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Original Articles: Gastroenterology

Nonadherence With Thiopurine Immunomodulator and Mesalamine Medications in Children with Crohn Disease

Oliva-Hemker, Maria M*; Abadom, Vivian*; Cuffari, Carmen*; Thompson, Richard E

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Journal of Pediatric Gastroenterology and Nutrition: February 2007 - Volume 44 - Issue 2 - p 180-184
doi: 10.1097/MPG.0b013e31802b320e
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Abstract

INTRODUCTION

Crohn disease (CD) is a chronic inflammatory bowel disease (IBD) that affects both children and adults and is characterized by symptomatic periods interspersed with symptom-free periods (1,2). There is no known cure for CD. Medical management typically consists of using multiple medications, often on an indefinite basis, to prevent relapse of symptoms and to reduce the risk of long-term complications (3–5).

Adherence (or compliance) to medication therapy is defined as the extent to which a person's behavior in taking medications coincides with medical advice (6). Adherence rates in clinical trials can be high because of the attention that the study patients receive and patient selection bias. Clinical IBD studies in adults have demonstrated efficacy in achieving and maintaining disease remission when patient adherence is high, from 70% to even >95% (7). However, community-based follow-up studies report medication adherence rates of only 40% to 50% (8,9). A few adult studies have suggested that better patient adherence with medical therapy in ulcerative colitis is associated with improved outcomes such as decreased risk of colorectal cancer or decreased disease exacerbation (10,11). In addition, increased costs to the health care system from medication nonadherence have been shown to occur from inappropriate changes to treatment regimens and unnecessary investigation (12).

Children with chronic illnesses are at an increased risk of being nonadherent given the variety of medications that they are often expected to take concurrently. Associations between medication nonadherence and poor patient outcomes or increased medical costs in children have been sparsely reported in the literature for some chronic pediatric disorders such as asthma, leukemia, and renal transplantation (13–15). Despite the importance of medications in the treatment of pediatric patients with IBD, scarce attention has been given to evaluating nonadherence in this group. The principle aim of this study was to assess the prevalence of medication nonadherence through the use of a prescription refill score for 2 medication classes that are routinely used to treat children with CD. The refill score provides information about the amount of medication dispensed and helps define a lower limit for medication nonadherence for each patient. Secondary aims of the study included evaluating whether health care contacts or disease activity was associated with nonadherence.

PATIENTS AND METHODS

Criteria and Protocol

Patients were recruited at the time of an outpatient visit with a pediatric gastroenterologist at the Johns Hopkins Children's Center, which is a tertiary care institution. Patients were invited to participate in the study if they were <18 years of age, had a confirmed diagnosis of CD for at least 6 months, and had been prescribed a thiopurine immunomodulator (6-mercaptopurine or azathioprine) and/or mesalamine for at least half of the previous 180-day period. Patient demographic information and clinical data, including disease extent, duration of disease and number of concomitant medications, were collected at the time of the enrollment visit from the patient, parent and medical records. A Pediatric Crohn Disease Activity Index (PCDAI) was calculated for each patient at the time of enrollment by the primary gastroenterologist (16). The telephone numbers for all pharmacies, including mail-order warehouses, used to fill patient prescriptions in the preceding 180 days were obtained from the patient's parent or primary caregiver. Knowing our patient population, we assumed that most of our patients would fill their prescriptions on a monthly basis; thus, a 180-day time period would potentially capture data for a maximum of 6 refill intervals. Information regarding medical visits, hospitalizations, and emergency room visits was obtained during the parent interview. Those visits in which the chief complaint was associated with gastrointestinal symptoms resulting from the patient's CD or known extraintestinal manifestations of CD were included in the study. In addition, names, telephone numbers, and other identifying information about health care providers and/or locations at which the patient was seen for a medical visit in the previous 180 days were obtained, and these medical contacts were subsequently confirmed with the health care providers and by reviewing the patient's medical records. The study was conducted between January 2002 and December 2003. The research protocol was approved by the Johns Hopkins Institutional Review Board. Informed consent was obtained from the parent or legal guardian, and assent was obtained from the patient when appropriate.

Analysis of Medication Adherence

Medication adherence was calculated for each patient during the 180-day period preceding study enrollment from pharmacy refill records. A refill score was obtained for each patient for each medication class that they were prescribed using a previously described and validated formula: cumulative days of medication dispensed during the study period divided by the total days in the study period (180 days) multiplied by 100 (17). Patients were classified as being adherent if their refill score was ≥80% during the 180-day study period. This 80% cutoff has often been used in the literature to define good compliance and is consistent with compliance rates reported in IBD drug trials for achieving and maintaining symptom-free periods (6,18–20). It is based on the principle that >20% loss of a patient population in a clinical trial may make the results potentially invalid (21).

Statistical Analysis

In initial exploratory analyses, descriptive statistics were used to quantify differences by adherence group. For univariate confirmatory analyses, 2-sided t tests and χ2 tests were used to assess the associations between adherence and both continuous and categorical outcome measures. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated to assess the strength of association between adherence and outcome measures. A value of P = 0.05 was considered statistically significant.

RESULTS

Patient Demographics

Fifty-one patients were enrolled in the study, and their characteristics are shown in Table 1. Sixty-three percent were male, 78% were white and the mean ± SD age was 14.2 ± 3.2 years (range, 5.3–20 y). Mean duration of illness from time of diagnosis was 25.5 ± 19.3 months (range, 6–79 mo). Fifty-five percent had ileocolonic CD and 37% had colonic CD. The median number of concurrent medications being taken at the time of study entry was 3 (range, 1–8).

T1-5
TABLE 1:
Patient characteristics

Thiopurine Immunomodulator Adherence

A total of 38 patients were prescribed once-daily doses of a thiopurine immunomodulator, which in 92% of the cases was 6-mercaptopurine. Two patients had incomplete data; thus, analysis was performed on the remaining 36 patients. Fifty percent of the patients were categorized as being adherent. The median refill score—the median amount of dispensed medication—was 78% (range, 0%–194%). Five patients (14%) did not refill their thiopurine immunomodulator prescription during the study period. Race, gender and age did not affect adherence for this medication.

Mesalamine Medication Adherence

A total of 44 patients were prescribed mesalamine; dosing schedules were either 2 or 3 times daily. Fifteen patients (34%) were adherent and 29 (66%) were not adherent to their prescribed dose of mesalamine. The median refill score for mesalamine was 50% (range, 0%–118%). Six patients (14%) did not refill any of their prescriptions during the study period. There was no significant difference in refill score by race, gender or age.

Association of Medical Visits and Health Status With Medication Adherence

The mean ± SD number of emergency department visits for a patient adherent to mesalamine was 0.80 ± 0.17, a difference that was significantly greater than the mean of 0.17 ± 0.09 for a patient classified as nonadherent (P < 0.0008). Paying a visit to the emergency department increased the odds of being adherent with mesalamine by >9-fold (OR, 9.6; 95% CI, 1.87–52.17). The mean number of health care contacts (emergency department outpatient and inpatient visits) for a patient adherent to mesalamine also was significantly greater than for a nonadherent patient (6.1 ± 0.8 vs 3.0 ± 0.4; P < 0.001). This difference was not affected by compliance with a thiopurine immunomodulator.

Patients who did not have clinical evidence of disease activity (PCDAI < 15) at the enrollment visit were more nonadherent to mesalamine compared with those who were not in remission (PCDAI > 15), a difference that tended toward statistical significance (P < 0.1). In fact, patients in remission were 4 times more likely to be nonadherent to mesalamine (OR, 4.19; 95% CI, 0.54–34.49) and were 3 times more likely to be nonadherent to thiopurine immunomodulators (OR, 3.47; 95% CI, 0.32–31.56) compared with patients not in remission. Given the low number of patients in this study, neither result approached statistical significance.

DISCUSSION

To the best of our knowledge, this is the first study to evaluate the prevalence of medication nonadherence in children with CD using a validated objective measure. Our results show that nonadherence with medical therapy was high, with 50% of patients being nonadherent to prescribed thiopurine immunomodulator therapy and 66% nonadherent to mesalamine therapy. In addition, 14% of patients did not refill their medications even once during the 180-day study period, although they were presumed to be taking it on a daily basis.

Our findings concur with those of other published adult IBD studies that have shown that similar to other chronic diseases, nonadherence to medication therapy is common in IBD. Van Hees and van Tongeren (22) found that serum sulfapyridine levels in hospitalized adults taking sulfasalazine dropped by >25% shortly after discharge. In addition, serum levels of maintenance sulfasalazine were undetectable in 12% of the subjects at outpatient follow-up. Shale and Riley (23) reported that 43% of their adult patients were nonadherent to their prescribed amount of mesalamine. Although 2% admitted to taking no medication at all, urinary drug analysis revealed no detectable drug or metabolite in 12% of patients. In a questionnaire-based study, Sewitch et al. (24) reported that 41.2% of adults indicated that they were either intentionally or nonintentionally nonadherent to their IBD medications. Kane et al. (20) studied adults with ulcerative colitis and found that 60% were nonadherent. A follow-up study of the same adult cohort during disease quiescence revealed that nonadherence to mesalamine increased the risk of clinical relapse by >5-fold (11).

One study evaluated medication adherence in children with IBD: Mackner and Crandall (25) reported on interviews conducted with children and their parents. Their study reports a better prevalence of adherence than our results, with 80% to 91% of parents and 85% to 100% of children reporting being adherent “most of the time” or “always” with specific IBD medications. The difference may in part be population related or may be due to the fact that these investigators used self-reporting and parent reporting. Inquiry to the patient via an interview or questionnaire is the most commonly used method for measuring adherence because of its ease of use, but it is known to be fraught with inaccuracies because patients typically overestimate their medication consumption (6,17).

Our results showed that patients who were adherent to mesalamine, in particular, had a greater number of health-care visits compared with those who were classified as nonadherent. Children who presented at enrollment with greater disease activity were more likely to be classified as adherent, which suggests that being symptomatic or having a health care visit may act as a prompt to become more adherent to medical therapy. Adult studies have associated active IBD and more extensive colitis with decreases in the risk of overall nonadherence to medication (11,24). Conversely, this may indicate that children who are feeling well are at highest risk for not taking their prescribed medications and is in agreement with the difficulty of having patients take medications over prolonged time periods when they are asymptomatic (6). Long-term medical therapy with thiopurine immunomodulators for CD is often prescribed because it is believed to reduce the frequency of relapse (5,26). Recent studies also have suggested that mesalamine may reduce the increased risk of colorectal cancer in some patients with ulcerative colitis (10,27,28). The high potential for nonadherence in these situations needs to be addressed.

Not surprisingly, the refill score was better for the drug class prescribed with fewer daily doses—once daily for thiopurine immunomodulators versus more frequently for mesalamine. Given that these 2 medication classes are completely different entities, it would be too simple to imply that the thiopurine immunomodulators had improved adherence solely because of decreased dosing frequency. However, studies have shown improved medication adherence when treatments are given only once or twice daily compared with ≥3 times per day or when patients view the dosing regimen as convenient or simple (23,29,30).

Although the factors that contribute to poor adherence in children are varied and similar to those affecting adults, an added dimension of the situation is the involvement of patients' families (6,31,32). In general, adherence to pediatric therapies for chronic disease can be particularly difficult to achieve because it is dependent on the child's behavior and developmental stage and requires a second individual, the caregiver, to be attentive and adherent. However, an important reason to focus on the pediatric population in terms of medication adherence is that there is evidence that complying with treatment may have an even greater effect on the health outcomes of children than on those of adults (33).

Pharmacy data were chosen as a measure of medication adherence for this study because they have been shown to correlate well with more direct measures of compliance such as serum or urine drug levels and drug treatment effect (34–36). Pharmacy data also have been found to be a useful measure of adherence for drugs intended for long-term, nondiscretionary use. This method was preferable to more intrusive or costly measures such as pill counts, metabolite measurements, and electronic recording devices, which are not easily amenable for use in clinical practice. A particular strength of using refill data is that we were able to obtain information about medication use during a time period when the patients and their families were not aware that adherence was being evaluated and thus could not artificially alter their behaviors. However, there are limitations to our study. For example, we cannot guarantee that patients did not receive their medications from multiple physicians. We tried to the best of our ability to ensure that subjects did not receive prescriptions from primary care physicians or others. Customarily, our patient population always receives prescriptions for their IBD medications from our group of providers. Second, the prescription refill measure assumes that the number of pills dispensed to a patient is an accurate estimate of pill consumption. Obviously, even if the patient fills a prescription, there is no guarantee that the medicine will actually be consumed; thus, the refill score is identifying an upper limit for medication consumption. Unfortunately, this indicates that the prevalence of medication nonadherence may be even higher than our numbers reflect. Nonetheless, refill data have a high specificity and may allow identification of a group of patients who cannot be taking enough medication to achieve a treatment goal because they have not obtained enough (17).

In conclusion, this study shows that nonadherence to thiopurine immunomodulator and mesalamine therapy in children with CD is high. Future studies establishing the impact of nonadherence to patient outcomes or health care costs are important to determine the amount of intervention required to enhance adherence.

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Keywords:

Inflammatory bowel disease; Crohn disease; Medication; Mesalamine; 6-Mercaptopurine; Azathioprine; Adherence; Compliance; Child

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