Patient Compliance and Outcomes

Multiple studies have demonstrated the efficacy of salicylates as well as other immunomodulators in achieving and maintaining remission. These well designed multicenter trials have used pill count and patient inquiry to assess compliance, with rates ranging from 70 to > 95%, depending on the study's definition of compliance and its patient population (1,2). Community-based follow-up studies put the percentage much lower, at about 40-50% (3). Despite the advances in treatment modalities, patients continue to relapse. In Riley's study looking at factors associated with relapse, a cohort of 92 patients with ulcerative colitis (UC) was followed for 48 weeks (4). Compliance with medications was one of the variables examined. Pill count was used to determine compliance with either sulfasalazine or mesalamine therapy. Multivariate analysis failed to find any differences in drug compliance between those who relapsed and those who remained in remission, and the conclusion was that compliance did not play a significant role in clinical relapse. However, there was a 95% compliance rate for medication use in both groups. Because this statistic is significantly higher than most estimates, this finding may reflect an effect of close follow-up by medical personnel. Many patients openly admit they do not take their medications as prescribed, and the impact of medication adherence on specific inflammatory bowel disease (IBD) outcomes has not been fully explored. The literature on other chronic diseases such as coronary artery disease, congestive heart failure, and diabetes has tried to address the issue of medication noncompliance and determine its risk factors. A study on hypertension found that younger patients and Black patients were associated with noncompliance with medications (5). Another meta-analysis on coronary disease outcomes found that medication adherence, whether to real drug or placebo, led to an improved outcome, suggesting that adherent behavior may be a marker of a better prognosis or that it confers a protective effect on patients (6). The psychiatry literature suggests that application of the five-factor model of personality could contribute to the prediction of adherent behavior (7). In IBD, the issue of noncompliance is not only confined to medications but other behaviors as well (smoking, obtaining surveillance colonoscopies, and diet). The following discussion highlights those studies that have addressed this issue in both a retrospective and prospective manner. The literature on sulfasalazine and compliance was borne from pharmacokinetic studies of sulfasalazine metabolism. Das and colleagues defined its metabolism in patients with UC, during both the active and quiescent phases of the disease. They subsequently studied the relationship between clinical status and serum concentrations of sulfasalazine and its metabolities (8). Levels of total sulphapyridine (SP) were demonstrated to be different in slow versus rapid acetylators, and that a serum concentration of 20 to 50 μg/mL appeared to coincide with clinical improvement in the absence of side effects. One year follow-up on 64 outpatients revealed that of the 43 patients with quiescent disease, 32 having total SP levels above 20 μg/mL remained in remission (9). Ten of 21 with active disease had levels below 20 μg/mL and remained symptomatic. The correlation between therapeutic levels and disease activity suggested that compliance was associated with an improved outcome. It was noted that side effects were most frequent in those patients who had a total SP concentration >50 μg/mL, which suggests that slow acetylators require lower doses to achieve clinical remission. The authors suggested that estimations of serum sulphapyridine concentrations, as well as identification of the patient's acetylation phenotype, may be useful in decreasing the incidence of side effects and assessing compliance. A subsequent study by van Hees measured sulfapyridine in hospitalized patients shortly before discharge and again during follow-up clinic visits (10). In 21 of 51 patients (41.2%), there was a greater than 25% decrease in outpatient serum levels compared with initial inpatient measurement. In 21 of 175 outpatients followed over 1-4 years, drug metabolites were undetectable. There were, however, short-lived increased levels during acute flares or periods of frequent clinic visits, suggesting that close physician follow-up improved compliance. As this was a prevalence study, however, no conclusions regarding outcomes could be reached. The authors did suggest that monitoring SP levels may help reduce side effects and therefore improve compliance. Realizing the potential difficulties for long-term compliance with sulfasalazine, Dickinson et al. studied continuous versus “on demand” sulfasalazine in 28 patients with quiescent UC (11). Of the 18 patients in the ondemand group, directed to take 3 g of sulfasalazine per day starting within 24 hours of symptom recurrence, 7 relapsed within the study period, 4 within the first 2 months of the trial. Three of the 10 patients randomized to the continuous group relapsed. Compliance was measured by serum sulfapyridine levels every 4 months for 1 year or until relapse, and was reported as adequate for patients in either group. The authors concluded that because there was no difference in relapse rates between the two groups, and that by serologic testing sulfapyridine levels were therapeutic, that an on-demand regimen may be as efficacious as continuous therapy. These results were published as preliminary, and to date no larger studies have been published to corroborate these results. There are two important studies correlating adherence with sulfasalazine therapy to the development of colorectal cancer. In a retrospective case control study, Pinczowski found that a record of at least a 3-month history of therapy with sulfasalazine had a protective effect for colon cancer (12). There was a 62% reduction in risk with any history of therapy in the 102 patients studied. The major weakness of the study was the imprecise documentation of dose and duration for each patient. The second study was also a retrospective study of 168 patients with at least a 10-year history of UC (13). The outcome of interest was cancer, and risk was assessed based on use of sulfasalazine. A patient was classified as noncompliant if there was clear evidence in the medical record of medications not taken or upon the advice of a physician, medication was discontinued. The crude cancer rate was 3% in compliant patients, and 31% in those not compliant. Since the authors found a colectomy rate and cancer incidence similar to previously published series, they concluded that medications were beneficial in reducing cancer risk. There is little data available regarding true compliance rates with the various 5-ASA preparations. The reported compliance rate is 75% or better in clinical trials for maintenance therapy. While the side effect profile is improved with the absence of the sulfa moiety, the number of pills required per day to maintain remission can be cumbersome and most likely affects compliance. One study looking at the effectiveness of 1,000 mg tablets versus 500 mg of mesalamine also incorporated information regarding patient preferences (14). Eighteen patients took 1 g tablets b.i.d. and 4 tablets of 500 mg for 4 weeks in this cross-over trial. The primary outcome was maintenance of remission, which was documented to be similar for either formulation. Eighty-nine percent of patients preferred the 1 g tablets, citing the decreased number of pills ingested per day as the reason. Despite the overwhelming patient preference for the 1 g tablets, the compliance for each formulation was high, with a mean pill consumption of 1.98 and 3.94 tablets per day, respectively. Two potential biases to this study were the early exclusion of two patients for protocol violation (10% of the original study population) and the short study period. At the University of Chicago, a retrospective survey to determine the prevalence of compliance with mesalamine is currently underway. This cohort will then be followed prospectively for clinical outcomes based on compliance status. Since many patients express a concern regarding the long-term safety of azathioprine or its metabolite 6-MP, the true compliance rate of this class of medicines is unknown. Cuffari et al. studied metabolites of 6-MP using high performance liquid chromatography (HPLC) to determine any correlation between blood levels and toxicity, remission, and compliance in 25 pediatric patients with Crohn's disease (CD) (15). 6-Thioguanine levels were found to correlate with remission, and 6-methylmercaptopurine correlated with toxicity. It was suggested that this assay could be used as a means to document compliance. A subsequent study by the same group compared an assay to quantify 6-thioguanine levels in peripheral blood leukocyte DNA with those found in erythrocyte levels via HPLC, again as a potential marker of toxicity and compliance (16). In 15 pediatric patients the correlation of metabolite levels was similar between the two assays. Currently, neither one of these tests is widely available for clinical use. In addition, the authors point out that many substrates can alter metabolite levels, including 5-ASA, and allopurinol as well as genetic variability. These factors limit the practicality of these assays as monitoring tools. Dietary manipulation is considered a treatment modality for IBD. Compliance with dietary recommendations can be extremely difficult to determine, even with diligent follow-up. Levenstein randomized 70 patients with nonstenosing CD to a low residue versus normal Mediterranean diet and followed them prospectively to document outcomes (17). Diet histories were obtained at enrollment for all patients, and then again at 3-6 months in 22 unselected patients. Twelve of the patients randomized were later dropped, as they failed to have evidence of active disease and were admittedly nonadherent with their prescribed diet. Another five of the remaining 58 patients were found to be noncompliant at the end of the 29-month trial. The compliance with diet in each group was considered good, and there were no differences in clinical outcomes including hospitalizations, surgeries, or change in Crohn's Disease Activity Index (CDAI) score. In another diet and outcome study, 122 patients with CD were enrolled to study dietary supplementation with Ensure versus dietary counseling (18). There was a 61% noncompliance rate for Ensure at 3 months, and up to 73% at 6 months, despite a generous definition of compliance being greater than 33% of product consumed. The high noncompliance rate was attributed to a high side effect profile. The conclusions that any patients having received Ensure supplementation had fewer hospitalizations and surgeries and a decreased CDAI score at the end of the 6-month trial should be met with some skepticism given this poor compliance rate. A third diet and outcomes trial was a randomized trial using omega-3 fatty acids, placebo, or diet to maintain remission after surgical resection (19). Compliance to the dietary restriction of carbohydrates was assessed by monthly telephone interview and dietary booklets. Eighteen of 69 patients from the diet group were deemed noncompliant, with 10 of 70 from the placebo group, and 5 of 63 from the fatty acids group. Only 11 patients (16%) in the diet group were adherent at 12 months. Based on these data, no differences were seen in relapse rates as measured by CDAI score between the three groups. The natural history of UC is the development of an increased risk for colon cancer after long-standing disease. Annual surveillance colonoscopies are recommended to decrease the incidence. The only study to directly address the outcomes in patients documented to be noncompliant with annual exams was published by Woolrich (20). In a cohort of 121 patients with UC > 7 years, seven patients developed cancer. Two of these seven had not complied with recommendations for repeat colonoscopy or colectomy after dysplasia was found. Both patients had clinically quiescent disease and presented years later with obstructive symptoms related to their tumor. The authors concluded that compliance was diminished when a patient was asymptomatic and thereby increased his risk of cancer. Compliance cannot be enhanced unless there is first and foremost a working relationship between patient and physician. An effective means of communication is the way to build and strengthen this relationship. Misperceptions by either patient or physician regarding recommendations lead to noncompliance and potentially poor outcomes. Calkins studied whether poor outcome might be the result of differing perceptions regarding a patient's understanding of a discharge treatment plan (21). While physicians believed that 89% of their patients had a comprehension of a discharge plan and follow-up after myocardial infarction, only 57% of patients reported full understanding of discharge instructions. The overestimation on the part of the physicians suggests that patient outcomes could suffer as a result. Even though this was a study on cardiovascular disease, the conclusions apply to other chronic conditions, including IBD. Patient education also plays an important role in improving compliance. Two studies have shown that patients do not know as much about their IBD as physicians may believe. Robinson surveyed 61 patients with UC regarding their level of knowledge concerning colorectal cancer (22). While 86% of patients responding knew of the increased risk of cancer, only 44% knew that it was possible to screen for early detection and possible prevention. In another questionnaire study, Martin and colleagues queried patients regarding their concerns about their disease (23). He found that 62% of UC and 78% of CD patients felt ill-informed regarding their disease. In Drossman's Rating Form of Inflammatory Bowel Disease Patient Concerns (RFIPC), the two most highly rated concerns are the nature of disease and the effect of medications (24). Educating patients will both dispel unwarranted fears and cure ignorance. Collaborative management is one method of practice that incorporates education as well as open communication. This is a construct based on behavioral principles and empirical evidence about effective care in chronic illness (25). The key components include collaborative definition of problems, goal-setting and planning, and active and sustained follow-up. This type of care was designed to facilitate patient participation in self-care, and improve outcomes via enhanced compliance. Experts agree that a simplified medical regimen helps with patient compliance. Farup et al., in their trial of mesalazine versus hydrocortisone foam enemas, incorporated the issue of tolerability, ease, and compliance into the data collection (26). In this 4-week trial, 79 patients with distal UC were randomized to either treatment group and followed for disease response. While both treatments were found to be efficacious, the mesalazine group had significantly lower disease scores at the end of the 4 weeks. This was attributed to the patients' evaluation of practicality and compliance with the mesalazine preparation. Patients were asked to mark on a 100-mm visual analog scale an assessment of their medication regimen with regard to ease of administration and practicality. Compliance, as measured by the return of unused bottles, was >80% at 2 weeks in both groups, then dropped to 73% for the foam patients, and remained >90% for the mesalazine group. The authors contend the better outcome in the mesalazine group was the convenient, simple preparation and thus better compliance. Establishing the prevalence and impact of nonadherence on outcomes is important, since the magnitude and significance of this will determine the degree to which potential benefits of intervention are unrealized. Small retrospective and prospective studies support the claim that patient compliance is associated with positive outcomes. However, larger population-based prospective studies are needed to document true compliance rates, as well as the association of noncompliance with significant clinical outcomes.