Impact of a patient-support program on mesalamine adherence in patients with ulcerative colitis — A prospective study

Methods Patients prescribed mesalamine for ulcerative colitis prospectively received either a 23 week, nurse-delivered, patient support program (PSP) by phone, or standard care (SC). Medication adherence and quality of life were measured before and at 3 and 6 months after the program started. Results Eighty-one patients completed the study; 60 who received standard care, and 21 who received the PSP. Patients were in remission (mean SCAI score 3) at enrollment. Mean % of prescribed mesalamine refilled was 71% and 74% in the SC and PSP groups at 3 months ( p = 0.7), and 73% and 84% at 6 months ( p = 0.4). The proportion of adherent patients at 3 months (39% vs 44%, p = 0.7) and 6 months (50% vs 67%, p = 0.3) were similar between the SC and PSP groups. There was no association between use of the PSP and adherence at 3 (OR 1.2, 95% CI 0.4 to 3.8) or 6 months (OR 2, 95% CI 0.6 to 7). The change from baseline in SIBDQ scores were similar between SC and PSP groups at 3 months (+ 0.3 vs + 0.2, p = 0.8), and 6 months (+ 0.6 vs + 0.2, p = 0.2). Conclusions This nurse-delivered patient-support program did not significantly improve medication adherence or quality-of-life beyond standard care at short and medium-term time-points. Simply discussing and measuring adherence improved mesalamine adherence in both groups in this study. Abbreviations: PSP Patient-Support Program SC Standard Care SIBDQ Short Inflammatory Bowel Disease Questionnaire SCAI Simple Colitis Activity Index. Keywords Mesalamine Adherence Behavioral interventions 1 Background Ulcerative colitis (UC) is a chronic disease of the colon characterized by periods of disease relapse and remission, and thus requires life-long treatment. Mesalamine is an effective medication for induction and maintenance of remission in this condition, and is a standard first-line agent. 1 Despite this, a significant proportion of patients do not adhere to the prescribed interval and dose regimen of mesalamine, especially those whose disease is inactive. 2 Most patients report that the reasons for their non-adherence are involuntary e.g. they forget to take the pills, rather than intentional. 3 Other factors that have been associated with non-adherence include male gender, full-time employment, and multiple dosing schedules. 2,4,5 It is unclear whether newer single daily dosing formulations of mesalamine will improve adherence rates. 6 Non-adherence to mesalamine has negative implications for patients and the healthcare system. The risk of disease recurrence is 5 times higher in patients who are non-adherent to maintenance mesalamine compared to adherent patients. 3 Since chronic inflammation is a risk factor for colorectal cancer development, this may also influence cancer risk. The crude proportions of patients developing colorectal cancer are 10-fold higher in patients deemed to be non-adherent with sulfasalazine, when compared to patients adherent to maintenance therapy. 7 Finally, patients who are non-adherent with 5-aminosalicylic acid agents (5-ASAs) have higher healthcare costs than adherent patients for in-patient, out-patient and office visit services. 8 Strategies to improve patient adherence, such as behavioral interventions and monitoring and feedback, have been studied in other chronic illnesses with mixed results. 9 Individualized care by telephone was shown to significantly improve medication adherence in a large cohort of diabetics. 10 However, phone calls from store-based pharmacists was not shown to improve persistence of prescription refills for chronic diseases beyond standard care. 11 There are few published data on interventions to improve mesalamine adherence in UC. An interventional strategy to minimize mesalamine dosing schedules did not significantly improve 6-month adherence rates in a small study of 22 patients. 6 Whether behavioral interventions can improve mesalamine adherence in these patients is unknown. Monitoring and feedback interventions have not been studied in mesalamine adherence to date. The objective of this study was to determine whether a patient-support program over 23 weeks would improve mesalamine adherence at 3 and 6 months in patients with ulcerative colitis. 2 Methods 2.1 Patient enrollment Patients with ulcerative colitis in remission (for at least 2 months) who were prescribed delayed-release mesalamine (Asacol, Proctor & Gamble, Ohio) were eligible for enrollment. Informed consent was obtained according to a study protocol approved by the local Committee on Clinical Investigations (BIDMC Protocol 2007P000083). Patient demographics and disease geography and pharmacy contact details were obtained after enrollment. A baseline Short Inflammatory Bowel Disease Questionnaire (SIBDQ) score, and Simple Colitis Activity Index score (SCAI) were obtained. Both scoring systems have been developed for patients with ulcerative colitis. 12,13 2.2 Interventions The first 44 patients were randomized by computer-generated random numbers to receive the PSP or SC during a period of 6 months. After the PSP was discontinued by the sponsor, a further 37 patients were sequentially enrolled into the SC arm. Patients in the standard care group (SC) continued to receive standard follow-up and medication refills as was their physicians' practice. All patients received information about the purpose of the study from the study coordinator, and signed a consent form. Patients in the Patient Support Program (PSP) group were enrolled in ScriptAssist (CenCorp Health Solutions, St Louis, MO) an independent treatment adherence program that provides disease-specific information and promotion of medication adherence to patients. Each patient in the PSP group received phone calls from a nurse at 24 h, 3 weeks, 7 weeks, 15 weeks and 23 weeks after enrollment (5 calls in total). The nurses are trained to assess patient risk for noncompliance and intervene with psychological techniques that improve patient medication persistence. A log of each phone conversation was faxed to the treating physician to ensure completion of planned interactions. The nurses involved were blinded to the fact that these patients were enrolled in a study to assess adherence. All patients were enrolled from the clinics of 3 physicians (AM, KF, AC) with an interest in IBD, with similar patient management practices. 2.3 Outcomes Each patient enrolled had their SCAI and SIBDQ measured at enrollment. At 3 and 6 months SIBDQ, medication adherence, number of hospitalizations, and number of disease flares were recorded. Medication adherence was calculated based on refill data from pharmacies according to Steiner's formula. 14 Only patients with adherence > 80% of the time at 3 and 6 months were considered to be “adherent”, as defined in prior studies of mesalamine adherence. 2 This method is considered to provide superior adherence information than patient reporting. “Number of hospitalizations” was based on discharge summaries for ulcerative colitis diagnoses. “Number of disease flares” was based on reports in electronic medical records of treatment intensification or adjustment due to clinical symptoms of active ulcerative colitis. All follow-up outcomes were recorded and analyzed by an investigator blinded to the intervention group. 2.4 Statistical analysis In total, 21 patients took part on the PSP, and formed the PSP cohort. A further 60 patients were prospectively enrolled who received SC over the same 6 month timeline. In order to determine the power of the study with these numbers, the average adherence effect size for “reminder and support” interventions was found to be r = 0.3 from prior studies. 15,16 Power analysis revealed that with 21patients in the PSP cohort, a 3:1 control to case ratio, an r = 0.3, and an α of 0.05, the study would have a power of 0.67 to detect an effect of this size. Since this was a pilot study, where type II errors are of greater concern, we considered it reasonable to reduce α to 0.1. This would provide an adequate power of 0.78 to detect an effect size of 0.3 or greater. For statistical analysis, continuous variables were compared using the t test if normally distributed or Wilcoxon rank sum test otherwise. Categorical outcomes were compared using the chi-squared test or Fisher's exact test if any individual cell size was less than 5. A nominal logistic regression model was created using significantly-associated variables ( p < 0.1), and the odds ratio for those variables that remained significant ( p < 0.05) in the model determined. A Goodness of Fit test was also performed to determine whether sufficient variables were included in the final model. JMP software was used for statistical analysis (SAS Institute, Cary, NC). 3 Results In total, 81patients were enrolled in the study; 21 in the PSP group and 60 in the standard care group. The demographic and phenotypic characteristics of the participants were similar in each group (detailed in Table 1 ). Both groups had inactive disease (SCAI score < 3), and high quality of life scores (> 5 on a 1–7 scale) at the time of enrollment. Their mean mesalamine doses prescribed (mean 3.9 g and 3.5 g) were higher than the approved standard maintenance of remission dose (2.4 g). 3.1 Medication adherence Adherence was measured based on refills at 3 and 6 months from enrollment. At 3 months the mean % of prescribed mesalamine refilled was 71% (SD 24%) in the SC group, and 74% (SD 19%) in the PSP group (p = 0.7) ( Fig. 1 ). By 6 months, the mean % of prescribed mesalamine refilled was 73% (SD 30%) in the SC group, and 84% (SD 18%) in the PSP group ( p = 0.4). The difference in refill percentage between the two groups was not significant. When the frequency of overall adherence (> 80% of prescribed mesalamine refilled) was compared between the two groups, the % of patients adherent at 3 months was 39% in the SC group and 44% in the PSP group ( Table 2 ). By 6 months, these rates had increased to 50% in the SC group and 67% in the PSP group, but the difference between both arms was not statistically significant ( p = 0.3). In a univariate analysis, age, gender, disease extent, mesalamine dose and initial disease activity score were not associated with adherence at 3 or 6 months. Patients receiving the PSP had no higher odds of adherence than standard care at 3 months (OR 1.2, 95% CI 0.4 to 3.8), or 6 months (OR 2, 95% CI 0.6 to 7). 3.2 Quality-of-life At baseline, mean SIBDQ scores were similar in both groups ( Table 1 ). After 3 months in the study, the mean scores increased slightly to 5.9 (SD 1.1) in the SC group and 5.4 (SD 1.3) in the PSP group ( p = 0.1). The mean change in SIBDQ (ΔSIBDQ) was + 0.3 (SD 1.0) in the SC group and + 0.2 (SD 0.7) in the PSP group. By 6 months, mean SIBDQ scores in the SC group (6.5, SD 0.7) were significantly higher than the PSP group (5.7, SD 0.7) ( p = 0.001) ( Fig. 2 ). However, the mean ΔSIBDQ from baseline was + 0.6 (SD 1.0) in the SC group and + 0.2 (SD 0.8) in the PSP group ( p = 0.2). 3.3 Secondary outcomes During the course of the study, 8/21 patients (38%) in the PSP arm, and 8/57 (14%) in patients in the control arm had disease exacerbations by 6 months ( p = 0.05), although this was non-significant after correction for multiple testing (Bonferroni). When hospitalizations for ulcerative colitis were compared, no patients in the PSP arm, and 3/57 patients (5%) in the control arm had been hospitalized by 6 months ( p = 0.5). When univariate analysis was performed, no patient or intervention factor measured (age, gender, disease location, mesalamine dose, SCAI score, SIBDQ score, or PSP use) was significantly associated with disease flares or hospitalizations over 6 months. 4 Discussion This prospective study has demonstrated that a patient-support program (PSP) by telephone did not significantly improve patient adherence, patient quality-of-life, disease exacerbation or hospitalization rates over 6 months when compared to standard care in patients prescribed mesalamine. There was a uniform increase in patient adherence over time in both groups during the study, which was numerically greater in the PSP arm, but not statistically significant. It is widely accepted that adherence to medications for inflammatory bowel disease is poor, and mesalamine is no exception. 2 Much debate has occurred in the recent literature on the topic of whether the large number of mesalamine pills, and their dosing frequency, contributes to this problem. 17 Data from other chronic illnesses have reported an inverse association between frequent dosing and medication adherence, and this was confirmed in one study in IBD. 5,18,19 However, other studies of mesalamine in IBD have not found any relationship between adherence and dose schedules. 6,20 Since patient-related factors appear to be of greater influence on medication adherence, addressing these through behavioral interventions appeared to be a logical next-step. 9,20 The patient-support program utilized in this study shares some features with successful interventions used in other chronic diseases. Two large behavioral studies that used regular telephone calls to encourage patient adherence and disease-comprehension reported significantly increased medication adherence at 6 months. 21,22 However, similar behavioral interventions in other studies did not improve adherence to medical therapy in patients with hypertension and asthma. 23,24 Since there is a wide variation in the effect size in these studies, patient factors such as age, educational level, and lifestyle may limit the comparability of results. Our patient population appears representative of most specialty IBD practices, and therefore likely applicable to this setting. In our study, the proportion of patients who were adherent increased over the time-course of the study, regardless of whether they received the PSP or not. This suggests that simply discussing adherence, and informing the patient that it will be monitored, is an effective intervention in improving adherence levels. It should be noted that the discussion of adherence took place with the study coordinator only, so there was no physician-patient reinforcement of adherence in either group. It also supports prior work that most non-adherence is unintentional, and that merely bringing the topic to their attention may improve refill rates of prescriptions. 3 There are a number of limitations to this study. As discussed in Section 2 , the initial plan for a randomized controlled trial was changed during the study, as the sponsor cancelled the PSP. Therefore this should be seen as a prospective cohort study, with well-matched cohorts. It is possible the patients enrolled after randomization was stopped had different characteristics to the initially-randomized patients, although a review of Table 1 shows similar characteristics. The numbers enrolled were sufficient to detect an expected 30% difference between groups, but not smaller differences. Thus it is possible a larger study would have reported a significant adherence difference between the interventions, albeit modest. Finally, the PSP intervention was outside of our direct control, so it was not optimized specifically for our patient population. Nonetheless, the education and advice was tailored to ulcerative colitis, and medication adherence compliance is a generic topic for chronic conditions. In conclusion, this study did not find an improvement in mesalamine adherence or quality-of-life when a patient-support program was used over 6 months in patients with ulcerative colitis. Further studies using other behavioral interventions should be examined in this setting. Acknowledgements We acknowledge the co-operation of the community pharmacists contacted for the study. The following were the authors' contributions; Alan C Moss — design, implementation, data analysis, manuscript preparation, final approval Nabeel Chaudhary, Melissa Tukey, Jahvari Junior, Didia Cury — implementation, data collection, final approval Kenneth Falchuk — implementation, article drafting, final approval Adam Cheifetz — design, implementation, manuscript preparation, final approval Authors' declaration of personal interests: Alan C Moss has received research funding from Proctor & Gamble pharmaceuticals Declaration of funding interests: This study was funded by an Investigator-Initiated Grant from Proctor & Gamble pharmaceuticals . The sponsor had no role in study design or implementation, data collection, data analysis, or manuscript preparation. References 1 L. Sutherland J.K. Macdonald Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis Cochrane Database Syst Rev 2006 CD000544 2 S.V. Kane R.D. Cohen J.E. Aikens S.B. Hanauer Prevalence of nonadherence with maintenance mesalamine in quiescent ulcerative colitis Am J Gastroenterol 96 2001 2929 2933 3 S. Kane D. Huo J. Aikens S. Hanauer Medication nonadherence and the outcomes of patients with quiescent ulcerative colitis Am J Med 114 2003 39 43 4 S.V. Kane Systematic review: adherence issues in the treatment of ulcerative colitis Aliment Pharmacol Ther 23 2006 577 585 5 M.J. Shale S.A. Riley Studies of compliance with delayed-release mesalazine therapy in patients with inflammatory bowel disease Aliment Pharmacol Ther 18 2003 191 198 6 S. Kane D. Huo K. Magnanti A pilot feasibility study of once daily versus conventional dosing mesalamine for maintenance of ulcerative colitis Clin Gastroenterol Hepatol 1 2003 170 173 7 G.A. Moody V. Jayanthi C.S. Probert K.H. Mac J.F. Mayberry 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 8 1996 1179 1183 8 S. Kane F. Shaya Medication non-adherence is associated with increased medical health care costs Dig Dis Sci 53 2008 1020 1024 9 S. Kripalani X. Yao R.B. Haynes Interventions to enhance medication adherence in chronic medical conditions: a systematic review Arch Intern Med 167 2007 540 550 10 P. Thiebaud M. Demand S.A. Wolf L.L. Alipuria Q. Ye P.R. Gutierrez Impact of disease management on utilization and adherence with drugs and tests: the case of diabetes treatment in the Florida: a Healthy State (FAHS) program Diabetes Care 31 2008 1717 1722 11 P.J. Nietert B.C. Tilley W. Zhao P.F. Edwards A.M. Wessell P.D. 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