Patient knowledge of and preferences for oral anticoagulation and vitamin B12 in the context of medication adherence

Adherence is defined as “the extent to which a person's behavior - taking medication, following a diet, and/or executing lifestyle changes, corresponds with agreed ecommendations from a healthcare provider”. Level of adherence to medication varies greatly and is related to treatment, patient and /or health care provider. The WHO stated in 2003 that adherence to long-term therapies in the general population is around 50% in developed countries. Non-adherence to medication is a complex, common healthcare problem and can be distinguished in unintentional and intentional non-adherence. It has been shown that poor medication adherence may cause toxicity or lack of efficacy, disease progression, lower quality of life, drug resistance, medication waste and hospital admission what results in costs of approximately 100 billion a year in the United States. Therefore, detection of non-adherence and interventions aiming at improving adherence are critically important. Adherence assessment methods can be broken down into direct and indirect methods. Each method has advantages and disadvantages. Within this thesis, different adherence assessment methods were applied including subjective self-reported measures (questionnaires) and objective measures such as electronic monitoring, rates of prescription refills and measurement of biomarker levels. In general, interventions to improve adherence can be divided into behavioural, technical,educational, and multifaceted methods. Behavioural interventions usually provide feedback, reminders or rewards to patients. Reduction of regimen complexity and use of fixed-dose regimen are examples for technical interventions. Educational interventions include patient education, provided to individuals or in group sessions using verbal, audio-visual or written material. Effectiveness of multifaceted approaches using combinations of different intervention types has been demonstrated in long-term situations. However, current methods of improving medication adherence for general chronic diseases are mostly complex and evidence of their effects remains low.
Patients have to make important health decisions that affect health outcomes. Furthermore,patients can play an important role in protecting their own health and taking appropriate action in acute episodes of ill health, as well as managing chronic illness. In particular, the management of chronic diseases, such as atrial fibrillation, require a high level of self-care skills that are determined by patients’ health literacy. Overall, health literacy can be described as the people’s capacity to manage their health. Patient knowledge about medical conditions and treatment regimen is an important aspect of health literacy. Patient medication knowledge or shortly named in this thesis “patient knowledge” refers to patient health knowledge related to medications including what is being used, why it is being used as well as instructions and precautions about certain medication. Lack of knowledge about medication and difficulties in understanding medication information may be related to misapprehension of instructions and/or symptoms, medication errors, low self-care behavior, poor health outcomes, and frequent visits to the emergency department. Therefore, detection of knowledge gaps and educational counselling about medication should be integrated in daily practice. Up to now, however, counselling practice in general practitioners’ practices and community pharmacies tend to concur on the relative poverty of such medication discussions. Therefore, it is not surprising that outpatients lack knowledge about their medication. For some therapies such as oral anticoagulation therapy (OAC), there is still insufficient evidence to draw definitive conclusion regarding the impact of educational interventions on therapeutic outcomes in patients, mostly due to the inhomogeneity of the study designs. Thus, educational contents need to be prioritized, educational domains should be standardized and validated instruments for the assessment of deficit knowledge are needed to demonstrate the impact of educational counselling on outcomes in clinical trials. Further, detection of knowledge gaps and individualized educational counselling enable patients to develop preferences and take appropriate health decisions.
Patient preferences result from unique values (i.e. potential benefits, convenience) and concerns (i.e. potential harms, costs) that are formed by patient knowledge, experiences, and reflection. Having preference for a treatment mirrors the patients evaluation of these values and concerns in comparison with an alternative treatment option. For a given disease, different patients may have different preferences. Patients bring their preferences to a clinical encounter that should be
integrated in decision making whenever they are to serve the patient. It has been shown that knowledge about patient preferences for a certain disease might lead to better-informed decisions in practice and in health policy. A better understanding of patient preferences is pivotal for shared decisions and important for increased adherence and ultimately patient health outcomes. Patient preferences in treatment-related decisions should be elicited and taken into account, because patients who felt less empowered with regard to treatment decisions reported lower rates of adherence. Assessment of patient preferences and Shared Decision Making is particularly recommended for situations with two or more equivalent available treatment options and similar treatment consequences for a patient’s daily life. The substitution of vitamin B12 (VB12) in deficient outpatients is one example where the evidence for equivalent efficacy between oral and intramuscular application offers to patients both treatment opportunities with similar clinical outcome.
The goal of this thesis was to assess patient knowledge of anticoagulation and patient preferences for VB12 therapy and to develop an educational program on adherence for outpatients with rivaroxaban therapy. We approached this goal with four individual projects:
Project A:
- Investigation of patient knowledge of OAC in Swiss community pharmacies in an
observational study.
- Development and validation of a self-assessment questionnaire for patient knowledge on direct oral anticoagulants (DOAC).
Project B:
- Assessment of the impact of type 2 diabetes and metformin use on VB12 associated biomarkers and their suitability to reflect VB12 supply.
- Exploration of patient preferences for and biomarker levels after oral and intramuscular vitamin B12 substitution.
- Investigation of patient preferences for oral and parenteral treatment in various diseases through literature review.
Project C:
- Translation and validation of the 8-item Morisky Medication Adherence Scale in German.
- Comparison of one subjective with one objective adherence score in a pilot study.
Project D:
-Development of a study protocol for a stepwise educational program on adherence for patients on rivaroxaban using feedback from electronic monitoring.
Overview of the projects:
Project A
Study A-1 aimed at screening for knowledge gaps about OAC in outpatients. We therefore amended the basic Polymedication Check (PMC) with specific open-ended questions on OAC and assessed its impact on knowledge in an observational study. Patients treated with vitamin K antagonists (VKA) or direct oral anticoagulants (DOACs) received an amended PMC. The study demonstrated that the majority of patients had knowledge gaps concerning OAC and that half of the patients did not know how to proceed in case of a missed dose. Identification of knowledge gaps led pharmacists to provide education spontaneously. Although verbally unstructured, the provision of this targeted and tailored education increased patient knowledge about OAC. We further found a trend that patients with DOAC therapy were more likely to have knowledge gaps compared to patients on VKAs. These observations served as a rationale for further studies on knowledge of DOAC, in particular the development and validation of a specific questionnaire to self-assess knowledge of DOAC (Study A-2).In Study A-2, we followed an evidence-based approach to select relevant items for patient knowledge of DOAC. After literature review, completeness of retrieved items were exhaustively verified and supplemented with Swiss summaries of Product Characteristics (SPCs), the Update EHRA Practical Guide on the use of non-vitamin K antagonist anticoagulants, and the patient guide for taking DOAC from the cardiology patient page. Twelve anticoagulation experts across different professions participated in the questionnaire development process to ensure content validity and selection of relevant items. The developed Knowledge Of Direct Oral Anticoagulants(KODOA) test was validated in patients on DOAC and pharmacists. The KODOA-test confirmed to be feasible, comprehensive, reliable and valid to self-assess patient knowledge of DOAC. Construct validity was supported by significant differences in scores between patients and pharmacists. Finally, the KODOA-test was responsive to educational counselling about DOAC supporting construct validity.
Project B
Several cross sectional studies and case reports have presented an increased frequency of VB12 deficiency among patients with type 2 diabetes (T2DM). Because VB12 deficiency is a reversible cause of demyelinating nervous system disease and bone marrow failure, its early detection is important. Literature suggests that clinical biochemistry of VB12 is influenced by diabetes and its treatment. Therefore, Study B-1 aimed to assess the impact of T2DM and metformin use on VB12 associated biomarkers and their suitability to reflect VB12 supply. Differences of VB12, holotranscobalamine (HoloTc), the biologically active fraction %AB12=HoloTc/VB12*100 and homocystein (Hcy) were analysed i) among diabetic outpatients with and without metformin use and ii) compared to an external non-diabetic reference group with low level of VB12 (<200pmol/L). We found that metformin treatment alone did not explain the altered VB12 metabolism as reflected by VB12 and HoloTc serum levels in all T2DM patients. Further analysis focused on VB12-deficient subgroups and included non-diabetic patients. In this sample, a significant difference of the %AB12 was observed and confirmed by multiple regression analysis. However, the model explained only 9.2% of the variance observed. These results suggest that VB12 metabolism is affected by diabetes itself as well as by other factors, which were not included in the model. Further, stepwise multiple regression analysis included HoloTc as independent variable to explain variance in Hcy levels and not VB12. Thus, HoloTc seems favorable compared to VB12 to predict hyperhomocysteinemia caused by VB12 deficiency in T2DM patients. Study B-2 was a prospective randomized unblinded parallel group trial. Patients were recruited by their general practitioner and randomly assigned to oral or intramuscular (i.m.)VB12 treatment. Group O-oral received oral daily 1000μg cyanocobalamine for 28 days and group I-i.m. received 4 weekly injections of 1000μg hydroxocobalamine. Blood samples were analyzed for VB12, HoloTc, Hcy and methylmalonic acid (MMA). Before and after treatment, patients were asked to fill in a questionnaire about their preferences. After 28 days of treatment with high-dose VB12 administered either by oral or i.m. route, median levels of VB12-associated biomarkers were normalized in both groups. Contrary to prior studies, we observed an exaggerated response after i.m. administration and therefore the hypothesis for non-inferiority of oral in comparison to i.m. treatment had to be rejected. Because we used electronic punch cards and monitored an almost perfect intake of tablets (99.6% taking adherence), non-adherence was ruled out as a contributor to the less pronounced biomarker response. We found that initial rating in favor of either i.m. or oral therapy changed over time. However, the majority of patients preferred oral treatment before and after the study. The literature review (Study B-3) across different diseases yielded similar results: A majority of patients prefer oral treatment. In order to investigate patient preferences for oral and parenteral treatment in various diseases, we conducted a literature research in the databases PubMed, EMBASE and Web of Science using the terms “patient preference” OR “patients’ preference” OR “patient perspective” AND “oral treatment” AND “inject*” (Study B-3). Our search was limited to original research articles that have been published after 1980, were accessible online and included intravenous, intramuscular or subcutaneous parenteral therapy options. Our search strategy delivered 74 articles of which 62 were excluded. One article was included by cross-referencing. Eleven out of 13 articles reported preference for the oral administration (84.6%). Out of the 13 articles retrieved, five concerned cancer therapy, three antibiotic therapies, two vitamin deficiency and three other indications. Oral or parenteral therapy was preferred according to the disease. Associated factors for the preferred route of administration varied between the studies. Most articles reported convenience as an important factor to influence preference, either in favour of the oral or the parenteral therapy.
Project C
Study C-1 aimed to translate and validate the 8-item Morisky Medication Adherence Scale (MMAS-8) in German against objective and subjective measures of adherence in cardiovascular patients with polypharmacy. Validation took place on a convenient sample of ambulatory patients on chronic antiplatelet therapy. Objective adherence was obtained from electronically monitored multidrug punch cards. Internal consistency was assessed using Cronbach’s alpha coefficient, construct validity using exploratory factor analyses and correlations between MMAS-8D and related measures. Convergent validity was assessed with a subjective questionnaire about beliefs about medicines (BMQ Specific, 2 subscales). A total of 70 patients were included in the study (mean score of MMAS-8D was 7.5 (SD 0.8; range 4.5-8)). Moderate internal consistency (alpha = 0.31) was observed, due to multidimensionality of the scale. Factor analysis yielded four components that accounted for 71.7% of the total variance. Convergent validity was supported by significant correlations with BMQ Necessity (r= 0.31; <0.01), BMQ Concerns (r= -0.16, p<0.05)and with electronic adherence reports (U-values 44 and 471, p<0.05). Platelet aggregation values were within therapeutic range for 80% of the patients. Antiplatelet blood values within therapeutic range were associated with a higher MMAS-8D score (U-value 125, p<0.05). Study C-2 aimed to assess whether the affirmative answer to the PMC question “Do you sometimes forget to take your medication?” coincides with a Medication possession ratio (MPR) <90% (non-adherence) in DOAC treated patients. For the pilot study, fifth-year pharmacy students recorded one PMC with an anticoagulated patient during internship in community pharmacies.Patient’s refills of the past 12 months were used to calculate a MPR if at least two refills were available. A total of 25 documented cases were included for analysis, of which all concerned patients treated with rivaroxaban. Refills (mean of 2.9±0.8 per patient) were available for a mean of 128±62 days. MPR ranged from 50.2 - 182.7%. MPR below 90% was observed in 4 patients (16%), out of them two self-reported to sometimes forget to take the DOAC. Two further patients reported non-adherence but showed a MPR >90%. Oversupply up to 110% was observed for 7 patients, and excessive oversupply for 6 patients (MPR: 114-183%). Consideration of composite adherence measures to get a more detailed picture of adherence and experiences with educational counselling about OAC have further been implemented in Project D.
Project D
Study D aimed to develop a study proposal to demonstrate the impact of a tailored and stepwise educational program to rivaroxaban on adherence. Otherwise than in the previous project on knowledge about OAC (Project A), educational counselling was foreseen to be offered in a repetitive manner according to patient needs. Additionally, visualizing of intake pattern obtained with the electronic monitoring should be employed for providing feedback based on the individual patient profile and stressing the need of time adherence, or adapting the treatment plan in collaboration with the physician. This study will be executed beyond this thesis.
The following conclusions could be drawn:
Project A: Patient knowledge about oral anticoagulation therapy
- A majority of outpatients show knowledge gaps concerning their therapy with OAC.
- Specific screening questions allow community pharmacists to detect deficient knowledge in short time and to provide spontaneous verbally unstructured education besides the
detection of deficient knowledge when needed.
- The newly developed and validated KODOA-test showed good psychometric properties in Swiss elderly outpatients taking DOAC. The KODOA-test is a reliable and valid questionnaire to assess patient knowledge about DOAC.
- To our knowledge, the KODOA-test is the first validated questionnaire specific for patients taking DOAC and sensitive to change. Therefore, the KODOA-test could be used in clinical trials where associations between knowledge of DOAC and adherence or clinical outcomes are of interest.
- Patient knowledge increases after having received educational counseling either provided spontaneously and in an unstructured manner with the help of the amended PMC or in a structured manner after testing with the KODOA-test.
- Patients show high acceptance and state to be more confident about how to take their anticoagulant agent either after having received educational counselling in an nstructured manner with the help of the amended PMC or in a structured manner after testing with the KODOA-test. More outpatients could be approached for educational counselling about OAC.
Project B: Patient preferences and vitamin B12 deficiency
- The clinical biochemistry of VB12 in T2DM patients with scarce VB12 supply is modified in comparison to nondiabetic patients. This results in higher %AB12 due to reduced VB12 levels. It needs to be clarified whether this effect is due to diabetes itself, metformin treatment and/ or a combination of other heath related situations.
- Assessment of HoloTc seems favorable compared to VB12 to predict hyperhomocysteinemia caused by VB12 deficiency in T2DM patients. This may be a direct consequence of the modified %AB12 in T2DM patients, which strengthens the recommendation to assess VB12 supply in clinical practice by measuring HoloTc.
- After oral and i.m. substitution with VB12, differences in VB12, HoloTc and Hcy levels between groups were higher than expected. Therefore, the hypothesis of non-inferiority of oral treatment had to be rejected. Normalization of HoloTc and MMA was reached by all patients and normalization of VB12 and Hcy by the majority of patients within group O-oral after a one-month treatment. The clinical benefit of exaggerated biomarker response after i.m. treatment within a typical primary care population is questionable. Therapeutic schemes should be chosen with the consideration of mid-term biomarker effects and patient preferences.
- Initial rating in favor of either i.m. or oral therapy can change over time. The majority of patients preferred oral treatment before and after the study, pointing out the need for a high dose oral VB12 preparation in Switzerland.
Project C: Adherence assessment methods
- The German MMAS-8D appears to be a reliable instrument to catch medication adherence in cardiovascular patients. Further, the MMAS-8D is endowed with simplicity and quickness of administration and scoring, which facilitates its use in several pathologies. It may be useful in patients with chronic therapy for detecting non-adherence.
- Combination of subjective and objective adherence measures may help to establish a more precise picture of adherence.
According to the conclusions and findings of this thesis, recommendations for future research and
practice are:
Project A: Patient knowledge about oral anticoagulation therapy
- The best way to counsel patients about OAC and association of increased patient knowledge about OAC with adherence and clinical outcomes should be assessed in further studies. Project D provides future researcher with a study proposal to investigate associations of increased patient knowledge about OAC and adherence.
- Patient opinions on counselling about OAC and acquisition of knowledge about barriers and facilitators for patient-centred counselling should be of interest in further studies in order to ameliorate educational counselling in primary care setting.
- Health care professionals (HCP) in primary care should screen for deficient knowledge and provide educational counselling about OAC actively. A patients whole therapy and daily experiences have to be included in counselling in order to achieve patient-centred counselling.
- In order to ensure continuous care in OAC patients, it may be helpful to provide different HCP with standardized screening questions and educational manuals about OAC counselling. Remuneration of counselling might increase implementation of such service in daily practise.
Project B: Patient preferences and vitamin B12 deficiency
- Assessment of HoloTc seems more favourable than VB12 to identify VB12 deficient patients. If these findings are restricted to T2DM patients, should be assessed in further studies.
- The impact of T2DM, metformin use and other factors (e.g. age, duration of VB12 deficiency) on VB12 associated biomarkers should be investigated in further studies.
- Optimal injection interval for i.m. hydroxocobalamine is still to be defined. Weekly admisnistration to guidelines lead to exaggerated biomarker response in non-anemic patients. Consequently, lower injection frequency is very likely to be equivalent and thus make treatment for patients more convenient and thereby influencing patient preferences.
- In practice, patient preferences should be assessed routinely before treatment initiation, across various diseases where equivalent treatment options exist. Repeated re-evaluation of patient preferences should be integrated in delivering continuous care because preferences might change over time.
Project C: Adherence assessment methods
- In practice, community pharmacists should screen for non-adherence by combining different methods such as MPR from pharmacy refill data and subjective questions.
- The collaboration with IT specialists to integrate non-adherence alerts from refill data within pharmacy software could support community pharmacists when screening for nonadherence in daily practice.