Alimentary Pharmacology & Therapeutics

Review article: medication non-adherence in ulcerative colitis – strategies to improve adherence with mesalazine and other maintenance therapies A. B. HAWTHORNE, G. RUBIN & S. GHOSH

Department of Medicine, University Hospital of Wales, Heath Park, Cardiff, UK Correspondence to: Dr A. B. Hawthorne, Department of Medicine, University Hospital of Wales, Heath Park, Cardiff CF14 4XW, UK. E-mail: barney.hawthorne@ cardiffandvale.wales.nhs.uk

Publication data Submitted 30 January 2008 First decision 13 February 2008 Resubmitted 26 March 2008 Accepted 27 March 2008 Epub OnlineAccepted 31 March 2008

SUMMARY Background Significant number of patients with ulcerative colitis (UC) fail to comply with treatment. Aims To review issues surrounding medication non-adherence in inflammatory bowel disease (IBD), including the clinical and health service implications in the UK, and discuss strategies for optimizing medication adherence. Methods Articles cited were identified via a PubMed search, utilizing the words IBD, adherence, compliance, medication and UC. Results Medication non-adherence is multifactorial involving factors other than dosing frequency. Male gender (OR: 2.06), new patient status (OR: 2.14), work and travel pressures (OR: 4.9) and shorter disease duration (OR: 2.1), among others are proven predictors of non-adherence in UC. These indicators can identify ‘at-risk’ patients and allow an individually tailored treatment approach to be introduced that optimizes medication adherence. A collaborative relationship between physician and patient is important; several strategies for improving adherence have been proven effective including open dialogue that takes into consideration the patient’s health beliefs and concerns, providing educational (e.g. verbal ⁄ written information, self-management programmes) and behavioural interventions (e.g. calendar blister packs, cues ⁄ reminders). Conclusions Educational and behavioural interventions tailored to individual patients can optimize medication adherence. Additional studies combining educational and behavioural interventions may provide further strategies for improving medication adherence rates in UC. Aliment Pharmacol Ther 27, 1157–1166

ª 2008 The Authors Journal compilation ª 2008 Blackwell Publishing Ltd doi:10.1111/j.1365-2036.2008.03698.x

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INTRODUCTION

DETECTING MEDICATION NON-ADHERENCE

The nature of ulcerative colitis (UC) dictates that therapy should be continued indefinitely in most patients. Treatment with 5-aminosalicylates (5-ASAs) is effective in inducing and maintaining remission in UC patients,1, 2 and is associated with a reduced risk of developing colorectal cancer (CRC) in the long term.3, 4 As with other chronic conditions, however, medication non-adherence in patients with UC is common. This review describes the extent of the problem, its clinical and health service implications in the UK, and considers the evidence for strategies to optimize medication adherence in UC.

Direct enquiry can detect most, but not all nonadherent patients. In a study of 98 IBD patients, self-reporting correctly identified 66% of patients that were non-adherent, as assessed by urinary drug measurements of 5-ASA.14 Urinary salicylate levels correlate positively with urinary 5-ASA levels, and its measurement has become the standard test in most UK hospitals, representing a simple method for assessing adherence to 5-ASA therapy.17 Other methods of ascertaining levels of medication nonadherence include asking family members, checking prescription uptake at the pharmacist or asking patients to bring their tablets to consultations.17

EXTENT OF THE PROBLEM

CLINICAL IMPLICATIONS OF MEDICATION NON-ADHERENCE

‘Compliance’ and ‘adherence’ are terms used synonymously to describe the extent to which patients follow the advice of healthcare professionals regarding their medication and disease management. Non-adherence describes the failure to take medication as intended by the physician and can be intentional or unintentional. Patients with chronic diseases may fail to comply with long-term therapies or clinicians’ recommendations. This has been demonstrated for, amongst others, patients with hypertension5, 6 and diabetes.7 Within the controlled environment of clinical trials, where there is a high presence of medical supervision, approximately 70–95% of patients with inflammatory bowel disease (IBD) adhere to their medication.8–10 However, this high rate of medication adherence is not reflected in normal clinical practice. A cross-sectional study of US outpatients with quiescent UC found that only 40% were adherent to maintenance mesalazine (mesalamine) therapy.8 Several community-based studies have reported non-adherence rates ranging from 43% to 72% of IBD patients.8, 11–14 In the UK, approximately 15% of patients fail to even redeem prescriptions at the pharmacist.15 Treatment non-adherence rates vary considerably between countries. Within Europe, a survey of 203 IBD patients revealed self-reported non-adherence rates ranging from 13% in France, to 26% in Italy, 33% in UK and 46% in Germany; with an overall non-adherence rate of 29% across Europe.16

Increased risk of relapse In UC, failure to take 5-ASA therapy increases the risk of relapse,18 which in turn impacts on healthrelated quality of life measures.19 A cohort study of 99 quiescent UC patients demonstrated that patients who were non-adherent to their prescribed 5-ASA therapy had a greater than fivefold increased risk of clinical relapse.18 Moreover, adherent patients were shown to have an 89% chance of maintaining remission, compared with only 39% in non-adherent patients.18

Increased risk of developing CRC The risk of developing CRC increases with the extent and duration of UC, and is associated with a lifetime risk of approximately 20%.20 Case-control studies have shown that the regular use of 5-ASA therapy significantly reduces the risk of developing CRC by up to 75% in UC patients in the long term.3, 21 A 10-year cohort study demonstrated that 31% of UC patients who had stopped 5-ASA therapy, or who did not comply with treatment, had developed CRC compared with only 3% who continued with long-term treatment.22 Furthermore, a systematic review and meta-analysis of observational studies confirmed the protective role of 5-ASA use against CRC development.4

ª 2008 The Authors, Aliment Pharmacol Ther 27, 1157–1166 Journal compilation ª 2008 Blackwell Publishing Ltd

R E V I E W : I M P R O V I N G M E D I C A T I O N A D H E R E N C E R A T E S I N U L C E R A T I V E C O L I T I S 1159

Increased healthcare costs In the UK, a single centre retrospective study of IBD patients showed individual patient costs ranged from £73 to £33 254, with a mean 6-month cost of £1256 (95% CI: £988, £1721) per UC patient.23 The high percentage of non-adherent patients who are at an increased risk of relapse is likely to contribute to the overall high costs associated with the treatment of UC. Indeed, disease relapse was associated with a two- to threefold increase in costs for non-hospitalized cases and a 20-fold increase in costs for hospitalized cases compared with quiescent cases of IBD.23

Healthcare system implications in the UK An estimated 100 000 people in the UK are affected with UC and incidence rates of 11 cases per 100 000 person-years have been reported.24 In the UK, UC is managed mainly in secondary care, and as a direct consequence of a Government target known as the ‘two-week wait’ for CRC, an increasing number of colorectal surgeons and not gastroenterologists are the first specialists to diagnose IBD patients in the clinic. Regular outpatient reviews are carried out by specialist clinicians and supported by IBD nurse specialists. General practitioners (GPs) rarely make the definitive diagnosis or initiate treatment, but they do contribute significantly to meeting the healthcare needs of patients, and generally continue treatment under the guidance of a specialist. Therefore, in the UK, the facilitation and monitoring of medication adherence in UC involves a multidisciplinary team, including gastroenterologists, consultant colorectal surgeons, IBD nurse specialists and GPs.25 An increasing emphasis on ‘efficiency’ in out-patient clinics in the NHS, by increasing the new ⁄ follow-up ratio, and thus encouraging fewer follow-up appointments each year, will reduce the opportunity for physicians to interact with patients and monitor their compliance.

PREDICTORS OF MEDICATION NON-ADHERENCE A number of factors are associated with non-adherence in UC (Table 1). Non-adherent patients are statistically more likely to be male (67% vs. 52% in adherent patients, respectively), single (86% vs. 53%), have left-sided disease (vs. pancolitis) (83% vs. 51%), or be taking four or more concomitant medications ª 2008 The Authors, Aliment Pharmacol Ther 27, 1157–1166 Journal compilation ª 2008 Blackwell Publishing Ltd

Table 1. Predictive factors of non-adherence in ulcerative colitis10, 14, 27, 28 and strategies to optimize adherence Predictive factors

Examples of strategies to optimize adherence

Male gender Single status Younger age Full-time employment

Identify these ‘at-risk’ group of patients and communicate risks of medication non-adherence, e.g. via patient information packs, etc.

Three times daily dosing Four or more concomitant medications

Address dosing regimen Suggest medication taking cues, e.g. alarm clocks, placing tablets near toothpaste, etc. Raise patient education ⁄ awareness, e.g. chemoprevention

New patient status Left-sided disease Depression

Arrange regular follow-up appointments Maximize time for consultation Sign-posting to patient support groups ⁄ services, patient website ⁄ chat-rooms Fully utilize IBD nurses

Patient discordance

Open communication with patients, e.g. open questions, appropriate tone and language

Disease duration

Periodic enforcement of educational information

(60% vs. 40%).8 Other factors, such as the approach ⁄ attitude of the physician, the perceptions ⁄ beliefs of patients, side effects, prescription costs and illness-related factors (i.e. the reduction ⁄ absence of symptoms) have also been linked to non-adherence.26 Shale and Riley’s study14 demonstrated that three times daily dosing and full-time employment were independent predictors of partial non-adherence in patients taking delayed-release mesalazine, whereas depression was an independent predictor of complete non-adherence. In addition, new patient status, shorter disease duration, younger age, patient discordance and work ⁄ travel pressures are also good predictors of nonadherence (Tables 1 and 2).27, 28 Many patients with IBD deliberately decide not to continue with treatment.13, 27, 29 As one Spanish study in 40 IBD patients has shown, up to 35% of patients are intentionally non-adherent compared with 67% who are unintentionally non-adherent.13 A greater association was found between intentional non-adherence and

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Table 2. Effects of different parameters ⁄ factors on medication non-adherence rates (%)

Number of IBD patients; UC vs. CD Gender Male

Female (%) Age Younger age

Cerveny´ et al.29

Kane et al.8

Shale and Riley14

Bernal et al.12

n = 94; 94 UC, 0 CD

n = 98; 62 UC, n = 214; n = 177; n = 485; 265 UC, 26 CD (10 IDC) 99 UC, 115 CD 60 UC, 117 CD 218 CD

67%; P < 0.05 vs. female; OR: 2.06 52

–

–

–

ns 42%; ns vs. female

–

–

–

35

na –

– –

– –

– –

–

–

D’Inca et al.28