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Patients’ Priorities for Oral Anticoagulation Therapy in Non-valvular Atrial Fibrillation: a Multi-criteria Decision Analysis

Patients’ Priorities for Oral Anticoagulation Therapy in Non-valvular Atrial Fibrillation: a... Introduction Effectiveness of oral anticoagulants (OACs) is critically dependent on patients’ adherence to intake regimens. We studied the relative impact of attributes related to effectiveness, safety, convenience, and costs on the value of OAC therapy from the perspective of patients with non-valvular atrial fibrillation. Methods Four attributes were identified by literature review and expert interviews: effectiveness (risk of ischemic stroke), safety (risk of major bleeding, minor bleeding, gastrointestinal complaints), convenience (intake frequency, diet restrictions, international normalized ratio [INR] blood monitoring, pill type/intake instructions), and out-of-pocket costs. Focus groups were held in Spain, Germany, France, Italy and the United Kingdom (N = 48) to elicit patients’ preferences through the use of the analytical hierarchy process method. Results Effectiveness (60%) and side effects (27%) have a higher impact on the perceived value of OACs than drug conveni - ence (7%) and out-of-pocket costs (6%). As for convenience, eliminating monthly INR monitoring was given the highest priority (40%), followed by reducing diet restrictions (27%), reducing intake frequency (17%) and improving the pill type/ intake instructions (15%). The most important side effect was major bleeding (75%), followed by minor bleeding (15%) and gastrointestinal complaints (10%). Furthermore, 71% of patients preferred once-daily intake to twice-daily intake. Discussion Although the relative impact of convenience on therapy value is small, patients have different preferences for options within convenience criteria. Besides considerations on safety and effectiveness, physicians should also discuss attributes of convenience with patients, as it can be assumed that alignment to patient preferences in drug prescription and better patient education could result in higher adherence. Key Points Effectiveness and safety are the most important attributes of oral anticoagulant (OAC) therapy. Although the relative impact of convenience on therapy value is small, patients have different preferences for options within the convenience criteria. Electronic supplementary material The online version of this article (https ://doi.org/10.1007/s4025 6-018-0293-0) contains It is recommended that besides considerations on safety supplementary material, which is available to authorized users. and effectiveness, physicians also discuss attributes of convenience with patients. * Janine A. van Til j.a.vantil@utwente.nl Department of Health Technology and Services Research, Faculty of Behavioural, Management and Social Sciences, Technical Medical Centre, University of Twente, P.O. Box 217, 7500 AE Enschede, The Netherlands Department of Cardiology, Thoraxcentrum Twente, Medisch Spectrum Twente, 7512 KZ Enschede, The Netherlands Vol.:(0123456789) 494 M. G. M. Weernink et al. therapy on the value of OAC therapy from the perspective 1 Introduction of patients with AF. More specifically this study aimed to: Non-valvular atrial fibrillation (AF) is the most com- • Estimate the strength of preference of patients between mon heart rhythm disturbance encountered by physicians criteria of convenience (e.g., intake once vs twice daily). in clinical practice. AF is associated with a high risk of • Estimate the relative impact of attributes of convenience ischemic stroke and systemic embolism and increased on overall convenience of OAC therapy (e.g., lower mortality [1]. Vitamin K antagonists (VKAs) have been intake frequency vs no blood monitoring). used as an effective oral anticoagulant (OAC) drug therapy Estimate the relative impact of drug convenience on the to prevent AF-related stroke for many years [2]. Of these total value of OAC therapy, compared to other medica- VKAs, warfarin is the most commonly used in clinical tion-related attributes (e.g., safety, effectiveness). practice. More recently, the European Medicines Agency has approved a number of direct (non-VKA) oral antico- agulants (DOACs) [3]. Several randomized controlled 2 Method trials and meta-analyses have shown that DOACs have a favorable risk–benefit profile when compared with warfa- The analytic hierarchy process (AHP) [18], a technique rin [4–8]. DOACs reduce the risk in stroke, intracranial within the multi-criteria decision making (MCDM) meth- hemorrhage and mortality, with similar major bleeding ods, was used to rank and prioritize the attributes. MCDM rates as warfarin. However, DOACs can also result in an methods allow for better structuring of the decision prob- increased risk of gastrointestinal bleeding [5]. Overall, the lem and are specifically helpful for people in making better relative efficacy and safety of DOACs are consistent across choices that are consistent with their preferences and values a wide range of patients [4]. The half-lives of DOACs are [19, 20]. AHP was originally developed in the 70 s and since shorter than those of VKAs. Although this means that the then has been successfully applied to determine preferences anticoagulant effect of the drug is reversed sooner in case for a variety of complex medical decisions [21, 22]. The of emergency, it also means that its anticoagulation effect first step of AHP is to decompose the criteria of the decision declines more rapidly with poor compliance compared to problem into a hierarchy of subcriteria, each of which can VKAs. Therefore, the effectiveness of DOACs is critically be analyzed independently. Subsequently, pairwise compari- dependent on patient adherence to intake regimens. sons of (sub)criteria determine the relative importance of In recent years, at least three conceptual models of each criterion. An extensive description of all steps within adherence have been developed [9–11]. In these models, AHP is presented in Hummel et al. [23]. one determinant that is thought to influence adherence is drug convenience. DOACs have overcome some of the 2.1 Developing the Value Tree perceived inconveniences related to warfarin. For example, the stable therapeutic effect of DOACs (pharmacokinet- A literature review was conducted in the PubMed and Sco- ics) does not require routine international normalized ratio pus electronic databases to identify all possible criteria (INR) monitoring. On the other hand, some DOACs have that affect the value of OACs among patients with AF. In to be taken twice instead of once daily [12]. total, seven groups of criteria were distinguished: biologi- However, studies that focused on patient preferences cal effects (e.g., efficacy, safety); convenience (e.g., intake found that drug efficacy and increased risk of bleeding were frequency, INR monitoring); healthcare organization (e.g., more important determinants of patient preferences for drugs waiting time, out-of-pocket costs); knowledge and com- compared to drug convenience [13–16]. Only when OACs munication (e.g., information, patient involvement); social have similar ec ffi acy and safety rates, convenience attributes environment (e.g., social support, family); physical status may matter to patients [12]. In addition, patient’s adherence (e.g., age, gender); and psychological status (e.g., anxiety, might be influenced by the convenience of the OAC therapy. concern). More detailed information on the literature review An observational study found that reducing intake frequency can be found in Appendix 1 (see the electronic supplemen- from twice to once daily is associated with a 26% higher tary material). Next, eight key informants with expertise in likelihood of adherence [17]. However, the actual impact the field of OAC therapy in patients with AF were asked to of convenience on therapy adherence is still unclear. Given validate the results of the literature review. Experts were the high number of determinants of therapy adherence, it asked to complete a web-based survey in which they were is difficult to determine relationships between these using questioned about the perceived impact of each criterion traditional epidemiological research. identified in the literature review. Subsequently, Skype inter - Therefore, the goal of this study was to gain more views were held to discuss the responses in detail. Based on knowledge about the relative impact of attributes of the literature review and the information obtained from key Patients’ Priorities for Oral Anticoagulation Therapy 495 informants, the hierarchical value tree was developed by the a pill once or twice daily. Certain foods and beverages may project team (Fig. 1). interact with OACs, and therefore it is important to follow Criteria that were included in the AHP had to be charac- food restrictions and maintain a well-balanced and consist- teristics that were modifiable, had to be relevant to patients ent diet. However, this can be bothersome and inconvenient. and had to differ between the available OACs. Four main Additionally, some patients need to have their blood levels domains of criteria were selected: effectiveness, safety, con- checked regularly to ensure that they are within the pre- venience and out-of-pocket costs. These will be explained scribed INR range to reduce the risk of clots or bleedings. in detail below, along with the lower level dimensions. They have to visit the clinic regularly or use a self-monitor- Literature showed that effectiveness is a main reason for ing device, which can be inconvenient. The last subcrite- patients to take OACs and therefore highly determines its rion of convenience is the type of pill and associated intake value (10). Different definitions of effectiveness are used instructions. It matters to patients whether they have to take across studies, but we defined effectiveness as the ability of a capsule or a tablet, whether the pill should be swallowed the OAC to reduce the risk of ischemic AF-related stroke. whole or can be taken with water or melts on the tongue, The safety domain includes the most common undesired and whether it is required to take the pill with a proper meal. adverse effects resulting from taking OACs, which are the The fourth criterion is out-of-pocket costs, defined as the risk of major bleeding, minor bleeding, and gastrointestinal amount a patient has to co-pay for the OAC therapy each complaints. Major bleeding was defined as significant blood month (copayments, coinsurance, deductible). DOACs are loss that requires medical intervention, possible hospitaliza- more expensive than VKAs, and due to the need to econo- tion, and blood transfusion. Minor bleeding might require mize expenses for healthcare, DOACs require higher out-of- medical attention, but is self-limiting and does not involve pocket costs in some countries [26]. a critical site, such as, for instance, epistaxis (nose bleed- ings) [24]. Gastrointestinal complaints included dyspepsia, 2.2 Pairwise Comparisons bloating, nausea, loss of appetite, and symptoms of feel- ing sick. Drug convenience highlights the degree to which After the main hierarchy and two subhierarchies were deter- a patient believes that taking an OAC will be free of effort mined, the next step was to construct the pairwise compari- [25]. Based on the interviews and literature [13, 14], we sons in which patients would be systematically asked for selected four criteria within the convenience domain: intake the importance of each (sub)criterion. Each patient judges frequency, food restrictions, monthly INR monitoring, and how important one criterion is compared to all other crite- pill type/intake instructions. The more often an OAC has to ria, with respect to its (sub)hierarchy. In total, patients had be taken each day, the more likely it is that patients forget to to complete 15 pairwise comparisons to estimate criteria take it [17]. Intake frequency for OACs differs from taking weights for all hierarchies. The judgment was made on a Fig. 1 Value tree for selecting the optimal anticoagulant drug for AF-related stroke preven- tion. AF atrial fibrillation 496 M. G. M. Weernink et al. double 9-point scale, where 1 reflects equal importance and on medication adherence and retrieve AHP weights, yet 9 reflects greater importance for one of the two criteria. An small enough to have enough time to discuss all relevant example of a pairwise comparison is shown in Fig. 2. topics. Furthermore, one of our specific aims was to estimate A specialist recruitment agency (Lightspeed Research) the strength of preference within the criteria of the conveni- recruited eligible patients via proprietary patient panels, ence hierarchy (e.g., preference for once- or twice-daily local AF support groups and referral by healthcare profes- intake). We used AHP pairwise comparisons to determine sionals in hospitals or primary care settings. Patients were the performance of possible options within each subcrite- eligible if they were at least 18 years old, had a formal/an rion of convenience (Fig. 3). The different options which expert diagnosis of AF, were currently using OACs and were compared to each other were intake frequency (once vs were able to provide informed consent. All patients were twice daily), food restrictions (yes vs no), and routine INR paid €90 for participation in the study. Ethical approval monitoring (yes vs no). Lastly, four different types of pills of this study was obtained from the institutional review and related intake instructions were compared: (1) a capsule, board of the University of Twente. All patients gave writ- swallowed whole, does not require intake with food; (2) a ten informed consent, and all data were anonymized before tablet, can be mixed with water, does not require intake with analysis. food; (3) a tablet, can be mixed with water, requires intake The 2-h focus groups were conducted by experienced with food; and (4) a tablet which dissolves (melts) on the moderators in the patients’ native language and were tape- tongue and does not require intake with food. These four recorded [28]. In the first hour, a qualitative discussion took were selected based upon what is currently available on the place on patients’ medication-taking behavior [29]. The sec- market and possible future developments. ond hour of the focus group was focused on determining the relative impact of the (sub)criteria of the value tree using the 2.3 Data Collection and Study Sample AHP pairwise comparisons and elicitation of performance weights. Patients received the answer form on paper, and the The AHP pairwise comparisons were questioned and dis- moderator introduced each group of pairwise comparisons cussed in 2-h focus group sessions with a convenience (subhierarchies) separately. Prior to answering, the mod- sample of patients with AF. To examine the European erator explained all (sub)criteria in a general way (e.g., not perspective, five sessions were conducted in France, Italy, mentioning specific effectiveness rates of available OACs) Spain, the United Kingdom and Germany between 31 and asked whether all was clear. After each subsection was January 2017 and 15 February 2017. The size of focus completed, the moderator asked whether some patients groups should be determined based on the research aims would like to explain their answers. Yet this was not done [27], so we aimed to have ten participants in each focus with the aim to reach consensus in the group, but to gather group. This is large enough to generate enough discussion reasons for their choice behavior. Fig. 2 Example of a pairwise comparison of two subcriteria of convenience rated on a pref- erence scale (verbal comparison format) Fig. 3 Example of a pairwise comparison to determine the performance of two options of ‘intake frequency’ (verbal comparison format) Patients’ Priorities for Oral Anticoagulation Therapy 497 the subhierarchy of side effects, the most important side effect 2.4 Data Analysis according to patients was major bleedings (0.75), followed by minor bleedings (0.15) and gastrointestinal complaints (0.10). First, the AHP pairwise comparisons are converted to the numeric scale and entered into a reciprocal matrix. There are The criteria convenience (0.07) and out-of-pocket costs (0.06) were considered the least important according to patients. No two ways to aggregate individuals’ judgments and priorities with the AHP [30]. In this research, we chose to combine notable differences in criteria weights were found for the dif- ferent subgroups of patients receiving DOACs or VKAs. individual judgments by taking the geometric mean and esti- mated priorities (criteria weights) from these judgments by Within the hierarchy of the convenience criterion, patients attached most importance to reducing the need for routine computing the principle right-hand eigenvector. This method was chosen because it meets several required axiomatic con- INR monitoring (0.40). However, when asked for a perfor- mance value on having or not having routine INR monitor- ditions, such as the reciprocal property [30]. The criteria weights indicate their relative importance in the overall ing, about 40% of patients stated that they preferred to have routine INR monitoring and the same number of patients value of OAC therapy or one of the subhierarchies (con- venience and side effects). The same method was also used preferred not to have routine INR monitoring (Table  3). Eight patients (18%) did not express a preference. to estimate the strength of preference (performance weights) for the options within the criteria of the convenience hierar- Subgroup analysis showed that the majority of patients on VKAs, who have INR monitoring, also prefer INR moni- chy (e.g., once- vs twice-daily intake). For both criteria and performance weights, bootstrap methods were used to obtain toring, and the majority of patients on DOACs, who do not have INR monitoring, also prefer this. However, there were standard deviations. In addition, Chi square tests were used to study significant differences between patient’s current and also 12 patients that prefer the opposite of what they cur- rently have. preferred options within convenience criteria. P values lower than 0.05 were considered statistically significant. Although the majority of patients (> 75%) were not both- ered by possible food restrictions, reducing them was the Lastly, the comparison matrix of weights is used to calcu- late a measure of the consistency within each (sub)hierarchy second most important criterion which impacted the per- ceived convenience of OAC therapy (0.27). Patients on of paired comparisons. This measure, called the inconsist- ency ratio, represents the ratio of the amount of inconsist- DOACs were more often bothered by possible food restric- tions, but the difference with patients on VKAs was not sta- ency in patient’s judgments in the pairwise comparisons. An inconsistency ratio of < 0.1 is acceptable, indicating that tistically significant (32 vs 16%, P = 0.22). Intake frequency had an impact of 17% on the perceived conclusions from the AHP comparisons are mathematically sound. However, a consistency rate of < 0.2 is generally convenience of the drug, and the majority of patients (> 70%) preferred once-daily intake compared to twice- accepted in individual preference-elicitation studies [23]. All analyses were performed using Microsoft Excel and daily intake. Most patients currently take an anticoagulant with the intake frequency of their preference. However, the IBM SPSS Statistics 24.0. patients who currently take and prefer twice-daily intake assigned a performance weight of 0.54 to twice-daily intake, 3 Results while the patients who currently take and prefer once-daily intake assigned a performance weight of 0.81 to once-daily 3.1 Respondent Sample intake. With regard to preference for intake regimen, a tablet that In total, 48 patients participated in the focus groups. How- can be mixed with water and does not have to be taken with food is preferred by most patients (36%) (Table 3). Its aver- ever, three patients (all from Italy) had multiple incoherent responses in their AHP pairwise comparisons and therefore age performance score was 0.33. The tablet that dissolves (melts) on the tongue and does not require intake with food were excluded from data analysis. The number of patients taking VKAs and DOACs across the sample was 58 versus was preferred by 30% of patients and had an average per- formance score of 0.29. Least preferred was the OAC in the 42%. Other background characteristics of the patient sample can be found in Table 1. form of a capsule (9% of patients, performance score 0.13). 3.2 Patient Preferences 4 Discussion The results of our study indicate that patients attach most The aim of the study was to elicit the patient perspec- importance to high effectiveness of the OAC therapy (impor - tance weight 0.60) (Table 2). The safety aspect of OAC ther- tive of the relative impact of attributes of convenience on the overall value of anticoagulants using a prescriptive apy was the second-most important criterion (0.27). Within 498 M. G. M. Weernink et al. Table 1 Socio-demographic and clinical characteristics of respondents across countries (N = 45). Data is reported as n (%) or mean ± SD Variables Overall UK Germany France Spain Italy (n = 45) (n = 10) (n = 10) (n = 8) (n = 10) (n = 7) Gender  Man 22 (49.0) 7 (70.0) 5 (50.0) 1 (13.0) 5 (50.0) 4 (57.0)  Woman 23 (51.0) 3 (30.0) 5 (50.0) 7 (87.0) 5 (50.0) 3 (43.0) Marital state  Yes 33 (73.0) 9 (90.0) 6 (60.0) 5 (63.0) 6 (60.0) 7 (100.0)  No 12 (27.0) 1 (10.0) 4 (40.0) 3 (37.0) 4 (40.0) – Age  Mean ± SD 62.3 ± 13.2 70.3 ± 7.5 60.3 ± 10.5 48.5 ± 11.1 71.1 ± 11.8 60.6 ± 13.9  Missing 3 (30.0) Education level  Low 10 (22.0) 4 (40.0) – – 5 (50.0) 1 (14.3)  Medium 10 (22.0) 2 (20.0) 3 (30.0) 3 (37.5) 1 (10.0) 3 (42.9)  High 25 (56.0) 4 (40.0) 7 (70.0) 5 (62.5) 4 (40.0) 3 (42.9) Employment status  Employed (full/part-time) 3 (6.7) 3 (30.0) 5 (50.0) 7 (87.5) 3 (30.0)  Retired 20 (44.4) 7 (70.0) 4 (40.0) – 5 (50.0) 3 (42.9)  Unemployed 21 (46.7) – 1 (10.0) 1 (12.5) 1 (10.0) 4 (57.1)  Missing 1 (2.2) – – – 1 (10.0) – Annual household income (€)  0–15,000 7 (15.6) 1 (10.0) 1 (10.0) 1 (12.5) 2 (20.0) 2 (28.6)  15,001–25,000 7 (15.6) – 2 (20.0) 1 (12.5) 2 (20.0) 2 (28.6)  25001–50,000 12 (26.7) 5 (50.0) 3 (30.0) 1 (12.5) 2 (20.0) 1 (14.3)  50,001+ 7 (15.6) 1 (10.0) 1 (10.0) 3 (37.5) 1 (10.0) 1 (14.3)  Unknown 11 (24.4) 3 (30.0) 3 (30.0) 2 (25.0) 2 (20.0) 1 (14.3)  Missing 1 (2.2) – – – 1 (10.0) – OAC therapy  Total no. of patients on VKA 26 (57.8) 6 (60.0) 6 (60.0) 4 (50.0) 5 (50.0) 5 (71.4)   Warfarin 10 (22.2) 6 (60.0) – – – 4 (57.1)   Acenocoumarol 6 (13.3) – – – 5 (50.0) 1 (14.3)   Phenprocoumon 6 (13.3) – 6 (60.0) - – –   Fluindione 4 (8.9) – - 4 (50.0) – –  Total no. of patients on DOAC 19 (42.2) 4 (40.0) 4 (40.0) 4 (50.0) 5 (50.0) 2 (28.6)   Dabigatran 7 (15.6) 1 (10.0) 3 (30.0) 1 (12.5) 1 (10.0) 1 (14.3)   Rivaroxaban 7 (15.6) 1 (10.0) 1 (10.0) 2 (35.0) 3 (30.0) -   Apixaban 5 (11.1) 2 (20.0) – 1 (12.5) 1 (10.0) 1 (14.3) Time period on OAC therapy  < 1 year 19 (42.2) 5 (50.0) 1 (10.0) 4 (50.0) 3 (30.0) 6 (85.7)  1–5 years 9 (20.0) – 6 (60.0) 3 (37.5) – –  > 5 years 15 (33.3) 4 (40.0) 3 (30.0) 1 (12.5) 6 (60.0) 1 (14.3)  Missing 2 (4.4) 1 (10.0) – – 1 (10.0) – DOAC direct (non-VKA) oral anticoagulant, OAC oral anticoagulant, SD standard deviation, VKA vitamin K antagonist Low educational level: lower technical and vocational training and lower general secondary education; medium educational level: intermediate vocational training and advanced secondary education; high educational level: higher vocational education and university multi-criteria decision model. The results of the study on drug value. These findings are in accordance with the indicate that patients clearly prioritize the effectiveness results of other studies, which found that the most impor- and side effects of OACs (safety profile), and that con - tant characteristics of therapy to patients are the effective- venience and out-of-pocket costs only have a minor impact ness and side effects of the drugs [13– 15]. Patients’ Priorities for Oral Anticoagulation Therapy 499 effect of drugs and the contact with the doctor. Advocates Table 2 Importance weights for the criteria and subcriteria, reported as weight (standard deviation) of having no routine INR monitoring assume that routine blood monitoring results in being restricted in activities, Attributes All patients VKA users DOAC users having to make appointments at specific times and feeling Main dimensions N = 44 N = 25 N = 19 anxious about the results [29]. Although only a few patients  Effectiveness 0.60 (0.02) 0.58 (0.03) 0.64 (0.02) were bothered with having food restrictions, patients who  Safety (side effects) 0.27 (0.02) 0.28 (0.03) 0.25 (0.02) have switched therapies (from VKA to DOAC) indicated  Convenience 0.07 (0.01) 0.08 (0.01) 0.06 (0.01) that the food restrictions were a main reason for them to  Out-of-pocket cost 0.06 (0.01) 0.06 (0.01) 0.06 (0.01) switch. Results have also shown that patients prefer simple  Consistency ratio 0.16 0.18 0.15 intake instructions; requirements with regard to swallowing Safety N = 45 N = 26 N = 19 the pill as a whole or taking the pill with food lowered the  Major bleedings 0.75 (0.02) 0.76 (0.02) 0.73 (0.03) performance value. Despite not being available on the mar-  Minor bleedings 0.15 (0.02) 0.14 (0.02) 0.16 (0.02) ket now, a melting pill was the second-most preferred type  Gastrointestinal complaints 0.10 (0.01) 0.10 (0.01) 0.11 (0.02) of pill. From this research, it is recommended that in clini-  Consistency ratio 0.03 0.04 0.02 cal decision making, the differences in convenience should Convenience N = 43 N = 24 N = 19 be discussed with the patient, it could be argued that drug  Routine blood monitoring 0.40 (0.04) 0.39 (0.04) 0.42 (0.05) prescriptions should follow patient preferences on this point.  Food restrictions 0.27 (0.03) 0.27 (0.04) 0.28 (0.05) Furthermore, convenience should always be balanced  Intake frequency 0.17 (0.02) 0.19 (0.03) 0.15 (0.02) with (out-of-pocket) costs of the drug: DOACs are more  Pill type/intake instruc- 0.15 (0.02) 0.16 (0.03) 0.15 (0.02) expensive than warfarin. In most countries, patients do tions not directly pay these costs, although in Spain and France,  Consistency ratio 0.002 0.004 0.01 patients pay part of the difference in actual drug costs. Obvi- ously, paying higher out-of-pocket costs for DOACs reduce All standard deviations were obtained by bootstrap analysis their overall value compared to warfarin, but in the focus DOAC direct (non-VKA) oral anticoagulant, VKA vitamin K antago- nist groups, the costs of treatment were only of minor impor- tance to focus group participants. None of the participants in these focus groups indicated that costs were a barrier to In taking drugs for preventive purposes, the positive having the drugs they wanted. effects of OAC therapy lie in the future, while the side This study had some limitations. First, the crite- effects may impact patients today or on a daily basis. Thus, ria that were included in the decision tree were chosen the frequency and severity of side effects were also very by the project team, based on the current literature and important to patients. Although the probability of experienc- support of an international expert team. For example, a ing a major bleeding with OAC therapy is low, the results of separate criterion for INR self-monitoring devices was this study show that patients attach higher priority to reduc- not included, but whether patients use a self-monitoring ing the frequency of major versus minor bleeds. One recom- device or visit the hospital might influence how patients mendation that would follow from this finding is to discuss perceive this need for regular INR monitoring. The struc- both the probability and consequences of side effects with ture of the value tree in MCDM is a recognized source of patients more explicitly, and to educate patients. uncertainty, and its impact has been shown in literature Compared to the ec ffi acy and safety criteria, convenience [31, 32]. Second, with regard to the method used to elicit was only of little importance to patients. Yet the available preferences, the total number of comparisons that had to OACs only differ slightly in efficacy and safety rates, while be made was high, which could influence patient concen- the differences with regard to the attributes of convenience tration. The pairwise comparisons of the main hierarchy have a direct impact on patient’s daily life. Moreover, our had a consistency ratio higher than 0.1 and was questioned results show that patients have different preferences for last, so, fatigue may have played an important role. Third, options within the convenience criteria. Although most we included a maximum of ten participants per country; patients preferred once-daily intake, some patients preferred therefore, it was not possible to focus on differences in twice-daily intake (30%) as they were used to this routine importance weights across countries. Differences were (e.g., taking the anticoagulants with breakfast and dinner). mostly expected with regard to costs, and in all countries Furthermore, patients differed on the opinion whether rou- the importance of costs was rated low. However, whether tine INR monitoring is preferred to no monitoring. The actual differences in preferences exist between countries qualitative focus group results showed that the perceived should be studied in a larger scale study. In addition, our benefits of routine INR monitoring were related to reas- sample of patients was relatively highly educated, which surance, mainly resulting from the routine feedback on the 500 M. G. M. Weernink et al. Table 3 Preferences and AHP performance weights for options within the convenience criteria Intake frequency All patients (n = 45) Once-daily takers (n = 33) Twice-daily takers (n = 12) Chi square N (%) Weight (SD) N (%) Weight (SD) N (%) Weight (SD) Prefers once daily 32 (71.1) 0.74 (0.04) 28 (84.8) 0.81 (0.03) 4 (33.3) 0.46 (0.11) 0.001 Prefers twice daily 13 (28.9) 0.26 (0.04) 5 (15.2) 0.19 (0.03) 8 (66.7) 0.54 (0.11) Routine INR monitoring All patients (n = 42) VKA users (monitoring) DOAC users (no monitoring) Chi square (n = 23) (n = 19) N (%) Weight (SD) N (%) Weight (SD) N (%) Weight (SD) Prefers monitoring 17 (37.8) 0.49 (0.05) 13 (56.6) 0.57 (0.08) 4 (21.1) 0.39 (0.06) 0.14 Does not prefer monitoring 17 (37.8) 0.51 (0.05) 8 (34.8) 0.43 (0.08) 9 (47.4) 0.61 (0.06) No preference 8 (17.8) – 2 (8.7) – 6 (31.6) – Food restrictions All patients (n = 44), N (%) VKA users (restrictions) DOAC users (no restrictions) Chi square (n = 23), N (%) (n = 19), N (%) N (%) Weight (SD) N (%) Weight (SD) N (%) Weight (SD) Not bothered 34 (75.6) – 21 (84.0) – 13 (68.4) – 0.22 Bothered 10 (22.2) – 4 (16.0) – 6 (31.6) – Pill type/intake All patients (n = 44) instructions N (%) Weight (SD) 1. Capsule, swallowed 4 (9.1) 0.13 (0.01) whole, does not require intake with food 2. Tablet, can be mixed 16 (36.4) 0.33 (0.03) with water, does not require intake with food 3. Tablet, can be mixed 5 (11.4) 0.25 (0.03) with water, requires intake with food 4. Tablet which dissolves 13 (29.5) 0.29 (0.03) (melts) on the tongue, and does not require intake with food 5. No preference 6 (13.6) Data are presented as N (%) and AHP performance weight (SD) AHP analytic hierarchy process, DOAC direct (non-VKA) oral anticoagulant, INR international normalized ratio, SD standard deviation, VKA vitamin K antagonist No consistency ratio is reported for intake frequency and routine INR monitoring, because it consisted of one pairwise comparison No pairwise comparison was questioned to estimate performance, because it was likely that all patients would have a preference for not having food restrictions The consistency ratio for pill type/intake instructions was 0.08 limits the generalizability of this study. Fourth, the pair- 5 Conclusion wise comparisons were completed during the second hour of the focus groups. Although the focus group was led Effectiveness and safety are the most important attributes by experience moderators and open and semi-structured of OAC therapy. Although the relative impact of conveni- questions were used, patients with dominant views might ence on therapy value is small, patients have different have influenced the answers of other patients, or prompted preferences for options within the convenience criteria. them to give socially desirable answers [33]. Finally, it is Besides considerations on safety and effectiveness, physi- clear that adherence is influenced by a large number of cians should also discuss attributes of convenience with factors that are not related to the characteristics of the drug patients, as it can be assumed that alignment to patient itself, such as knowledge and motivation of the patient. A preferences in drug prescription, and better patient edu- broader model of adherence is required to understand and cation could result in higher adherence to treatment. The improve patient adherence to OACs. differences in individual preferences for convenience found within this study support the notion that decisions Patients’ Priorities for Oral Anticoagulation Therapy 501 fibrillation. N Engl J Med. 2009;361(12):1139–51. https ://doi. on which OAC therapy to take is a decision that has to be org/10.1056/NEJMo a0905 561. made with, and not for, the patient. 6. Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. Edoxaban versus warfarin in patients with atrial Compliance with Ethical Standards fibrillation. N Engl J Med. 2013;369(22):2093–104. https ://doi. org/10.1056/NEJMo a1310 907. 7. Granger CB, Alexander JH, McMurray JJV, Lopes RD, Hylek Funding This study was funded by Daiichi Sankyo Europe GmbH EM, Hanna M, et al. Apixaban versus warfarin in patients with (Munich, Germany). Besides the initial review process before funding atrial fibrillation. N Engl J Med. 2011;365(11):981–92. https :// and amendments, Daiichi Sankyo was only involved in the design of the doi.org/10.1056/NEJMo a1107 039. study. The funders had no role in data collection and analysis, decision 8. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, to publish, or the preparation of this manuscript. et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883–91. https ://doi.org/10.1056/ Conflict of interest Marieke G.M. Weernink, Melissa C.W. Vaan- NEJMo a1009 638. holt, Catharina G.M. Groothuis-Oudshoorn, Clemens von Birgelen, 9. Brown TM, Siu K, Walker D, Pladevall-Vila M, Sander S, Mor- Maarten J. IJzerman and Janine A. van Til declare that they have no din M. Development of a conceptual model of adherence to oral conflicts of interest that might be relevant to the contents of this manu- anticoagulants to reduce risk of stroke in patients with atrial script. In addition, CvB indicated non-related institutional research fibrillation. J Manag Care Pharm. 2012;18(5):351–62. h tt p s : // grants provided by several device-manufacturing companies. doi.org/10.18553 /jmcp.2012.18.5.351. 10. Bajorek BV, Ogle SJ, Duguid MJ, Shenfield GM, Krass I. Bal- Ethical approval All procedures performed in studies involving human ancing risk versus benefit: the elderly patient’s perspective on participants were in accordance with the ethical standards of the insti- warfarin therapy. Pharm Pract. 2009;7(2):113–23. tutional and/or national research committee and with the 1964 Helsinki 11. Abdou JK, Auyeung V, Patel JP, Arya R. Adherence to long-term declaration and its later amendments or comparable ethical standards. anticoagulation treatment, what is known and what the future The study protocol, focus group guide and answer form were reviewed might hold. Br J Haematol. 2016;174(1):30–42. h t t p s : / / d o i . and approved by the institutional review board of the University of org/10.1111/bjh.14134. Twente. 12. Mekaj YH, Mekaj AY, Duci SB, Miftari EI. New oral anticoagu- lants: their advantages and disadvantages compared with vitamin Informed consent Informed consent was obtained from all individual K antagonists in the prevention and treatment of patients with participants included in the study. thromboembolic events. Ther Clin Risk Manag. 2015;11:967–77. https ://doi.org/10.2147/TCRM.S8421 0. 13. Ghijben P, Lancsar E, Zavarsek S. Preferences for oral antico- Open Access This article is distributed under the terms of the Crea- agulants in atrial fibrillation: a best-best discrete choice experi- tive Commons Attribution-NonCommercial 4.0 International License ment. PharmacoEconomics. 2014;32(11):1115–27. https ://doi. 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Patients’ Priorities for Oral Anticoagulation Therapy in Non-valvular Atrial Fibrillation: a Multi-criteria Decision Analysis

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Springer Journals
Copyright
Copyright © 2018 by The Author(s)
Subject
Medicine & Public Health; Cardiology; Pharmacotherapy; Pharmacology/Toxicology
ISSN
1175-3277
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1179-187X
DOI
10.1007/s40256-018-0293-0
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Abstract

Introduction Effectiveness of oral anticoagulants (OACs) is critically dependent on patients’ adherence to intake regimens. We studied the relative impact of attributes related to effectiveness, safety, convenience, and costs on the value of OAC therapy from the perspective of patients with non-valvular atrial fibrillation. Methods Four attributes were identified by literature review and expert interviews: effectiveness (risk of ischemic stroke), safety (risk of major bleeding, minor bleeding, gastrointestinal complaints), convenience (intake frequency, diet restrictions, international normalized ratio [INR] blood monitoring, pill type/intake instructions), and out-of-pocket costs. Focus groups were held in Spain, Germany, France, Italy and the United Kingdom (N = 48) to elicit patients’ preferences through the use of the analytical hierarchy process method. Results Effectiveness (60%) and side effects (27%) have a higher impact on the perceived value of OACs than drug conveni - ence (7%) and out-of-pocket costs (6%). As for convenience, eliminating monthly INR monitoring was given the highest priority (40%), followed by reducing diet restrictions (27%), reducing intake frequency (17%) and improving the pill type/ intake instructions (15%). The most important side effect was major bleeding (75%), followed by minor bleeding (15%) and gastrointestinal complaints (10%). Furthermore, 71% of patients preferred once-daily intake to twice-daily intake. Discussion Although the relative impact of convenience on therapy value is small, patients have different preferences for options within convenience criteria. Besides considerations on safety and effectiveness, physicians should also discuss attributes of convenience with patients, as it can be assumed that alignment to patient preferences in drug prescription and better patient education could result in higher adherence. Key Points Effectiveness and safety are the most important attributes of oral anticoagulant (OAC) therapy. Although the relative impact of convenience on therapy value is small, patients have different preferences for options within the convenience criteria. Electronic supplementary material The online version of this article (https ://doi.org/10.1007/s4025 6-018-0293-0) contains It is recommended that besides considerations on safety supplementary material, which is available to authorized users. and effectiveness, physicians also discuss attributes of convenience with patients. * Janine A. van Til j.a.vantil@utwente.nl Department of Health Technology and Services Research, Faculty of Behavioural, Management and Social Sciences, Technical Medical Centre, University of Twente, P.O. Box 217, 7500 AE Enschede, The Netherlands Department of Cardiology, Thoraxcentrum Twente, Medisch Spectrum Twente, 7512 KZ Enschede, The Netherlands Vol.:(0123456789) 494 M. G. M. Weernink et al. therapy on the value of OAC therapy from the perspective 1 Introduction of patients with AF. More specifically this study aimed to: Non-valvular atrial fibrillation (AF) is the most com- • Estimate the strength of preference of patients between mon heart rhythm disturbance encountered by physicians criteria of convenience (e.g., intake once vs twice daily). in clinical practice. AF is associated with a high risk of • Estimate the relative impact of attributes of convenience ischemic stroke and systemic embolism and increased on overall convenience of OAC therapy (e.g., lower mortality [1]. Vitamin K antagonists (VKAs) have been intake frequency vs no blood monitoring). used as an effective oral anticoagulant (OAC) drug therapy Estimate the relative impact of drug convenience on the to prevent AF-related stroke for many years [2]. Of these total value of OAC therapy, compared to other medica- VKAs, warfarin is the most commonly used in clinical tion-related attributes (e.g., safety, effectiveness). practice. More recently, the European Medicines Agency has approved a number of direct (non-VKA) oral antico- agulants (DOACs) [3]. Several randomized controlled 2 Method trials and meta-analyses have shown that DOACs have a favorable risk–benefit profile when compared with warfa- The analytic hierarchy process (AHP) [18], a technique rin [4–8]. DOACs reduce the risk in stroke, intracranial within the multi-criteria decision making (MCDM) meth- hemorrhage and mortality, with similar major bleeding ods, was used to rank and prioritize the attributes. MCDM rates as warfarin. However, DOACs can also result in an methods allow for better structuring of the decision prob- increased risk of gastrointestinal bleeding [5]. Overall, the lem and are specifically helpful for people in making better relative efficacy and safety of DOACs are consistent across choices that are consistent with their preferences and values a wide range of patients [4]. The half-lives of DOACs are [19, 20]. AHP was originally developed in the 70 s and since shorter than those of VKAs. Although this means that the then has been successfully applied to determine preferences anticoagulant effect of the drug is reversed sooner in case for a variety of complex medical decisions [21, 22]. The of emergency, it also means that its anticoagulation effect first step of AHP is to decompose the criteria of the decision declines more rapidly with poor compliance compared to problem into a hierarchy of subcriteria, each of which can VKAs. Therefore, the effectiveness of DOACs is critically be analyzed independently. Subsequently, pairwise compari- dependent on patient adherence to intake regimens. sons of (sub)criteria determine the relative importance of In recent years, at least three conceptual models of each criterion. An extensive description of all steps within adherence have been developed [9–11]. In these models, AHP is presented in Hummel et al. [23]. one determinant that is thought to influence adherence is drug convenience. DOACs have overcome some of the 2.1 Developing the Value Tree perceived inconveniences related to warfarin. For example, the stable therapeutic effect of DOACs (pharmacokinet- A literature review was conducted in the PubMed and Sco- ics) does not require routine international normalized ratio pus electronic databases to identify all possible criteria (INR) monitoring. On the other hand, some DOACs have that affect the value of OACs among patients with AF. In to be taken twice instead of once daily [12]. total, seven groups of criteria were distinguished: biologi- However, studies that focused on patient preferences cal effects (e.g., efficacy, safety); convenience (e.g., intake found that drug efficacy and increased risk of bleeding were frequency, INR monitoring); healthcare organization (e.g., more important determinants of patient preferences for drugs waiting time, out-of-pocket costs); knowledge and com- compared to drug convenience [13–16]. Only when OACs munication (e.g., information, patient involvement); social have similar ec ffi acy and safety rates, convenience attributes environment (e.g., social support, family); physical status may matter to patients [12]. In addition, patient’s adherence (e.g., age, gender); and psychological status (e.g., anxiety, might be influenced by the convenience of the OAC therapy. concern). More detailed information on the literature review An observational study found that reducing intake frequency can be found in Appendix 1 (see the electronic supplemen- from twice to once daily is associated with a 26% higher tary material). Next, eight key informants with expertise in likelihood of adherence [17]. However, the actual impact the field of OAC therapy in patients with AF were asked to of convenience on therapy adherence is still unclear. Given validate the results of the literature review. Experts were the high number of determinants of therapy adherence, it asked to complete a web-based survey in which they were is difficult to determine relationships between these using questioned about the perceived impact of each criterion traditional epidemiological research. identified in the literature review. Subsequently, Skype inter - Therefore, the goal of this study was to gain more views were held to discuss the responses in detail. Based on knowledge about the relative impact of attributes of the literature review and the information obtained from key Patients’ Priorities for Oral Anticoagulation Therapy 495 informants, the hierarchical value tree was developed by the a pill once or twice daily. Certain foods and beverages may project team (Fig. 1). interact with OACs, and therefore it is important to follow Criteria that were included in the AHP had to be charac- food restrictions and maintain a well-balanced and consist- teristics that were modifiable, had to be relevant to patients ent diet. However, this can be bothersome and inconvenient. and had to differ between the available OACs. Four main Additionally, some patients need to have their blood levels domains of criteria were selected: effectiveness, safety, con- checked regularly to ensure that they are within the pre- venience and out-of-pocket costs. These will be explained scribed INR range to reduce the risk of clots or bleedings. in detail below, along with the lower level dimensions. They have to visit the clinic regularly or use a self-monitor- Literature showed that effectiveness is a main reason for ing device, which can be inconvenient. The last subcrite- patients to take OACs and therefore highly determines its rion of convenience is the type of pill and associated intake value (10). Different definitions of effectiveness are used instructions. It matters to patients whether they have to take across studies, but we defined effectiveness as the ability of a capsule or a tablet, whether the pill should be swallowed the OAC to reduce the risk of ischemic AF-related stroke. whole or can be taken with water or melts on the tongue, The safety domain includes the most common undesired and whether it is required to take the pill with a proper meal. adverse effects resulting from taking OACs, which are the The fourth criterion is out-of-pocket costs, defined as the risk of major bleeding, minor bleeding, and gastrointestinal amount a patient has to co-pay for the OAC therapy each complaints. Major bleeding was defined as significant blood month (copayments, coinsurance, deductible). DOACs are loss that requires medical intervention, possible hospitaliza- more expensive than VKAs, and due to the need to econo- tion, and blood transfusion. Minor bleeding might require mize expenses for healthcare, DOACs require higher out-of- medical attention, but is self-limiting and does not involve pocket costs in some countries [26]. a critical site, such as, for instance, epistaxis (nose bleed- ings) [24]. Gastrointestinal complaints included dyspepsia, 2.2 Pairwise Comparisons bloating, nausea, loss of appetite, and symptoms of feel- ing sick. Drug convenience highlights the degree to which After the main hierarchy and two subhierarchies were deter- a patient believes that taking an OAC will be free of effort mined, the next step was to construct the pairwise compari- [25]. Based on the interviews and literature [13, 14], we sons in which patients would be systematically asked for selected four criteria within the convenience domain: intake the importance of each (sub)criterion. Each patient judges frequency, food restrictions, monthly INR monitoring, and how important one criterion is compared to all other crite- pill type/intake instructions. The more often an OAC has to ria, with respect to its (sub)hierarchy. In total, patients had be taken each day, the more likely it is that patients forget to to complete 15 pairwise comparisons to estimate criteria take it [17]. Intake frequency for OACs differs from taking weights for all hierarchies. The judgment was made on a Fig. 1 Value tree for selecting the optimal anticoagulant drug for AF-related stroke preven- tion. AF atrial fibrillation 496 M. G. M. Weernink et al. double 9-point scale, where 1 reflects equal importance and on medication adherence and retrieve AHP weights, yet 9 reflects greater importance for one of the two criteria. An small enough to have enough time to discuss all relevant example of a pairwise comparison is shown in Fig. 2. topics. Furthermore, one of our specific aims was to estimate A specialist recruitment agency (Lightspeed Research) the strength of preference within the criteria of the conveni- recruited eligible patients via proprietary patient panels, ence hierarchy (e.g., preference for once- or twice-daily local AF support groups and referral by healthcare profes- intake). We used AHP pairwise comparisons to determine sionals in hospitals or primary care settings. Patients were the performance of possible options within each subcrite- eligible if they were at least 18 years old, had a formal/an rion of convenience (Fig. 3). The different options which expert diagnosis of AF, were currently using OACs and were compared to each other were intake frequency (once vs were able to provide informed consent. All patients were twice daily), food restrictions (yes vs no), and routine INR paid €90 for participation in the study. Ethical approval monitoring (yes vs no). Lastly, four different types of pills of this study was obtained from the institutional review and related intake instructions were compared: (1) a capsule, board of the University of Twente. All patients gave writ- swallowed whole, does not require intake with food; (2) a ten informed consent, and all data were anonymized before tablet, can be mixed with water, does not require intake with analysis. food; (3) a tablet, can be mixed with water, requires intake The 2-h focus groups were conducted by experienced with food; and (4) a tablet which dissolves (melts) on the moderators in the patients’ native language and were tape- tongue and does not require intake with food. These four recorded [28]. In the first hour, a qualitative discussion took were selected based upon what is currently available on the place on patients’ medication-taking behavior [29]. The sec- market and possible future developments. ond hour of the focus group was focused on determining the relative impact of the (sub)criteria of the value tree using the 2.3 Data Collection and Study Sample AHP pairwise comparisons and elicitation of performance weights. Patients received the answer form on paper, and the The AHP pairwise comparisons were questioned and dis- moderator introduced each group of pairwise comparisons cussed in 2-h focus group sessions with a convenience (subhierarchies) separately. Prior to answering, the mod- sample of patients with AF. To examine the European erator explained all (sub)criteria in a general way (e.g., not perspective, five sessions were conducted in France, Italy, mentioning specific effectiveness rates of available OACs) Spain, the United Kingdom and Germany between 31 and asked whether all was clear. After each subsection was January 2017 and 15 February 2017. The size of focus completed, the moderator asked whether some patients groups should be determined based on the research aims would like to explain their answers. Yet this was not done [27], so we aimed to have ten participants in each focus with the aim to reach consensus in the group, but to gather group. This is large enough to generate enough discussion reasons for their choice behavior. Fig. 2 Example of a pairwise comparison of two subcriteria of convenience rated on a pref- erence scale (verbal comparison format) Fig. 3 Example of a pairwise comparison to determine the performance of two options of ‘intake frequency’ (verbal comparison format) Patients’ Priorities for Oral Anticoagulation Therapy 497 the subhierarchy of side effects, the most important side effect 2.4 Data Analysis according to patients was major bleedings (0.75), followed by minor bleedings (0.15) and gastrointestinal complaints (0.10). First, the AHP pairwise comparisons are converted to the numeric scale and entered into a reciprocal matrix. There are The criteria convenience (0.07) and out-of-pocket costs (0.06) were considered the least important according to patients. No two ways to aggregate individuals’ judgments and priorities with the AHP [30]. In this research, we chose to combine notable differences in criteria weights were found for the dif- ferent subgroups of patients receiving DOACs or VKAs. individual judgments by taking the geometric mean and esti- mated priorities (criteria weights) from these judgments by Within the hierarchy of the convenience criterion, patients attached most importance to reducing the need for routine computing the principle right-hand eigenvector. This method was chosen because it meets several required axiomatic con- INR monitoring (0.40). However, when asked for a perfor- mance value on having or not having routine INR monitor- ditions, such as the reciprocal property [30]. The criteria weights indicate their relative importance in the overall ing, about 40% of patients stated that they preferred to have routine INR monitoring and the same number of patients value of OAC therapy or one of the subhierarchies (con- venience and side effects). The same method was also used preferred not to have routine INR monitoring (Table  3). Eight patients (18%) did not express a preference. to estimate the strength of preference (performance weights) for the options within the criteria of the convenience hierar- Subgroup analysis showed that the majority of patients on VKAs, who have INR monitoring, also prefer INR moni- chy (e.g., once- vs twice-daily intake). For both criteria and performance weights, bootstrap methods were used to obtain toring, and the majority of patients on DOACs, who do not have INR monitoring, also prefer this. However, there were standard deviations. In addition, Chi square tests were used to study significant differences between patient’s current and also 12 patients that prefer the opposite of what they cur- rently have. preferred options within convenience criteria. P values lower than 0.05 were considered statistically significant. Although the majority of patients (> 75%) were not both- ered by possible food restrictions, reducing them was the Lastly, the comparison matrix of weights is used to calcu- late a measure of the consistency within each (sub)hierarchy second most important criterion which impacted the per- ceived convenience of OAC therapy (0.27). Patients on of paired comparisons. This measure, called the inconsist- ency ratio, represents the ratio of the amount of inconsist- DOACs were more often bothered by possible food restric- tions, but the difference with patients on VKAs was not sta- ency in patient’s judgments in the pairwise comparisons. An inconsistency ratio of < 0.1 is acceptable, indicating that tistically significant (32 vs 16%, P = 0.22). Intake frequency had an impact of 17% on the perceived conclusions from the AHP comparisons are mathematically sound. However, a consistency rate of < 0.2 is generally convenience of the drug, and the majority of patients (> 70%) preferred once-daily intake compared to twice- accepted in individual preference-elicitation studies [23]. All analyses were performed using Microsoft Excel and daily intake. Most patients currently take an anticoagulant with the intake frequency of their preference. However, the IBM SPSS Statistics 24.0. patients who currently take and prefer twice-daily intake assigned a performance weight of 0.54 to twice-daily intake, 3 Results while the patients who currently take and prefer once-daily intake assigned a performance weight of 0.81 to once-daily 3.1 Respondent Sample intake. With regard to preference for intake regimen, a tablet that In total, 48 patients participated in the focus groups. How- can be mixed with water and does not have to be taken with food is preferred by most patients (36%) (Table 3). Its aver- ever, three patients (all from Italy) had multiple incoherent responses in their AHP pairwise comparisons and therefore age performance score was 0.33. The tablet that dissolves (melts) on the tongue and does not require intake with food were excluded from data analysis. The number of patients taking VKAs and DOACs across the sample was 58 versus was preferred by 30% of patients and had an average per- formance score of 0.29. Least preferred was the OAC in the 42%. Other background characteristics of the patient sample can be found in Table 1. form of a capsule (9% of patients, performance score 0.13). 3.2 Patient Preferences 4 Discussion The results of our study indicate that patients attach most The aim of the study was to elicit the patient perspec- importance to high effectiveness of the OAC therapy (impor - tance weight 0.60) (Table 2). The safety aspect of OAC ther- tive of the relative impact of attributes of convenience on the overall value of anticoagulants using a prescriptive apy was the second-most important criterion (0.27). Within 498 M. G. M. Weernink et al. Table 1 Socio-demographic and clinical characteristics of respondents across countries (N = 45). Data is reported as n (%) or mean ± SD Variables Overall UK Germany France Spain Italy (n = 45) (n = 10) (n = 10) (n = 8) (n = 10) (n = 7) Gender  Man 22 (49.0) 7 (70.0) 5 (50.0) 1 (13.0) 5 (50.0) 4 (57.0)  Woman 23 (51.0) 3 (30.0) 5 (50.0) 7 (87.0) 5 (50.0) 3 (43.0) Marital state  Yes 33 (73.0) 9 (90.0) 6 (60.0) 5 (63.0) 6 (60.0) 7 (100.0)  No 12 (27.0) 1 (10.0) 4 (40.0) 3 (37.0) 4 (40.0) – Age  Mean ± SD 62.3 ± 13.2 70.3 ± 7.5 60.3 ± 10.5 48.5 ± 11.1 71.1 ± 11.8 60.6 ± 13.9  Missing 3 (30.0) Education level  Low 10 (22.0) 4 (40.0) – – 5 (50.0) 1 (14.3)  Medium 10 (22.0) 2 (20.0) 3 (30.0) 3 (37.5) 1 (10.0) 3 (42.9)  High 25 (56.0) 4 (40.0) 7 (70.0) 5 (62.5) 4 (40.0) 3 (42.9) Employment status  Employed (full/part-time) 3 (6.7) 3 (30.0) 5 (50.0) 7 (87.5) 3 (30.0)  Retired 20 (44.4) 7 (70.0) 4 (40.0) – 5 (50.0) 3 (42.9)  Unemployed 21 (46.7) – 1 (10.0) 1 (12.5) 1 (10.0) 4 (57.1)  Missing 1 (2.2) – – – 1 (10.0) – Annual household income (€)  0–15,000 7 (15.6) 1 (10.0) 1 (10.0) 1 (12.5) 2 (20.0) 2 (28.6)  15,001–25,000 7 (15.6) – 2 (20.0) 1 (12.5) 2 (20.0) 2 (28.6)  25001–50,000 12 (26.7) 5 (50.0) 3 (30.0) 1 (12.5) 2 (20.0) 1 (14.3)  50,001+ 7 (15.6) 1 (10.0) 1 (10.0) 3 (37.5) 1 (10.0) 1 (14.3)  Unknown 11 (24.4) 3 (30.0) 3 (30.0) 2 (25.0) 2 (20.0) 1 (14.3)  Missing 1 (2.2) – – – 1 (10.0) – OAC therapy  Total no. of patients on VKA 26 (57.8) 6 (60.0) 6 (60.0) 4 (50.0) 5 (50.0) 5 (71.4)   Warfarin 10 (22.2) 6 (60.0) – – – 4 (57.1)   Acenocoumarol 6 (13.3) – – – 5 (50.0) 1 (14.3)   Phenprocoumon 6 (13.3) – 6 (60.0) - – –   Fluindione 4 (8.9) – - 4 (50.0) – –  Total no. of patients on DOAC 19 (42.2) 4 (40.0) 4 (40.0) 4 (50.0) 5 (50.0) 2 (28.6)   Dabigatran 7 (15.6) 1 (10.0) 3 (30.0) 1 (12.5) 1 (10.0) 1 (14.3)   Rivaroxaban 7 (15.6) 1 (10.0) 1 (10.0) 2 (35.0) 3 (30.0) -   Apixaban 5 (11.1) 2 (20.0) – 1 (12.5) 1 (10.0) 1 (14.3) Time period on OAC therapy  < 1 year 19 (42.2) 5 (50.0) 1 (10.0) 4 (50.0) 3 (30.0) 6 (85.7)  1–5 years 9 (20.0) – 6 (60.0) 3 (37.5) – –  > 5 years 15 (33.3) 4 (40.0) 3 (30.0) 1 (12.5) 6 (60.0) 1 (14.3)  Missing 2 (4.4) 1 (10.0) – – 1 (10.0) – DOAC direct (non-VKA) oral anticoagulant, OAC oral anticoagulant, SD standard deviation, VKA vitamin K antagonist Low educational level: lower technical and vocational training and lower general secondary education; medium educational level: intermediate vocational training and advanced secondary education; high educational level: higher vocational education and university multi-criteria decision model. The results of the study on drug value. These findings are in accordance with the indicate that patients clearly prioritize the effectiveness results of other studies, which found that the most impor- and side effects of OACs (safety profile), and that con - tant characteristics of therapy to patients are the effective- venience and out-of-pocket costs only have a minor impact ness and side effects of the drugs [13– 15]. Patients’ Priorities for Oral Anticoagulation Therapy 499 effect of drugs and the contact with the doctor. Advocates Table 2 Importance weights for the criteria and subcriteria, reported as weight (standard deviation) of having no routine INR monitoring assume that routine blood monitoring results in being restricted in activities, Attributes All patients VKA users DOAC users having to make appointments at specific times and feeling Main dimensions N = 44 N = 25 N = 19 anxious about the results [29]. Although only a few patients  Effectiveness 0.60 (0.02) 0.58 (0.03) 0.64 (0.02) were bothered with having food restrictions, patients who  Safety (side effects) 0.27 (0.02) 0.28 (0.03) 0.25 (0.02) have switched therapies (from VKA to DOAC) indicated  Convenience 0.07 (0.01) 0.08 (0.01) 0.06 (0.01) that the food restrictions were a main reason for them to  Out-of-pocket cost 0.06 (0.01) 0.06 (0.01) 0.06 (0.01) switch. Results have also shown that patients prefer simple  Consistency ratio 0.16 0.18 0.15 intake instructions; requirements with regard to swallowing Safety N = 45 N = 26 N = 19 the pill as a whole or taking the pill with food lowered the  Major bleedings 0.75 (0.02) 0.76 (0.02) 0.73 (0.03) performance value. Despite not being available on the mar-  Minor bleedings 0.15 (0.02) 0.14 (0.02) 0.16 (0.02) ket now, a melting pill was the second-most preferred type  Gastrointestinal complaints 0.10 (0.01) 0.10 (0.01) 0.11 (0.02) of pill. From this research, it is recommended that in clini-  Consistency ratio 0.03 0.04 0.02 cal decision making, the differences in convenience should Convenience N = 43 N = 24 N = 19 be discussed with the patient, it could be argued that drug  Routine blood monitoring 0.40 (0.04) 0.39 (0.04) 0.42 (0.05) prescriptions should follow patient preferences on this point.  Food restrictions 0.27 (0.03) 0.27 (0.04) 0.28 (0.05) Furthermore, convenience should always be balanced  Intake frequency 0.17 (0.02) 0.19 (0.03) 0.15 (0.02) with (out-of-pocket) costs of the drug: DOACs are more  Pill type/intake instruc- 0.15 (0.02) 0.16 (0.03) 0.15 (0.02) expensive than warfarin. In most countries, patients do tions not directly pay these costs, although in Spain and France,  Consistency ratio 0.002 0.004 0.01 patients pay part of the difference in actual drug costs. Obvi- ously, paying higher out-of-pocket costs for DOACs reduce All standard deviations were obtained by bootstrap analysis their overall value compared to warfarin, but in the focus DOAC direct (non-VKA) oral anticoagulant, VKA vitamin K antago- nist groups, the costs of treatment were only of minor impor- tance to focus group participants. None of the participants in these focus groups indicated that costs were a barrier to In taking drugs for preventive purposes, the positive having the drugs they wanted. effects of OAC therapy lie in the future, while the side This study had some limitations. First, the crite- effects may impact patients today or on a daily basis. Thus, ria that were included in the decision tree were chosen the frequency and severity of side effects were also very by the project team, based on the current literature and important to patients. Although the probability of experienc- support of an international expert team. For example, a ing a major bleeding with OAC therapy is low, the results of separate criterion for INR self-monitoring devices was this study show that patients attach higher priority to reduc- not included, but whether patients use a self-monitoring ing the frequency of major versus minor bleeds. One recom- device or visit the hospital might influence how patients mendation that would follow from this finding is to discuss perceive this need for regular INR monitoring. The struc- both the probability and consequences of side effects with ture of the value tree in MCDM is a recognized source of patients more explicitly, and to educate patients. uncertainty, and its impact has been shown in literature Compared to the ec ffi acy and safety criteria, convenience [31, 32]. Second, with regard to the method used to elicit was only of little importance to patients. Yet the available preferences, the total number of comparisons that had to OACs only differ slightly in efficacy and safety rates, while be made was high, which could influence patient concen- the differences with regard to the attributes of convenience tration. The pairwise comparisons of the main hierarchy have a direct impact on patient’s daily life. Moreover, our had a consistency ratio higher than 0.1 and was questioned results show that patients have different preferences for last, so, fatigue may have played an important role. Third, options within the convenience criteria. Although most we included a maximum of ten participants per country; patients preferred once-daily intake, some patients preferred therefore, it was not possible to focus on differences in twice-daily intake (30%) as they were used to this routine importance weights across countries. Differences were (e.g., taking the anticoagulants with breakfast and dinner). mostly expected with regard to costs, and in all countries Furthermore, patients differed on the opinion whether rou- the importance of costs was rated low. However, whether tine INR monitoring is preferred to no monitoring. The actual differences in preferences exist between countries qualitative focus group results showed that the perceived should be studied in a larger scale study. In addition, our benefits of routine INR monitoring were related to reas- sample of patients was relatively highly educated, which surance, mainly resulting from the routine feedback on the 500 M. G. M. Weernink et al. Table 3 Preferences and AHP performance weights for options within the convenience criteria Intake frequency All patients (n = 45) Once-daily takers (n = 33) Twice-daily takers (n = 12) Chi square N (%) Weight (SD) N (%) Weight (SD) N (%) Weight (SD) Prefers once daily 32 (71.1) 0.74 (0.04) 28 (84.8) 0.81 (0.03) 4 (33.3) 0.46 (0.11) 0.001 Prefers twice daily 13 (28.9) 0.26 (0.04) 5 (15.2) 0.19 (0.03) 8 (66.7) 0.54 (0.11) Routine INR monitoring All patients (n = 42) VKA users (monitoring) DOAC users (no monitoring) Chi square (n = 23) (n = 19) N (%) Weight (SD) N (%) Weight (SD) N (%) Weight (SD) Prefers monitoring 17 (37.8) 0.49 (0.05) 13 (56.6) 0.57 (0.08) 4 (21.1) 0.39 (0.06) 0.14 Does not prefer monitoring 17 (37.8) 0.51 (0.05) 8 (34.8) 0.43 (0.08) 9 (47.4) 0.61 (0.06) No preference 8 (17.8) – 2 (8.7) – 6 (31.6) – Food restrictions All patients (n = 44), N (%) VKA users (restrictions) DOAC users (no restrictions) Chi square (n = 23), N (%) (n = 19), N (%) N (%) Weight (SD) N (%) Weight (SD) N (%) Weight (SD) Not bothered 34 (75.6) – 21 (84.0) – 13 (68.4) – 0.22 Bothered 10 (22.2) – 4 (16.0) – 6 (31.6) – Pill type/intake All patients (n = 44) instructions N (%) Weight (SD) 1. Capsule, swallowed 4 (9.1) 0.13 (0.01) whole, does not require intake with food 2. Tablet, can be mixed 16 (36.4) 0.33 (0.03) with water, does not require intake with food 3. Tablet, can be mixed 5 (11.4) 0.25 (0.03) with water, requires intake with food 4. Tablet which dissolves 13 (29.5) 0.29 (0.03) (melts) on the tongue, and does not require intake with food 5. No preference 6 (13.6) Data are presented as N (%) and AHP performance weight (SD) AHP analytic hierarchy process, DOAC direct (non-VKA) oral anticoagulant, INR international normalized ratio, SD standard deviation, VKA vitamin K antagonist No consistency ratio is reported for intake frequency and routine INR monitoring, because it consisted of one pairwise comparison No pairwise comparison was questioned to estimate performance, because it was likely that all patients would have a preference for not having food restrictions The consistency ratio for pill type/intake instructions was 0.08 limits the generalizability of this study. Fourth, the pair- 5 Conclusion wise comparisons were completed during the second hour of the focus groups. Although the focus group was led Effectiveness and safety are the most important attributes by experience moderators and open and semi-structured of OAC therapy. Although the relative impact of conveni- questions were used, patients with dominant views might ence on therapy value is small, patients have different have influenced the answers of other patients, or prompted preferences for options within the convenience criteria. them to give socially desirable answers [33]. Finally, it is Besides considerations on safety and effectiveness, physi- clear that adherence is influenced by a large number of cians should also discuss attributes of convenience with factors that are not related to the characteristics of the drug patients, as it can be assumed that alignment to patient itself, such as knowledge and motivation of the patient. A preferences in drug prescription, and better patient edu- broader model of adherence is required to understand and cation could result in higher adherence to treatment. The improve patient adherence to OACs. differences in individual preferences for convenience found within this study support the notion that decisions Patients’ Priorities for Oral Anticoagulation Therapy 501 fibrillation. N Engl J Med. 2009;361(12):1139–51. https ://doi. on which OAC therapy to take is a decision that has to be org/10.1056/NEJMo a0905 561. made with, and not for, the patient. 6. Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. Edoxaban versus warfarin in patients with atrial Compliance with Ethical Standards fibrillation. N Engl J Med. 2013;369(22):2093–104. https ://doi. org/10.1056/NEJMo a1310 907. 7. Granger CB, Alexander JH, McMurray JJV, Lopes RD, Hylek Funding This study was funded by Daiichi Sankyo Europe GmbH EM, Hanna M, et al. Apixaban versus warfarin in patients with (Munich, Germany). Besides the initial review process before funding atrial fibrillation. N Engl J Med. 2011;365(11):981–92. https :// and amendments, Daiichi Sankyo was only involved in the design of the doi.org/10.1056/NEJMo a1107 039. study. The funders had no role in data collection and analysis, decision 8. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, to publish, or the preparation of this manuscript. et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883–91. https ://doi.org/10.1056/ Conflict of interest Marieke G.M. Weernink, Melissa C.W. Vaan- NEJMo a1009 638. holt, Catharina G.M. Groothuis-Oudshoorn, Clemens von Birgelen, 9. Brown TM, Siu K, Walker D, Pladevall-Vila M, Sander S, Mor- Maarten J. IJzerman and Janine A. van Til declare that they have no din M. Development of a conceptual model of adherence to oral conflicts of interest that might be relevant to the contents of this manu- anticoagulants to reduce risk of stroke in patients with atrial script. 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