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).
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.
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).
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.
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.
1. Baldassano RN, Piccoli DA. Inflammatory bowel disease in pediatric and adolescent patients. Gastroenterol Clin North Am 1999; 28:445–458.
2. Podolsky DK. Inflammatory bowel disease. N Engl J Med 2002; 347:417–429.
3. Lichtenstein GR, Hanauer SB, Kane SV, et al
. Crohn's is not a 6-week disease: lifelong management of mild to moderate Crohn's disease. Inflamm Bowel Dis 2004; 10(Suppl 2):S2–S10.
4. Lichtenstein GR, Abreu MT, Cohen R, et al
. American Gastroenterological Association Institute technical review on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology 2006; 130:940–987.
5. Hanauer SB, Dassopoulos T. Evolving treatment strategies for inflammatory bowel disease. Annu Rev Med 2001; 52:299–318.
6. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med 2005; 353:487–497.
7. Gendre JP, Mary JY, Florent C, et al
. Oral mesalamine (Pentasa) as maintenance treatment in Crohn's disease: a multicenter placebo-controlled study: the Groupe d'Etudes Therapeutiques des Affections Inflammatoires Digestives (GETAID). Gastroenterology 1993; 104:435–439.
8. Horwitz RI, Horwitz SM. Adherence to treatment and health outcomes. Arch Intern Med 1993; 153:1863–1868.
9. Miller NH. Compliance with treatment regimens in chronic asymptomatic diseases. Am J Med 1997; 102:43–49.
10. Pinczowski D, Ekbom A, Baron J, et al
. Risk factors for colorectal cancer in patients with ulcerative colitis: a case-control study. Gastroenterology 1994; 107:117–120.
11. Kane S, Huo D, Aikens J, et al
. Medication nonadherence and the outcomes of patients with quiescent ulcerative colitis. Am J Med 2003; 114:39–43.
12. Matsui DM. Drug compliance in pediatrics: clinical and research issues. Pediatr Clin North Am 1997; 44:1–14.
13. Weinstein AG. Clinical management strategies to maintain drug compliance in asthmatic children. Ann Allergy Asthma Immunol 1995; 74:304–310.
14. Festa RS, Tamaroff MH, Chasalow F, et al
. Therapeutic adherence to oral medication regimens by adolescents with cancer. I: laboratory assessment. J Pediatr 1992; 120:807–811.
15. Meyers KE, Thomson PD, Weiland H. Noncompliance in children and adolescents after renal transplantation. Transplantation 1996; 62:186–189.
16. Hyams JS, Ferry GD, Mandel FS, et al
. Development and validation of a Pediatric Crohn's Disease Activity Index. J Pediatr Gastroenterol Nutr 1991; 12:439–447.
17. Steiner JF, Prochazka AV. The assessment of refill compliance using pharmacy records: methods, validity, and applications. J Clin Epidemiol 1997; 50:105–116.
18. McHutchison JG, Manns M, Patel K, et al
. Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology 2002; 123:1061–1069.
19. Paterson DL, Swindells S, Mohr J, et al
. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med 2000; 133:21–30.
20. Kane SV, Cohen RD, Aikens JE, et al
. Prevalence of nonadherence with maintenance mesalamine in quiescent ulcerative colitis. Am J Gastroenterol 2001; 96:2929–2933.
21. Guyatt GH, Sackett DL, Cook DJ. Users' guides to the medical literature. II: how to use an article about therapy or prevention. A: are the results of the study valid? Evidence-Based Medicine Working Group. JAMA 1993; 270:2598–2601.
22. van Hees PA, van Tongeren JH. Compliance to therapy in patients on a maintenance dose of sulfasalazine. J Clin Gastroenterol 1982; 4:333–336.
23. Shale MJ, Riley SA. Studies of compliance with delayed-release mesalazine therapy in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2003; 18:191–198.
24. Sewitch MJ, Abrahamowicz M, Barkun A, et al
. Patient nonadherence to medication in inflammatory bowel disease. Am J Gastroenterol 2003; 98:1535–1544.
25. Mackner LM, Crandall WV. Oral medication adherence in pediatric inflammatory bowel disease. Inflamm Bowel Dis 2005; 11:1006–1012.
26. Markowitz J, Grancher K, Kohn N, et al
. A multicenter trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn's disease. Gastroenterology 2000; 119:895–902.
27. Moody GA, Jayanthi V, Probert CS, et al
. Long-term therapy with sulphasalazine protects against colorectal cancer in ulcerative colitis: a retrospective study of colorectal cancer risk and compliance with treatment in Leicestershire. Eur J Gastroenterol Hepatol 1996; 8:1179–1183.
28. Eaden J, Abrams K, Ekbom A, et al
. Colorectal cancer prevention in ulcerative colitis: a case-control study. Aliment Pharmacol Ther 2000; 14:145–153.
29. Pullar T, Birtwell AJ, Wiles PG, et al
. Use of a pharmacologic indicator to compare compliance with tablets prescribed to be taken once, twice, or three times daily. Clin Pharmacol Ther 1988; 44:540–545.
30. Farup PG, Hovde O, Halvorsen FA, et al
. Mesalazine suppositories versus hydrocortisone foam in patients with distal ulcerative colitis: a comparison of the efficacy and practicality of two topical treatment regimens. Scand J Gastroenterol 1995; 30:164–170.
31. Loghman-Adham M. Medication noncompliance in patients with chronic disease: issues in dialysis and renal transplantation. Am J Manag Care 2003; 9:155–171.
32. Brackis-Cott E, Mellins CA, Abrams E, et al
. Pediatric HIV medication adherence: the views of medical providers from two primary care programs. J Pediatr Health Care 2003; 17:252–260.
33. DiMatteo MR, Giordani PJ, Lepper HS, et al
. Patient adherence and medical treatment outcomes: a meta-analysis. Med Care 2002; 40:794–811.
34. Steiner JF, Koepsell TD, Fihn SD, et al
. A general method of compliance assessment using centralized pharmacy records: description and validation. Med Care 1988; 26:814–823.
35. Inui TS, Carter WB, Pecoraro RE, et al
. Variations in patient compliance with common long-term drugs. Med Care 1980; 18:986–993.
36. Bond CA, Monson R. Sustained improvement in drug documentation, compliance, and disease control: a four-year analysis of an ambulatory care model. Arch Intern Med 1984; 144:1159–1162.