to “I am sometimes careless about whether I have taken my medication”.
Table 2 Characteristics of inflammatory bowel disease patients who completed the survey. Number of patients Type of disease Age (mean ± standard deviation) Gender Duration of the IBD Activity of the IBD
Treatment for the IBD
Table 1 True/false questions used to explore adherence to treatment. 1 2 3 4
Did you sometimes forget to take your medication? Were you careless at times about taking your medication? When you felt better, did you sometimes stop taking your medication? If you felt worse when you took your medication, did you sometimes stop taking your medication?
True
False
True
False
True
False
True
False
Rectal therapy IBD-related hospital admission in the past IBD-related surgical procedure in the past Long term stable partnership Work outside the home Level of education
107 63.5% Crohn's disease, 35.5% ulcerative colitis 41.3 ± 11 years 60% female 6 years (IQR: 3–10) Crohn's disease: 70.5% inactive, 29.5% active Ulcerative colitis: 69% inactive, 31% active 66% aminosalicylates 51% azathioprine/mercaptopurine 8% glucocorticoids 13% mesalazine 66% with some hospital admission 17% with some surgical procedure 80% of patients 58% 18% 45% 27% 10%
of patients without studies primary studies medium studies university degree
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On the other hand, 16% of patients (95CI%: 9–22%) acknowledged some degree of voluntary non-adherence; more specifically, a 13% agreed to “sometimes I stopped my medication because I was feeling better”, and a 6% agreed to the statement “I sometimes stopped my medication because I was feeling worse”. Globally, a 69% of patients (95CI%: 60– 77%) showed some type of non-adherence. When we asked about the frequency and causes of nonadherence in the last 12 months (Table 3), we found a 25% (95CI%: 17–33%) of patients forgot at least one dose a week (median forgotten doses 1.6 per week, range 1–4). The percentage of these weekly medication omissions was higher with mesalazine (30%) than with azathioprine (17%) (n.s.). Different factors such as gender, time since diagnosis of IBD, previous IBD-related admissions or surgeries, or being in a stable affective relationship, did not correlate with the degree of adherence. There was also no association between non-adherence and disease type (p = 0.6), and clinical activity of disease (p = 0.56). On the other hand, patients treated with azathioprine showed better adherence that those receiving mesalazine (p = 0.005). In the multivariate analysis, risk factors for a lower adherence were medication scheduled in three or more daily doses (OR 3; 95CI% 1.1–8.4; p = 0.03) and patients who felt insufficiently informed about the disease (OR 4.9; 95CI% 1.1–23.8; p = 0.04); on the contrary, therapy with immunomodulators predicted a better degree of adherence (OR 0.29; 95CI% 0.11–0.74; p = 0.01). When analyzing factors specifically and independently associated with the type of non-adherence, therapy with immunomodulators was a protective factor against both voluntary and involuntary non-adherence. Administration of the medication in three or more daily doses was a risk factor for involuntary non-adherence (Table 4). Patient's and physician's enumeration of the prescribed drugs and doses were concordant in 86% of cases; in 10.3% they did not agree in the prescribed doses and in the remaining 3.7% there were differences between the actual therapy and the patient's recall. A 9% acknowledged selfmedication during flares (4% with mesalazine, 4% with steroids, and 1% with alternative therapies).
4. Discussion Treatment compliance in clinical trials on IBD varies between 70 and 95%10,11; however, trials are an ideal situation, in which patient and therapy supervision is way more intense than usual. Treatment adherence in real life is noticeably lower, with the percentage of non-adherent patients ranging
Table 3 Frequency and causes of forgetting medication in the last 12 months. Frequency
Causes
75.7 % less than one dose a week 14% one dose a week 6.5% two doses a week 2.8% three doses a week 1% four doses a week
39% 27% 19% 15%
being out of home simple forgetfulness being at work being a weekend
Table 4 Multivariate analysis of the risk factors related with the adherence to therapy. Factors: odds ratio; 95CI%; p Some type of non-adherence
Involuntary non-adherence
Voluntary non-adherence
Therapy with immunomodulators: OR 0.29; 0.11–0.74; p = 0.01 Medication scheduled in 3 or more daily doses: OR 3; 1.1–8.4; p = 0.03 Patients insufficiently informed: OR 4.9; 1.1–23.8; p = 0.04 Therapy with immunomodulators: OR 0.41; 0.17–0.98; p = 0.04 Medication scheduled in 3 or more daily doses: OR 2.8; 1.05–7.4; p = 0.03 Patients insufficiently informed: OR 2.9; 0.7–11; p = 0.11 Therapy with immunomodulators: OR 0.28; 0.09–0.91; p = 0.03 Medication scheduled in 3 or more daily doses: OR 0.66; 0.2–2.1; p = 0.48 Patients insufficiently informed: OR 2.6; 0.7–9.3; p = 0.12
from 35 to 87%.1,10–18 Thus, a significant percentage of patients do not experience the whole potential benefit of their therapy2,6 and we can mistakenly label as “nonresponder” a patient who, in reality, is not taking the correct amount of medication in a proper way. Non-adherence is significant whenever it determines a change in the therapeutic effect intended when prescribing the drug. The significant level of non-adherence is thus different from drug to drug, and even from disease to disease. A very strict adherence is advisable in drugs with a short halflife and exerting their actions through narrowly regulated plasmatic levels. Practical examples would be antiepileptic or antiarrhytmic drugs. The action of other drugs is less strictly regulated, and depend more on biological than on chemical effects. Adherence is still important, but not as determining. Examples could be antibiotics, hypolipemiants or immunomodulators. A limit of 80% of the prescribed dose has been agreed upon as a convention in clinical trials, but it is far to be applicable to every drug and every situation. The only true exponent of the adequacy of a certain level of adherence is the observation of its effect (or lack of it) in the attempted therapeutic goals. Differentiating voluntary non-adherence (after own conscious decision) and involuntary non-adherence (due to forgetfulness or carelessness) is useful to be able to lay out a strategy aiming at the correction of the problem. Sewitch and co-workers describe a prevalence of non-adherence reaching 41%, involuntary in two thirds of cases.1 D'Inca and co-workers communicate a similar prevalence of nonadherence (39%), involuntary in 61% of cases.16 The magnitude of involuntary non-adherence described by these authors is similar to what we have observed (66%). Different strategies could address this involuntary nonadherence,19 such as medication reminders that can use newer technologies such as short mobile phone messages, mechanical alarms (phone, watch, etc.) and e-mail, or
Adherence to therapy in inflammatory bowel disease simply employ traditional reminders (storing medication close to objects used on a daily basis, like the breakfast mug or the toothbrush. More sophisticated options are calendar blisters and pill boxes that can hold supplies for up to one month.6 All these possibilities can be employed in the group of patients in which therapy non-adherence is just involuntary (27% in our series), or related to situations such as being away from home (39%), being at work (19%) or simply weekends (15%). Voluntary non-adherence is less frequent, but its significance is greater, due to the implication of an active decision by the patient. In our series, 16% of patients presented voluntary non-adherence, slightly less than what has been described by other authors.1,13,16 Patient education and empowering19 could reverse this situation, through the optimization of the information made available to the patient, ongoing medical education20 and highlighting potential benefit of therapy, for instance colorectal cancer prevention through mesalazine.21,22 In our patients, immunomodulator therapy predicted a better adherence to treatment; we also described a tendency of a more likely forgetfulness in patients treated with mesalazine than with azathioprine, (30 vs. 17%), as described by Bernal and co-workers (45 vs. 25%).14 It has been postulated, that the quantification of drug or metabolite levels in blood (6-tioguanine nucleotides for thiopurines) or urine (salicylates) could be useful in asserting adherence to treatment.13,15,23 In a survey on 65 Crohn's disease patients treated with azathioprine or mercaptopurine, only 9.2% showed levels of metabolites indicative of non-adherence.24 The reason for a better adherence in patients taking immunomodulators could be determined either by the more severe disease that these patients suffer, or by the patients' impression that this treatment should be handled more carefully, because of its potential toxicity. Also, these patients are subject to a closer medical control due to follow-up and monitoring visits, which could exert a positive effect on adherence. Different possible risk factors for non-adherence have been described in IBD patients.1,13,16,18,19,23 Some of them depend on the disease itself (inactive disease, longer duration of disease, recently diagnosed cases, patients treated with multiple drugs, three daily dose schedules, and rectal administration of the drug). Others depend on the patient himself or herself: persons who are not in a stable affective relationship, male, full time employees, patients who do not trust their physician, patients who have been insufficiently informed. The identification of at-risk patients is in no doubt interesting to concentrate surveying in the subset of cases that are exposed to a higher non-compliance risk. In our series, factors predicting a lower adherence were the distribution of the drug in three or more daily doses (that made the risk three fold higher) and feeling insufficiently informed about the disease (with an almost five-fold increase of non-adherence risk). A fundamental aspect that could ameliorate compliance in any therapy is the simplification of treatment administration. Schedules every 24 or 12 h result in a higher adherence.23,25 A review of studies measuring therapy compliance confirmed that the number of daily doses inversely correlates to compliance.25 In IBD patients, the full dose of thiopurine immunomodulators can be administered in a single dose; several recent contribu-
425 tions have shown that a single daily dose of mesalazine has a similar effectiveness to fractioned doses, on a short26 as well as on a long term.27 Similar results have been described with Multimatrix®, a new mesalazine formulation.28 As to the importance of the information the patient gets about his or her disease, to optimize its accuracy and understandability is a key aspect to enhance adherence to therapy.6 Ideally, the patient should be provided both with verbal and written information, and the allowance of a relaxed and unhurried interview with the caring physician is desirable. The participation in talks and meetings, the contact with patient organizations and a proper use of Internet resources, should be always encouraged. In our patients, the patient–physician concordance was quite high, regarding the administered therapy. The treatment-related behaviour is influenced, among others, by the knowledge the patient possesses about the disease, the acceptance of therapy, fears about the treatment and the patient–physician relationship.29 All these factors influence concordance and condition the degree of adherence to therapy. Self-medication during a flare-up was acknowledged by 9% of our patients. An informed reaction can empower the patient to react against a flare, probably shortening its duration and consequences. It has been shown in controlled studies, that when patients were instructed on how to act if a flare developed, this resulted in less and shorter medical visits, and a more limited duration of the symptoms.30,31 These instructions to follow when confronted with a worsening disease are better established in ulcerative colitis, and almost absent in Crohn's disease. Increasing the dose of salicylates is an effective measure that should be encouraged, but self-adjustment of glucocorticoid therapy is not recommendable and usually leads to a higher exposure and increased adverse effects. In conclusion, adherence to therapy in IBD patients is not satisfactory in our setting. Our results are in agreement with previous observations in a number of aspects. We confirm that involuntary non-adherence is higher than voluntary nonadherence, and the figures observed by us are similar to other experiences.1,16 We are also able to reaffirm that immunomodulator therapy predicts a better adherence14 and a lower rate of forgotten doses, possibly influenced by the patient's perception of this being a “more powerful” therapy. Our study suggests that we should make a closer control of patients treated with salicylates. There are two predictors of non-adherence, namely the prescription of three or more daily doses, and insufficient information, that are of utmost importance, because they can be easily targeted and modified, presumably leading to a better compliance. Optimizing the information on the disease and giving the medication in one or two daily doses could enhance therapeutic adherence in IBD patients.
Acknowledgement Alicia Algaba benefited from a grant by Schering-Plough Spain. Statement of authorship: study conception and design: FB, AL. Data collection: FB, AA, IG. Statistical analysis: FB, AA. Drafting of article: FB, AL. Clinical revision: IG, PV, SG, BP, CV, AB, JR. All authors read and approved the final manuscript.
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