Inflammatory bowel disease comprises a group of chronic relapsing inflammatory disorders affecting the bowel. In the last decade, the advent of biological drugs brought about a drastic change in the treatment of the disease. Adalimumab, golimumab and ustekinumab are three biologic agents that patients can self-administer subcutaneously after collecting them from the pharmacy department. However, for the treatment to be effective, adherence is paramount. The purpose of the present study is to evaluate adherence in patients who collected all three drugs from the dispensary of a tertiary care hospital.
MethodA cross-sectional observational analysis was carried out of patients who had been receiving treatment with adalimumab, golimumab and ustekinumab for at least four months. The medication possession ratio was calculated based on information extracted from the pharmacy dispensing records. Patients with a ratio < 85% were enrolled in the study and asked to respond to Morisky-Green Medication Adherence Questionnaire.
ResultsOne-hundred and seventy-eight patients were included, of whom 60.1% (107) were male and 30.9% (55) had been treated previously with other biologics. According to the pharmacy dispensing records, mean adherence was 91.79%, with 45 patients (25.28%) classified as scarcely compliant (< 85%). The Morisky-Green Medication Adherence Questionnaire revealed that carelessness about administering the drug at the right time and forgetfulness were the main reasons for therapeutic non-adherence. Female sex (odds ratio 0.42; p = 0.013) and lengthy treatments (p = 0.002) were associated to lower adherence rates.
ConclusionsAlthough most patients in the studied population were seen to be compliant, low levels of adherence were observed in a number of patients who would benefit from interventions aimed at boosting their adherence. It must be said, however, that the statistical power of this study should be enhanced in order to increase the significance of the results obtained.
La enfermedad inflamatoria intestinal es un grupo de trastornos crónicos, inflamatorios y recidivantes que afectan al intestino. En la última década, los fármacos biológicos han supuesto un gran cambio en la terapia de esta enfermedad. Adalimumab, golimumab y ustekinumab son tres de ellos que se administran por vía subcutánea tras su dispensación en los servicios de farmacia de los hospitales. Para que se alcance la efectividad del tratamiento es necesaria una adecuada adherencia al mismo. El objetivo del presente trabajo fue evaluar la adherencia en pacientes que recogían los tres fármacos en el servicio de farmacia de un hospital de tercer nivel.
MétodoSe realizó un estudio analítico observacional de corte transversal en el que se incluyó a pacientes que recibían tratamiento con los anteriores fármacos durante al menos cuatro meses. Se recogió la tasa de posesión de la medicación proporcionada por el registro de dispensaciones y se seleccionó a los pacientes que presentaron un valor inferior o igual al 85%. A estos pacientes se les aplicó el cuestionario de medida del cumplimiento terapéutico de Morisky-Green.
ResultadosSe incluyeron 178 pacientes, de los cuales el 60,1% (107) fueron hombres y el 30,9% (55) habían sido tratados con otros fármacos biológicos previamente. La adherencia media, según el registro de dispensaciones, fue del 91,79% y se clasificó a 45 pacientes (25,28%) como mal adherentes (≤ 85%). La no administración en la fecha indica-da y el olvido se identificaron como principales razones de la falta de cumplimiento terapéutico según el resultado del test de Morisky-Green. El sexo femenino (odds ratio 0,42; p = 0,013) y la duración del tratamiento (p = 0,002) se asociaron a una peor adherencia a la medicación.
ConclusionesEl porcentaje de adherencia obtenido resultó elevado en la población de estudio, pero se identificaron pacientes mal cumplidores susceptibles de recibir intervenciones para mejorar su adherencia. No obstante, se debería aumentar la potencia estadística para mejorar la validez de los resultados obtenidos.
Inflammatory bowel disease (IBD) comprises a group of chronic relapsing inflammatory conditions mainly affecting the bowel. Such conditions are Crohn's disease (CD), ulcerative colitis (UC) and indeterminate colitis (IC)1. Although these conditions have of late shown an increasing incidence, efforts to determine their etiology have so far been fruitless2.3.
As regards clinical management, fecal calprotectin (FC) is a biomarker that makes it possible to accurately identify the presence of mucosal lesions and correlate the extent of mucosal damage to the response to the treatment applied4.
The goals of treatment in patients with IBD include inflammation suppression, mucosal healing and symptom remission. To achieve them, clinicians can avail themselves of two classes of drugs: biologics and non-biologics (aminosalicylates, corticosteroids, antibiotics, immunomodulators, prebiotics and probiotics)5.
The former class of drugs heralded an about-face in the therapeutic approach to IBD. Currently approved drugs in this category include infliximab, vedolizumab, adalimumab, golimumab (only for UC) and ustekinumab (only for CD). These agents modulate inflammation, inducing and maintaining the clinical response6. According to GETECU (Spanish Working Group on CD and UC), first-line treatment in patients with these conditions should be based on conventional (non-biologic) drugs, with biologics to be reserved for patients who fail conventional agents. The exception to this rule would be patients with an aggressive onset, where biologics could be used as first-line treatment7.8.
For a drug to be optimally effective, good therapeutic adherence is of the essence. The World Health Organization (WHO), defines adherence as the extent to which a person's behavior (taking medication, following a diet and/or executing lifestyle changes) corresponds with agreed recommendations from a healthcare provider.
A concept that is akin yet different from adherence is persistence, which is defined as the length of time over which treatment is maintained9.
According to a systematic review carried out in 2013 by López et al., adherence to adalimumab and infliximab is highly variable, ranging from 36.8 to 96%10.
Poor therapeutic adherence could result in the loss of clinical response and a higher risk of developing adverse reactions, which tend to impair the patients’ quality of life and increase the healthcare bill11.
An understanding of the factors that may potentially influence treatment adherence could help identify patients likely to be poor adherents so that more attention can be focused on them. These factors can be classified into 4 categories: demographic (sex, age…); clinical (IBD type, age at diagnosis…); treatment-related (type of drug, administration route…); and psychosocial (quality of life, perception of the disease.)12.
Several methods have been developed to measure adherence in patients with chronic conditions. The most common ones are those based on questionnaires and those based on pharmacy dispensing records.
As regards questionnaires, the most commonly used validated questionnaires to determine adherence in patients with IBP are the following: the Morisky-Green Medication Adherence Questionnaire (MAQ)13; the Visual Analog Scale (VAS); the Forget Medicine Scale14; and the 5-Medication Adherence Report Scale (MARS-5)15, commonly used to determine adherence in patients with chronic conditions. The 8-item Morisky Medication Adherence Scale, an IBD-specific scale developed based on the MAQ questionnaire, was also used16.
The medication possession ratio (MPR) is an easy-to-calculate low-cost tool to determine adherence to a given medication. In the case of anti-TNF agents, it has been shown that an MPR < 80% is associated with a loss of response, which results in a poorer prognosis17.
According to the literature, the most accurate estimation of treatment adherence is usually obtained by combining two methods such as MPR and self-administered questionnaires18.
The overarching goal of the present study was to use the MPR score to determine adherence to treatment with adalimumab, golimumab and ustekinumab in patients afflicted with IBD who obtained such agents from the pharmacy dispensary of a tertiary care hospital.
Secondary endpoints included a comparison of the adherence rates obtained using the MAQ questionnaire and the MPR scale (in the subgroup of patients where adherence was ≤ 85%); an identification of factors responsible for non-adherence; an analysis of the relationship between adherence and effectiveness of treatment (according to the FC levels present) in patients with adherence ≤ 85%; and, lastly, an evaluation of persistence and the reasons why previous treatments with biologic agents were discontinued.
MethodsBetween January and June 2019. a cross-sectional observational analysis was carried out to determine adherence to treatment drawing upon data obtained from the dispensation records of the pharmacy department of a tertiary care hospital. Potential causes of non-adherence were analyzed based on the answers to the MAQ questionnaire given by the subgroup of patients exhibiting adherence 85% according to the pharmacy dispensing records.
Inclusion criteria were as follows: patients had to be older than 18 years; they were required to have been diagnosed with either CD or UC; and they had to have been on adalimumab, golimumab or ustekinumab for four months or longer. They were also required to have a MPR ≤ 85%. Indeed, although most studies use an 80% threshold10, a decision was made to establish an 85% cutoff in order to enhance the statistical power of the results. Patients with disabling mental illness were excluded.
The variables recorded for the whole patient population were sociodemographic (age, sex) and clinical (type of treatment, length of treatment, previous use of other biologics and use of concomitant drugs). In the poor adherence group the variables analyzed fell into two groups: sociodemographic variables (weight, height, smoking status, educational status and occupational status) and clinical variables (diagnosis, age at diagnosis, duration of the disease [in months], reason for discontinuation of other biologics, MAQ questionnaire results, discontinuation of treatment, hospital admissions, infections requiring deferral of treatment; and FC levels).
The MPR rate was calculated using data from the pharmacy dispensing records corresponding to the previous 4 months. The formula is as follows:
MAQ is a standardized self-administered questionnaire designed to measure therapeutic adherence on the basis of four yes/no questions that the patient must ansswer13.
The analysis also investigated whether patients had received any previous biological treatment, the reasons for discontinuing it and their persistence, which was calculated as the length of treatment from the initial to the last prescription issued.
The SSPS 25.0 software package was used for the statistical analysis. An initial analysis was made of the whole patient population, which was followed by a second analysis that only included the low-adherence subgroup. First of all, an univariate analysis was performed. Differences between continuous variables were calculated using either Student's t-test or its nonparametric equivalent to identify differences between continuous variables (depending on normality). The chi-squared test was used for categorical variables. Significant variables (p ≤ 0.05) were included in a logistic regression model.
Prior to filling in the questionnaire, the low adherence patients included in the study (n = 32) were required to sign an informed consent form granting the research team access to their clinical records. The study was authorized by the relevant Ethical Committee.
ResultsFigure 1 provides details on patient adherence to the different types of treatment. Firstly, the pharmacy dispensation records for the 178 patients who met the inclusion criteria were used to determine their adherence to treatment over the previous four months. The records revealed that 45 of those patients exhibited an adherence rate ≤ 85%. Of those 45 patients, only 32 were eventually included in the study.
Of the 13 patients who were not included, 6 had discontinued their treatment, 1 had to be admitted for acute leukemia, 4 did not show up to collect their medication, and another 2 patients refused to participate.
Of the total sample, 107 (60.10%) subjects were male, with a mean age of 46.08 (14.86) years. Of them 136 (76.40%) were treated with adalimumab, 15 (8.42%) with golimumab and 27 (15.16%) with ustekinumab. Mean duration of treatment was 135.18 (93.33) weeks. Forty-six patients (25.80%) received concomitant treatment with mesalamine and 55 (30.90%) had received previous treatment with other biologics, particularly infliximab (22.50%). The demographics of the poor adherence group are shown in Table 1.
Sociodemographic profile of patients in the low-adherence subgroup
Variable | Category | Poor adherents (%) (n = 32) | Adalimumab (%) (n = 27) | Golimumab (%) (n = 3) | Ustekinumab (%) (n = 2) |
---|---|---|---|---|---|
Sex | Male | 14 (43.80) | 12 (44.40) | 1 (33.30) | 1 (50.00) |
Female | 18 (55.20) | 15 (55.60) | 2 (65.67) | 1 (50.00) | |
Age | Mean SD | 45.28 (12.18) | 45.22 (12.04) | 48 (15.77) | 58 (2.82) |
Occupational status | Employed | 24 (75.00) | 22 (81,50) | 2 (65.67) | 0 (0.00) |
Unemployed | 8 (25.00) | 5 (18.50) | 1 (33.30) | 2 (100.00) | |
Smoking status | Smoker | 11 (34.40) | 10 (37.00) | 0 (0.00) | 1 (50.00) |
Non-smoker | 21 (65.60) | 17 (63.00) | 3 (100.00) | 1 (50.00) | |
No education | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | |
Educational status | Primary | 5 (15.60) | 3 (11,10) | 1 (33.30) | 1 (50.00) |
Secondary | 14 (43.80) | 13 (48.10) | 0 (0.00) | 1 (50.00) | |
University | 13 (40.60) | 11 (40.70) | 2 (65.67) | 0 (0.00) | |
Weight | Mean SD | 68.63 (14.17) | 70.56 (14.33) | 58 (10.39) | 58.5 (4.95) |
Height | Mean SD | 167.75 (9.89) | 168.56 (10.20) | 166 (5.91) | 159.5 (10.60) |
BMI | Mean SD | 24.47 (4.08) | 24.93 (4.06) | 21.13 (3.19) | 23.3 (4.98) |
Diagnosis | CD | 24 (75.00) | 22 (81,50) | 0 (0.00) | 2 (100.00) |
UC | 8 (25.00) | 5 (18.50) | 3 (100.00) | 0 (0.00) | |
Age at diagnosis | Mean SD | 32.88 (11,59) | 33.78 (11,10) | 28.67 (17.15) | 27 (15.97) |
Duration of disease (months) | Mean SD | 160.06 (115.13) | 135.37 (95.18) | 232 (114.05) | 372 (169.70) |
Corticosteroids | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | |
Mesalamine | 3 (9.40) | 2 (7.40) | 1 (33.30) | 0 (0.00) | |
Concomitant treatments | Azathioprine | 8 (25.00) | 5 (18.50) | 2 (65.67) | 1 (50.00) |
Methotrexate | 1 (3.10) | 1 (3.10) | 0 (0.00) | 1 (50.00) | |
Tacrolimus | 1 (3.10) | 1 (3.40) | 0 (0.00) | 0 (0.00) | |
Length of treatment (weeks) | Mean SD | 190.69 (125.73) | 191.33 (119.04) | 216 (248.29) | 144 (0.00) |
Previous use of biologics | Yes | 11 (34.40) | 8 (29.60) | 1 (33.30) | 2 (100.00) |
No | 21 (65.60) | 19 (70.40) | 2 (65.67) | 0 (0.00) | |
Infliximab | 11 (34.40) | 8 (29.60) | 1 (33.30) | 2 (100.00) | |
Golimumab | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | |
Biologic type | Certolizumab | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) |
Adalimumab | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | |
Others | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 (0.00) | |
Reason for discontinuation | Primary failure | 8 (25.00) | 6 (22.20) | 0 (0.00) | 2 (100.00) |
Secondary failure | 3 (9.40) | 2 (7.40) | 1 (33.33) | 0 (0.00) |
BMI: body mass index; CD: Crohn's disease; SD: standard deviation; UC: ulcerative colitis.
A mean adherence rate of 91.79% (± 11.62) was obtained for the 178 patients included in the study. Mean adherence was 91.15% for adalimumab, 91.74% for golimumab and 95.05% for ustekinumab (p = 0.045). The pharmacy dispensing records revealed that 45 patients (25.28%) exhibited low levels of adherence (≤ 85%).
Within the subgroup of low adherence patients (n = 32), mean adherence was 75.6% (± 12.95), with no statistically significant differences between the drugs. After administering the MAQ questionnaire to this group of patients, 15 were classified as noncompliant (46.9%) and 17 (53.1%) as compliant. The first question about forgetting to take their medication was answered in the affirmative by 9 patients (28.10%) while the second question on taking the medication at the right time was answered negatively by 20 patients (62.50%). The third and fourth questions were answered in the affirmative by 1 patient (3.10%).
The results of the MPR and the MAQ questionnaire were compared for this subgroup de patients. Mean adherence among patients classified as compliant was 79.33 % (± 10.51); among non-compliant patients it was 71.38% (± 14.46) (p = 0.064).
Lastly, an analysis was made of the relationship between adherence and the demographic and/or clinical factors of both the whole patient population and the low-adherence subgroup. Firstly, an univariate analysis was carried out of the variables studied in both patient groups. Given the high number of variables, concomitant treatments and the type of biologic drug used previously were excluded from the analysis. The results are shown in tables 2 and 3.
Results of the uni- and multivariate analyses of the total patient sample
Variable | Univariate analysis | Multivariate analysis3 | |||||
---|---|---|---|---|---|---|---|
Chi squared | OR | CI 95% | pvalue | OR | CI 95% | pvalue | |
Sex1 | 6.16 | 0.42 | (0.21-0.84) | 0.013* | 0.438 | (0.216-0.888) | 0.022* |
Age2 | (−3.65-6.48) | 0.583 | |||||
Length of treatment (weeks)2 | (18.64-80.62) | 0.002* | 0.995 | (0.991-0.998) | 0.006* | ||
Previous use of biologics1 | 0.17 | 0.86 | (0.42-1.77) | 0.683 |
Results of the univariate analysis in the low-adherence subgroup
Variable | Chi squared | OR | CI 95% | pvalue |
---|---|---|---|---|
Sex1 | 0.16 | 0.75 | (0.18-3.06) | 0.688 |
Age2 | (−11.44-6.36) | 0.565 | ||
Occupational status1 | 0.38 | 0.60 | (0.12-3.09) | 0.691 |
Smoking status1 | 2.58 | 3.55 | (0.73-13.32) | 0.108 |
Educational status1* | 0.01 | 1.05 | (0.26-4.32) | 0.946 |
BMI2 | (−2.02-3.94) | 0.514 | ||
Diagnosis1 | 0.38 | 1.67 | (0.32-8.59) | 0.691 |
Age at diagnosis2 | (−11.41-5.11) | 0.441 | ||
Duration of disease (months)2 | (−78.87-90.42) | 0.890 | ||
Concomitant use of aminosalicylates1 | 0.24 | 1.87 | (0.15-22.93) | 0.621 |
Concomitant use of immunosuppressors1 | 0.276 | 1.50 | (0.33-6.83) | 0.712 |
Previous use of biologics1 | 0.744 | 1.92 | (0.43-8.61) | 0.388 |
Length of treatment (weeks)2 | (−140.07-38.60) | 0.255 | ||
Discontinuation of treatment1 | 1.45 | 0.25 | (0.02-2.71) | |
Hospital admissions1 | 0.11 | 1.39 | (0.20-9.71) | |
Infections in the last 4 months1 | 1.88 | 0.50 | (0.35-0.72) | |
Treatment intensification1 | 0.376 | 1.66 | (0.32-0.59) | |
FC levels (μg/g)3 | 0.105 |
On the multivariate analysis, only female sex and the length of treatment were associated to lower adherence levels (Table 3).
DiscussionThe results of the present study show high levels of adherence (91.79%) for the overall patient sample, with 45 patients (25.28%) identified as scarcely compliant.
No reports exist in the literature that compare the adherence to the three subcutaneously administered agents used to treat IBD. The first systematic review on the adherence to anti-TNF drugs was published in 2013 and includes 13 studies on 93,998 patients. Four of the studies reviewed determined the patients’ adherence to infliximab and adalimumab using the MPR. Mean adherence to adalimumab was shown to be 83.1% (36.8-96%), which is lower than the 91.15% adherence rate found in the present study10. Other, more recent, studies obtained even lower adherence rates for adalimumab (57%) also using the MPR. These differences between earlier studies and the present one could be due to the fact that, in the former, adherence was evaluated over a longer period of time (24 months)19.
A retrospective cohort study from the United States used the MPR rate to study adherence to golimumab and adalimumab in 27 and 226 patients respectively. It obtained an adherence rate of 95% for golimumab (similar to our 91.74%) and 77% for adalimumab20. As regards ustekinumab, no study was found that looked into adherence in an IBP population. Nonetheless, a Canadian study on psoriasis obtained a mean adherence of 93.5%, similar to the 95.05% found in the present study21. However, it must be taken into account that the clinical situations evaluated are different.
In this study, female sex was found to be associated to poorer therapeutic adherence, which is in line with earlier findings. In a systematic review, López et al. identified four studies where female sex is associated to poorer adherence10. In the same vein, a Swedish study on golimumab identified women as less compliant (hazard ratio [HR] 6.59; confidence interval [CI]: 95%: 1.04-41.62)22. A study on ustekinumab showed higher adherence levels in men (OR =1.28 (1.08-1.51) p= 0.004)23.
In this study it was also found that the longer the treatment, the poorer the adherence. A Spanish study on patients treated with aminosalicylates revealed a statistically significant association (p = 0.05) between increased duration of treatment and poorer adherence24.
Of the total 178 patients, 55 (30.9%) had received some form of previous treatment. The most commonly used drug was infliximab (22.5%). In the low adherence subgroup, patients who had received previous treatment had only taken infliximab, which had been discontinued in 72% of them as a result of primary failure in the course of the first few infusions. In line with the findings in this study, an analysis of the persistence to biologic agents in IBD by Chen et al. showed that the majority of patients begin their biologicsbased therapy with either adalimumab, which is maintained for a mean of 1.04 years, or infliximab, which is maintained for 0.88 years25. In our study, the 136 patients on adalimumab exhibited a higher persistence rate, with a mean of 2.9 years.
The MAQ questionnaire was administered in our study in order to obtain a more accurate determination of adherence and to understand who some patients show poor levels of adherence. MAQ was also applied un one of the first studies on patients on mesalamine, but the results obtained were not comparable to those of the present study24. Using a simple set of questions, Billioud et al. concluded that forgetfulness in taking the medication was the chief culprit for non-adherence in 24.6% de los patients26.
FC levels were analyzed in order to determine whether lack of adherence played a role in the effectiveness of treatment, but the two parameters did not appear to be related in a statistically significant manner. Sipponen et al. found that a 12-week-long treatment with anti-TNF agents resulted in a significant decrease of FC levels (p = 0.001)27.
The present study is subject to several limitations. The main one is related to the fact that adherence was monitored over a period of only four months. It has been found that, in the setting of chronic diseases, adherence should be measured over at least six months28. In addition, the percentages presented herein may be slightly distorted as they were calculated on the basis of the date on which the drugs were dispensed, which could have been entered incorrectly. Another shortcoming about this method is that the fact that a drug was dispensed does not necessarily imply that the patient actually administered it29.
Another limitation of this study has to do with its statistical power. The number of patients classified as scarcely compliant was too low for any associations observed in that subgroup of patients to be considered statistically significant. It would be useful to include patients on infliximab or vedolizumab in the analysis as this would provide a broader overview of adherence to all biologic agents in the setting of IBD.
Lastly the MAQ questionnaire was selected because it is an easy-torespond to, general-purpose questionnaire used to measure adherence in patients with chronic conditions. As regards the MMAS-8. although it is a questionnaire specifically validated for IBP, De Castro et al. pointed out that its accuracy in detecting noncompliant patients is questionable30.
On the other hand, one of the strengths of this study lies in the fact that it is the first study to compare the adherence to the three drugs analyzed. It therefore affords a valuable insight into the adherence to the subcutaneous biologic agents used to treat IBD. Moreover, as recommended by other authors, adherence was measured using two indirect methods, namely the MPR rate and the MAQ questionnaire17.
As all the patients included in this study came from one single hospital, the results cannot be extended to the whole European, or even Spanish, population as there may well be demographic, clinical and treatment protocolrelated differences between different sites.
To conclude, the adherence rate obtained in the present study is high for the general population and 75% lower for patients classified as scarcely compliant. Female sex and length of treatment were associated to poorer therapeutic adherence.
FundingNo funding.
Conflict of interestsNo conflict of interest.
Contribution to the scientific literature
Low adherence to treatment reduces therapeutic effectiveness and negatively impacts patients’ quality of life, resulting in increased hospital admissions and higher healthcare costs. Several studies have been published on adherence in the setting of immunological disorders, but most of them focus on one or more of the first monoclonal antibodies that reached the market, such as infliximab o adalimumab. As far as inflammatory bowel disease is concerned, no original study has yet been published that looks into the adherence to the three subcutaneously administered monoclonal antibodies approved for this indication, i.e. adalimumab, golimumab and ustekinumab.
An understanding of adherence to medication in the inflammatory bowel disease population is crucial to detect patients with poor therapeutic adherence. Once these patients have been identified, healthcare providers can develop interventions geared toward boosting adherence and achieving therapeutic success.