Jyotsna Kapoor1, Narendra Agrawal2, Rayaz Ahmed2, Sanjeev Kumar Sharma3, Anshul Gupta2 and Dinesh Bhurani2
1 Masters in
Clinical Research, Department of Hematology,
Rajiv Gandhi Cancer Institute and
Research Centre, Sector - 5, Rohini,
Delhi, India. PIN 110085
2 DM, Consultant Hematology, Department of Hematology, Rajiv Gandhi Cancer Institute and Research Centre, Sector - 5, Rohini, Delhi, India. PIN 110085
3 DM, Consultant Hematology, Hemato-Oncology and BMT Unit, BLK Superspeciality Hospital, Rajendra Place, New Delhi, India, PIN 110008
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Adherence to imatinib (IM) is of utmost importance in patients with chronic myeloid leukemia (CML) to maximise treatment effectiveness. The main objective is to measure adherence to IM by evaluating individual patient characteristics, personal behaviour and, treatment related psychological factors influencing adherence behaviour. Hundred patients receiving IM were analysed for adherence behaviour using 9 item Morisky Medication Adherence Scale (9-MMAS). Various factors were assessed for their impact on adherence behaviour. These factors were age, gender, duration of treatment, frequency and dosing of treatment, use of tobacco and alcohol, educational qualification, employment status, monthly income, side effects, financial assistance in treatment, social support, knowledge about medicine and disease, concomitant drug burden, polypharmacy, physician patient interaction, patient educational sessions and prevalence of depression. Seventy five percent of patients were found to be adherent. On univariate analysis, prevalence of depression (p<0.000001), moderate severe depression (p<0.000001), concomitant drug burden (p=0.036) and monthly income (p=0.015) were found to be significantly influencing adherence. The final multivariate model retained prevalence of depression with OR= 10.367 (95% CI, 3.112- 34.538) as independent predictor of adherence to therapy. This study suggests that identification and treatment of depression among CML patients may further enhance adherence to IM therapy.
More than a decade ago, revolution came in the treatment of CML with
the introduction of the Imatinib Mesylate (IM), a BCR- ABL tyrosine
kinase inhibitor. After 5 years of follow – up, continuous treatment of
chronic – phase CML with imatinib, as initial therapy, was found to
induce durable responses in a high proportion of patients.[1,2] With IM
being so effective, the allogenic stem cell transplantation no longer
remains the first line treatment, despite being a curative treatment.
Though IM is the first line treatment, few drawbacks are associated
with its use as it is still not considered to be a curative therapy; it
requires indefinite treatment on daily basis and ensuring optimal
adherence to treatment for long term. Adherence to medication has been
recently defined by an international panel of experts as ‘the process
by which patients take their medications as prescribed’ and this
process has three main components: initiation, implementation, and
Various studies and several case reports have shown that non adherence to IM is common[4-10,13] and intertwined with non-achievement of molecular responses[4,5,7,10] and event free survival emphasising strict adherence to the prescribed dose of IM holds paramount importance to maximise treatment effectiveness in CML patients. For example, a Belgian study found that one third of the patients were non adherent and only 14% were adherent to all the prescribed dose. On average, patients with suboptimal response had significantly higher mean percentages of IM not taken (23.2%,standard deviation [SD] 23.8) than did those with optimal response (7.3%, SD 19.3, P.005), Marin et al found that 26% of the patients had adherence rate <90% (considered to be nonadherent) and adherence is a critical factor for achieving molecular responses in patients with CML who achieve complete cytogenetic responses on IM. Darkow et al found 31% of nonadherence rate among US CML population using electronic data of dispensation of IM and also found non- adherence led to increased healthcare costs. Adherence to IM have been also studied in the past in Indian population using records of Glivec International Patient Assistance Program (GIPAP) retrospectively in which one third of the patients were found to be non-adherent to IM and concluded that non- adherence to IM adversely affects event free survival (EFS) in chronic phase CML (CP-CML) patients.
There is scarce availability of literature citing the potential reasons for non-adherence to oral anticancer treatment and few existing data on reasons why CML patients might be non- adherent to IM. Treatment related aspects (side effects, knowledge of disease or treatment, financial cost of treatment etc.), individual patient characteristics (gender, age) and personal factors (social support) have been found to be influencing adherence in chronic illnesses.[11-13] We hypothesized that these factors might affect adherence to IM in CML patients too. Ganesan et al tried to explore reasons of non- adherence to IM in Indian CML patients and assessed age, sex, economic status and Sokal score. No study has completely investigated the treatment related, individual patient characteristics, personal and psychological factors influencing adherence in Indian patients with CML so far. Therefore, we conducted this personal interview based study to assess the adherence of CML patients using 9 MMAS and to evaluate personal, treatment related, and psychological factor associated with adherence at Rajiv Gandhi Cancer Institute and Research Centre, India.
Study Design and Setting.
This study was carried out at Rajiv Gandhi Cancer Institute and
Research Centre, Delhi, India. All CML patients over 18 years of age
and below 80 years, with ongoing IM therapy for minimum duration of
three months, and who visited the outpatient department during a period
of February 2013 and May 2013 were considered for inclusion in the
study. Patients who were dumb and/or deaf or undergone allogenic
hematopoietic stem cell transplant were excluded from the study. The
questionnaires were available in Hindi and English, the patients who
did not understand these languages were excluded. The patients included
in the study were taking IM either 400mg/day or 600mg/day or 800mg/day.
The patients who were taking 600mg/day or 800mg/day were advised to
take half the dose after heavy meal in the morning and the other half
dose after heavy meal in the evening to manage the gastric side
effects. Optimal sample size was calculated and found to be 84 in
accordance with the previous adherence study conducted on Indian
population by Ganesan et al (30% of non-adherence rate was found), we
approximated the sample size to be 100. The total number of patients
visiting the OPD within this period were 139 and 82.7% (115 patients)
of these fulfilled the inclusion criteria.
The questionnaire was translated by official translators in Hindi allowing the majority of patients to undergo personal interview in their native language. The patients were given oral and written information regarding the study when asked to participate. After giving oral and written consent for participation, the study coordinator personally interviewed the patients using questionnaires in their preferred language. This study was approved by the Institutional Review Board of our centre. This study was conducted in accordance with latest version of Declaration of Helsinki.
Questionnaires. The questionnaire used consisted of 9-MMAS (to measure adherence behaviour), additional questionnaire (to assess the factors influencing adherence except depression) and PHQ-9 (to assess prevalence of depression). The questionnaire asked about adherence behaviour, socio-demographic background, knowledge about disease and medicine, social support, physician patient relationship, role of patient educational sessions, side effects of medicine, financial assistance in treatment, concomitant drug burden, polypharmacy, details about therapy, and depression. Additional questionnaire was partly devised from questionnaire, previously used by Jonsonn et al9 and questions regarding role of patient educational sessions, polypharmacy, financial assistance in treatment and concomitant drug burden were added in view of our cohort. The internal consistency reliability of the combined questionnaire to assess the factors influencing adherence (additional questionnaire and PHQ-9), using Crohnbach α was found to be 0.72.
Adherence Behaviour. The 9-item Morisky Medication Adherence Scale (9-MMAS), a standardised test, was used to measure adherence, with scores ranging from 1-13, where 13 indicates perfects adherence. This test has been developed from the well validated Morisky Green Test and the eight item MMAS.[15,16] The internal consistency reliability of the English version of 9- item MMAS, measured by the Crohnbach α, had a value of 0.89. The 9- item MMAS is composed of 9 questions explores adherence behaviour based on forgetfulness, negligence, interruption of drug intake and restart of drug intake when symptoms worsen. Patients scoring 11 or above in the summary score were classified as adherent. This definition of adherence is based on how patients theoretically would have completed the MMAS if they had taken at least 95% of prescribed doses.
Factors Influencing Adherence. Socio-demographic background composed of 8 questions asking about gender, age, marital status, employment status, educational qualification, monthly income, and use of tobacco or alcohol in any form. For example, with regard to employment status, a question was asked ‘Do you work?’ with an option of ‘Yes/No’. Knowledge about Medicine and Disease composed of 5 questions along with subparts to find out whether the respondents have basic knowledge about their disease and treatment. For each correct answer ‘1’ was scored. Support given by family, friends and colleagues was assessed using 10 questions comprising of Yes/No option. A healthy and regular physician patient interaction was assessed using a set of 7 questions followed by a Yes/ No option except one question. Questions included were ‘Do you visit your physician at regular intervals?’, ‘Do you feel the physician is very helpful to you?’ ‘Do you trust your physician?’etc. Patients were interviewed whether they have attended the last patient educational session on CML and if yes, did they found it helpful to find out the role of patient educational sessions on adherence. Patients were questioned about being financially assisted in treatment, if so, and then what were the means of assistance. Concomitant drug burden was defined as the assumption of additional drugs related to diseases other than CML may affect the adherence to IM (Yes/No). Polypharmacy was defined as taking at least one alternative medicine apart from IM for CML (Yes/No) may affect the adherence to IM. Commonly used alternative medicines were from ayurvedic, homeopathic and unani system of medicine. Patients were also questioned about the side effects if they ever had with the use of imatinib and if they had, the side effects were recorded accordingly. The prevalence of depression among CML patients was evaluated with a Patient Health Questionnaire-9 (PHQ -9), a validated and standardized instrument with good specificity and sensitivity. The PHQ-9 focuses on the nine signs and symptoms of depression from DSM-IV. In addition, the sum score of PHQ-9 (0-27) is used for screening purposes and for measuring depression severity. As a severity measure the PHQ-9 score can range from 0-27, since each of the 9 items can be scored from 0 (Not at all) to 3 (Nearly every day).
In this study, 100 out of 115 eligible patients completed the interview (response rate 86.9%) (Figure 1). 51% of the respondents were interviewed in Hindi language.
|Figure 1. Patient Recruitment Details|
Descriptive Statistics. Descriptive statistical data of 100 patients analyzed are present in Table 1. The majority of the respondents were male (63%) and the mean age was 41.08 years (range 18-70) and median duration of imatinib therapy was 30 months (range 3-101).
|Table 1. Socio Demographic, Clinical, Personal, and Treatment Related Factors|
Adherence Behaviour. All patients included
in the study (n=100) completed the 9-MMAS. The median Morisky Score of
100 patients included was 12 (Range; 7-13). 75 (50 male and 25 female)
out of 100 patients had Morisky score ≥ 11, therefore classified as
adherent. Twenty two percent of the respondents scored 13, i.e. perfect
adherence. Forty six percent of the respondents had special routine or
reminder system which helps them taking medication. Ninety three
percent patients took their medicine prior to the day of interview.
None of the patients had summary score <5. Four out of twenty five
non adherent patients had summary score between 5 and 8.
Comparison of variables with Adherence. The univariate analysis is presented in Table 2 and 3. Among the quantitative variables, monthly income of the patients was found to be significantly associated with adherence (p-value 0.015). Among the categorical variables, prevalence of depression (p value <0.000001), moderate severe depression (p<0.000001) and concomitant drug burden (p value = 0.036) were found to be significantly associated with adherence behaviour. Non depressed people were more likely to be adherent (84.4% vs 43.5%). Patients with no concomitant drug burden were more likely to be adherent (78.8% vs 53.3%).
|Table 2. Comparison of quantitative data with adherence|
|Table 3.Comparison of Categorical Variables with Adherence|
The results of the logistic regression
analysis of factors associated with adherence (9-MMAS summary score ≥
11), adjusted for covariates are presented in Table 4. The variables
included in the study were age, knowledge about medicine and treatment,
physician patient interaction, those who attended patient educational
sessions, male, depressed patients, smokers, alcoholics, educational
qualifications, employed patients, patients who had side effects, being
financially assisted in treatment, had concomitant drug burden, having
polypharmacy and dosage of imatinib. Full data were available for all
the 100 patients, who were included in the logistic regression
analysis. Prevalence of depression among CML patients remained
independently associated with adherence (OR= 10.367, 95% CI 3.112-
|Table 4. Multiple logistic regression analysis to identify the predictors of adherence|
We thank Dr. Jes Rafael for his valuable suggestions to improve the design and conduct of the study. Dr. Tabassum, Dr. Shishir Seth played a vital role in helping to recruit the patients in the study. We would like to pay our gratitude to Dr. Ram Chandra Bajpai for performing the statistical analysis and critically reviewing the manuscript. We are indebted to Dr. Suman Pramanik for critical reading of the manuscript and Mrs. Niharika Bhatia, Miss Priyanka Shrivastav for the unconditional support in the conduct of the study. We thank all the members and staff of Rajiv Gandhi Cancer Institute and Research Centre, India.