Overcoming Adherence Issues in Ulcerative Colitis

Abstract

Ulcerative colitis (UC) is a chronic condition requiring lifelong medication to minimize the incidence of symptomatic flares. Nevertheless, studies have shown that a large proportion of patients are nonadherent to their prescribed therapeutic regimen. This review examines studies of patient adherence to 5-aminosalicylic acid (5-ASA) therapy in real world settings and considers the reasons that patients do not adhere to medication. Patients offer numerous reasons for not taking medication as prescribed; however, neither clinical nor community studies have consistently identified the same groups of patients as being high risk for poor adherence. Indeed, the problem of nonadherence is complex and requires a combination of strategies to be improved. Physicians, physician assistants, and nurse practitioners need to take the time to explain the importance of continual therapy, even when patients feel well, and should engage patients in a discussion to aid in the understanding of their nonadherence. Then, healthcare providers can determine how to best amend the regimen to improve adherence. As taking several tablets several times daily may be confusing or difficult for patients, higher strength 5-ASA formulations that require fewer daily doses have the potential to enhance patient adherence as part of an overall management strategy.

Ulcerative colitis (UC) is a chronic inflammatory disease affecting the colonic mucosa. Using data from a epidemiologic study in Olmstead County, Minnesota, the annual incidence of UC in the United States can be estimated to be 7.6 cases in 100,000 people, with a prevalence of approximately 200 cases per 100,000 people.¹ The profile of UC is generally relapsing-remitting, with patients experiencing periods with few or no gastrointestinal symptoms followed by symptomatic flares, or relapses.

The etiology of UC remains unclear. However, a genetic pre-disposition with an inappropriate or excessive response to the normal colonic bacterial population and unidentified infectious agents or dietary triggers that affect an insufficiently regulated mucosal immune system are factors thought to play a role in the chronic inflammation and symptom manifestation.^2–4 The objectives of current therapeutic treatment of UC are to induce and maintain remission of symptoms and mucosal inflammation.⁵

Treatment of Ulcerative Colitis

The standard first-line treatment for the induction and maintenance of remission in patients with mild-to-moderate UC is 5-aminosalicylic acid (5-ASA). Its mechanism of action is thought to involve blocking a number of anti-inflammatory processes acting at the level of the colonic mucosa.⁶ Aminosalicylates have been shown to inhibit production of interleukin-1 and tumor necrosis factor-α. 5-ASA and its prodrug, mesalamine, are potent inhibitors of both the cyclooxygenase and lipoxygenase pathways, as well as being among the most potent known free radical scavengers and antioxidants.⁶ 5-ASA also inhibits activation of nuclear factor-κB (NF-κB), a central transcription regulatory factor involved in the inflammatory process. NF-κB has been detected in cells of inflamed mucosa in patients with UC.⁷

There are several different 5-ASA delivery systems available, including oral and rectal formulations, that share the same aim, namely to achieve maximal drug delivery to the colon while minimizing systemic absorption. Oral 5-ASA therapies are recommended over topical therapies as first-line treatment of both left-sided and extensive mild-to-moderate UC, as they have shown efficacy in treating the entire large intestine.^5,8 For mild-to-moderate distal disease, a combination of topical and oral 5-ASA therapy is recommended.^5,8

This review will examine the problem of low adherence in patients with UC and the reasoning behind it, and will provide suggestions for its improvement. Although there are numerous 5-ASA delivery systems, many of them involve daily doses of multiple medications, a factor that is frequently cited by patients as a barrier to adherence. Therefore, switching to therapy for a 5-ASA product with fewer or, ideally, once-daily doses may be a suitable approach to improving adherence.

Nonadherence in Ulcerative Colitis

Patient adherence can be defined as the extent to which a patient's behavior is in accordance with the instructions given by their healthcare practitioner. Although adherence is known to be low—in the range of 50%— in other chronic diseases such as hypertension, diabetes, and asthma,⁹ few data have been published regarding the level of outpatient adherence in UC outside of the clinical trial setting.

A small number of trials have been conducted using different methods to investigate the level of adherence in patients with UC in real world settings. In a cohort study of 92 patients with clinically inactive disease followed for more than 48 weeks with appointments every 12 weeks, 43% of patients were found to be 100% adherent, whereas in the remaining 57% of patients, adherence did not fall below 95%.¹⁰ However, these patients had consented to being studied, making it is likely that they did not reflect common, real world behavior. An earlier study by van Hees and van Tongeren assessed adherence to sulfasalazine therapy by measuring the levels of sulfapyridine in the serum of 51 patients as a marker for metabolized sulfasalazine shortly before and 1–6 months after discharge from hospital.¹¹ Upon questioning, the majority of patients claimed that they were adherent; however, approximately 41% of the patients were found to have serum sulfapyridine levels substantially below their levels prior to discharge, and were thus considered to be nonadherent.¹¹

In my previous research with colleagues at the University of Chicago, I studied 99 UC patients in remission, examining their prescription refill history as a measure of adherence.¹² The objective nature of pharmacy data is thought to provide a more accurate reflection of medication consumption outside of the structured clinical trial environment. In the study, only 40% of patients were adherent, and the median amount of medication consumed was 71% of the prescribed dose.

The clinical outcomes of nonadherence can be detrimental to patients. A correlation has been demonstrated between poor adherence and increased frequency of relapses. In the cohort of patients previously described, clinical outcome was measured prospectively. Nonadherent patients experienced more than a 5-fold increased risk (61%) of disease relapse compared with those who were adherent (11%; P=.001) (Figure 1).

Figure 1.

Relapse rates in adherent and nonadherent patients.

Reproduced with permission from Kane SV et al.¹²

Nonadherence to 5-ASA–based therapy has also been linked to an increased risk of developing colorectal cancer. Moody and associates showed a correlation between nonadherence to or discontinuation from sulfasalazine therapy and increased risk of colon cancer; 5 out of 152 adherent patients and 5 out of 16 nonadherent patients developed colorectal cancer (X² test, P<.001).¹³ This finding was supported by Eaden and coworkers, who showed in a case-controlled study among 102 cases of colorectal cancer in UC with matched controls that colorectal cancer risk was reduced by 81% in patients receiving regular mesalamine therapy (≥1.2g/day) compared with those receiving no treatment (P=.006).¹⁴

Factors Affecting Adherence

It is important for physicians to understand patient characteristics that may be associated with a risk of non- adherence. My previous study identified a list of patient characteristics that correlate with adherence and nonadherence (Table 1).¹⁵

Table 1.

Patient Characteristics Found to Correlate With Adherence and Nonadherence

Factors associated with adherence	Factors associated with nonadherence
Being married	Being single
Having more extensive disease	Having left-sided disease
Having undergone a recent colonoscopy	Being prescribed 4 or more concomitant medications
	Being male

Reproduced from Kane SV et al.¹⁵

Patient nonadherence is more likely to be a problem during periods of disease remission, as there are no clinical symptoms to act as a reminder to take medication. At these times, rather than continuing with the prescribed regimen, patients often adjust their medication by taking it less frequently than instructed, altering the dose from that prescribed, taking it only when they feel unwell, or forgetting to take it at the scheduled time.¹⁶ However, this forgetfulness may often be linked to a form of disease-denial: they are in remission and do not wish to be reminded that they have a disease when they feel well.

Many factors associated with nonadherence are financial, emotional, or treatment-related, rather than disease-related. Upon questioning, patients list numerous reasons for nonadherence, including heavy pill burden, unclear treatment regimen, forgetfulness, financial burden, lack of adequate information, and lack of support.¹⁷

The Manitoba Inflammatory Bowel Disease Cohort Study also looked at the nature of adherence in patients with either Crohn's disease or UC. Patients from this population-based cohort were queried by mailed questionnaire regarding adherence to a range of therapies for treatment of inflammatory bowel disease.¹⁸

A total of 35% of patients fulfilled the criteria for low adherence in the study. Men with UC were significantly more likely to have poor adherence than men with Crohn's disease (P<.01). In this study, the investigators found that age was a predictive factor for adherence in women: younger women were less adherent than older women. Men of all ages had comparable levels of adherence, and the rate of poor adherence in men was broadly similar to that of older women, which was a novel finding and contrasted with the results of my previous study in which younger men were the least adherent.¹²

Other factors contributing to poor adherence in the Manitoba Cohort study included heavy pill burden and frequent dosing, which are findings similar to previous studies. The main factors, however, were cost (reported by 25% of patients), reinforcement of status as a person with a disease condition (13%), unpleasant side effects (13%), and lack of belief in the effectiveness of the medication (12%).¹⁸

Strategies for Improving Adherence

The conflicting evidence regarding the most at-risk populations suggests that the problem of poor adherence is multifaceted. The decision not to take medication is a common issue that physicians may not fully understand, as many patients are reluctant to discuss it and offer inaccurate representations of their adherence levels. The risk of problems with adherence is likely to increase with a poor relationship between patients and physicians.¹⁹ If patients do not feel comfortable with or do not trust their physician or they feel that they are not being taken seriously, they may be less likely to follow the guidance of their physician. Patients also need to understand the continuous requirement for medication, because if they do not, they are less likely to take it in the correct manner. A recent study by Davis and associates testing the concept commonly referred to as health literacy found that approximately half of the patients in the study could not understand at least one of five pill-bottle labels.²⁰ To help improve adherence, therefore, physicians should make efforts to engage their patients in discussion and ensure that they understand their medication instructions. By listening to medication-related problems, not being judgmental, and being prepared to suggest alternative therapies, physicians can effectively gauge adherence levels.

Since pill burden and multiple daily dosing have demonstrated an association with nonadherence, formulations that require less frequent and/or fewer doses may assist in improving patient adherence. A recent systemic review of interventions to enhance adherence to medications in chronic illnesses found that the only consistent successes have been associated with simplifying the dosing regimen.²¹ Several mesalamine formulations designed to improve patient adherence by decreasing pill burden and dose frequency have been recently licensed or are in late-stage development. These formulations include a newly developed multimatrix system (MMX) formulation, higher-dose mesalamine tablets, and micropellet sachets.

MMX mesalamine (Lialda, Shire), a high-strength formulation using MMX technology designed to provide prolonged release throughout the entire colon,²² was licensed in the United States in early 2007 for the induction of remission in active, mild-to-moderate UC. Placebo-controlled clinical trials have demonstrated that MMX mesalamine is the first efficacious once-daily mesalamine treatment to induce remission of UC symptoms when given once daily, or twice daily in a divided dose.^23,24

High-dose (800 mg) delayed-release mesalamine tablets (Asacol, Procter & Gamble) have recently been tested as a formulation that reduces the number of total tablets required daily.^25,26 Sachet micropellet formulations of mesalamine (Salofalk Granu-Stix, Axcan) and controlled-release mesalamine (Pentasa, Shire) are designed for ease of swallowing and thus enable patients to take large doses at one time and reduce the need for frequent dosing. A once-daily controlled-release mesalamine sachet formulation is currently in phase III clinical trials.²⁷

Selecting an Appropriate 5-Aminosalicylic Acid Therapy to Improve Adherence

As many patients fail to adhere to their treatment regimen, there is a strong case for attempting to improve adherence by simplifying the dosing regimen. Since pill burden and frequent (or confusing) dosing regimens are the most consistent problems cited by patients who are nonadherent, newer therapies that require fewer daily doses and/or reduce the number of tablets taken in each dose may prove successful for improving adherence.

One pilot study assessed patient adherence levels to once-daily versus twice- or 3-times–daily dosing with mesalamine.²⁸ The study followed 22 patients with quiescent UC over a 6-month period who were randomized to receive mesalamine either once daily or at the conventional dosing frequency of 2 or 3 times daily. Adherence was assessed using the prescription refill method described previously in studies and was defined as a rate of more than 80%. A good tolerability profile was suggested, as there was no obvious difference between the two groups in terms of adverse clinical outcomes. Interestingly, the overall consumption of medication was higher in the once-daily dosing group, as was patient satisfaction with treatment. These findings suggest that a longer period of observation may have revealed improvements in clinical outcomes.

It may, therefore, be an appropriate strategy to improve adherence by changing a patient's prescription from a multiple–daily dose formulation to one of the newer formulations with fewer daily doses. However, the importance of continuous medication must be considered, and physicians would need to be confident that the patient can be switched from one 5-ASA therapy to another while maintaining treatment efficacy.

To investigate the effectiveness of switching patients from one 5-ASA formulation to another, studies need to be conducted to determine whether switching reduces efficacy and whether more convenient dosing schedules improve adherence. One study has assessed efficacy while switching formulations. However, in this study, the change in formulation was to a less convenient dosing regimen and, therefore, the impact of switching formulations in regard to adherence should not be considered. This study was carried out in 9 UC patients who were prone to relapse (defined as a UC Disease Activity Index [UCDAI] endoscopy score of ≥2). Patients were switched from routine delayed-release mesalamine oral therapy (2.4 g/day administered as 2 tablets, dosed 3 times daily) to controlled-release mesalamine microgranules (4 g/day, given as 2 tablets, dosed 4 times daily).²⁹ A significantly lower (P=.013) mean UCDAI score was observed after 12 weeks following the switch (6.81±0.72 vs 8.18±0.58).

Efficacy has also been assessed in patients switched to a 5-ASA formulation with once-daily doses. The results of this study showed that MMX mesalamine 4.8 g daily was effective for providing clinical and endoscopic remission in patients with active, mild-to-moderate UC who had transferred directly from low-dose (≤2.0 g/day) oral 5-ASA therapy. Because the second formulation used the convenient dosing regimen of once-daily dosing, the improvement in efficacy may also be matched by increased adherence rates.³⁰

These studies suggest that changing a patient's medication regimen to a different formulation can prove to be efficacious. Larger studies need to be carried out to assess the effects of switching to a formulation with less frequent dosing on patient adherence levels in a community setting.

Summary

Adherence levels in patients with UC are low with traditional oral 5-ASA regimens. Physicians and their staff play an important role in patient adherence; their engagement with patients may help to identify nonadherence and enable important steps to be taken toward improving adherence. Novel therapies with simpler dosing regimens (eg, once-daily dosing) have proven to be efficacious in UC patients and have the potential to improve adherence, providing a rationale for switching a 5-ASA prescription to a formulation with a less frequent dosing regimen, where there is a need to improve the rate of adherence.