Intake reminders are effective in enhancing adherence to direct oral anticoagulants in stroke patients: a randomised cross-over trial (MAAESTRO study)

Background Direct oral anticoagulants (DOAC) effectively prevent recurrent ischaemic events in atrial fibrillation (AF) patients with recent stroke. However, excellent adherence to DOAC is mandatory to guarantee sufficient anticoagulation as the effect quickly subsides. Aim To investigate the effect of intake reminders on adherence to DOAC. Methods MAAESTRO was a randomised, cross-over study in DOAC-treated AF patients hospitalised for ischaemic stroke. Adherence was measured by electronic monitoring for 12 months. After an observational phase, patients were randomised to obtain an intake reminder either in the first or the second half of the subsequent 6-month interventional phase. The primary outcome was 100%-timing adherence. Secondary outcomes were 100%-taking adherence, and overall timing and taking adherence. We analysed adherence outcomes using McNemar’s test or mixed-effects logistic models. Results Between January 2018 and March 2022, 130 stroke patients were included, of whom 42 dropped out before randomisation. Analysis was performed with 84 patients (mean age: 76.5 years, 39.3% women). A 100%-timing adherence was observed in 10 patients who were using the reminder, and in zero patients without reminder (p = 0.002). The reminder significantly improved adherence to DOAC, with study participants having 2.7-fold increased odds to achieve an alternative threshold of 90%-timing adherence (OR 2.65; 95% CI 1.05–6.69; p = 0.039). A similar effect was observed for 90%-taking adherence (OR 3.06; 95% CI 1.20–7.80; p = 0.019). Overall timing and taking adherence increased significantly when using the reminder (OR 1.70; 95% CI 1.55–1.86, p < 0.01; and OR 1.67; 95% CI 1.52–1.84; p < 0.01). Conclusion Intake reminders increased adherence to DOAC in patients with stroke attributable to atrial fibrillation. Trial registration ClinicalTrials.gov: NCT03344146. Supplementary Information The online version contains supplementary material available at 10.1007/s00415-023-12035-z.


Introduction
Non-adherence to chronic treatments is common, and the consequences are severe [1][2][3].In stroke patients with atrial fibrillation (AF), anticoagulants are essential to prevent thromboembolic events, such as ischaemic strokes.The mainstay of treatment for AF patients are direct oral anticoagulants (DOAC), which are recommended in preference over vitamin K antagonists and have largely replaced them [4].A literature review of 18 studies shows that adherence to DOAC is mediocre, ranging between 38.0 and 99.7% [1].Low perceived treatment benefits and the necessity of medication are associated with sub-optimal adherence [5].Unlike other preventive treatments, DOAC must be taken strictly on time owing to their comparatively short half-lives ranging from 8 to 17 h [6].However, routine methods for monitoring adequate anticoagulation are lacking.Therefore, the evaluation of adherence to DOAC might facilitate the evaluation of treatment efficacy.
The level of adherence to DOAC that is required for sufficient stroke prevention remains unclear.Few studies suggest adherence thresholds to maintain the therapeutic concentration of DOAC [2,7].Solla-Ruiz et al. observed increased thromboembolic events in patients who took less than 95% of DOAC doses compared to perfect adherers [2].In another study, the lowest risk for cardiovascular events occurred in patients taking at least 90% of DOAC doses [7].These results highlight the clinical relevance of optimising adherence to DOAC to ensure treatment effectiveness.However, the impact of individual adherence patterns, such as delayed intakes, on the anticoagulation level is unknown.Several methods are available to measure adherence that deliver different information [8].Electronic monitoring is the "gold standard" to assess treatment implementation because the data obtained highly correlate with the actual intake behaviour [9,10].Electronic adherence data deliver the exact time of each medicine intake, which allows for a detailed analysis of omitted doses, delays and intake intervals [6].
Although several interventions to optimise medication adherence have been proposed, their effectiveness is ambiguous.Studies that investigate adherence interventions are often limited by small samples or the poor description of complex interventions [11].Promising interventions are motivational interviewing, feedback on adherence monitoring data, and intake reminders [12,13].However, which adherenceenhancing intervention is appropriate for patients after a stroke remains unknown.Even mild ischaemic events can cause neurological or cognitive deficits that might compromise medication adherence [14].Thus, stroke survivors might require particular support with medication administration.This study aimed to investigate the effect of an intake reminder on the adherence to DOAC of stroke survivors.

Study design
The MAAESTRO study (electronic Monitoring and improvement of Adherence to direct oral Anticoagulant treatment-a randomized crossover study of an Educational and reminder-based intervention in ischemic STROke patients under polypharmacy) [15] included patients who (i) were hospitalised in the University Hospital of Basel, Switzerland, for ischaemic stroke, (ii) were diagnosed with AF, (iii) were prescribed a DOAC and at least two other medicines, and (iv) self-administered their medication.Recruitment of participants was performed during hospitalisation (visit 0).Participants electronically monitored their daily DOAC intakes for 12 months following hospital discharge using the Time4Med™ Smart card (Adherence Innovations, Hong Kong) [16].By pushing the button of the Smart card, time stamps are recorded on a built-in microchip.The first 6 months after hospital discharge were observational.A staggered intervention was delivered.First, during the follow-up visit at 6 months (visit 1), a counselling session and a pillbox were provided to all patients.Then and according to randomisation, patients obtained an additional reminder device that was used beginning either at visit 1 (group 1) or 3 months later (group 2, Fig. 1), for a total of 3 months in each group.Study investigators were not involved in DOAC prescription, which was up to the hospital physician, general practitioners and other healthcare providers as standard of care.
Clinical and neuroimaging parameters (Fazekas score for white matter lesions on neuroimaging [17], National Institutes of Health Stroke Scale (NIHSS) for stroke severity [18], and Montreal Cognitive Assessment (MoCA) scores) [19] and self-reported variables (satisfaction with reminder) were assessed at each visit, as described in the study protocol [15].

Study intervention
The reminder was the main intervention in this trial.It generates acoustic and visual alarms at time points chosen by the patient.In addition, all patients received a pillbox and a counselling session with a pharmacist during which they were shown a visualisation of their intake data from the observational phase (Fig. 2).

Study outcomes
The primary outcome was 100%-timing adherence, defined as no dose taken outside the grace interval.The grace interval is defined as allowing an intake ± 6 h (for oncedaily DOAC) and ± 3 h (for twice-daily DOAC) around the median intake time.We hypothesised that when patients use a reminder, they will reach 100%-timing adherence more often than without a reminder.
The secondary outcomes were: (i) percentage of patients with 100%-taking adherence (no dose omitted), (ii) overall timing adherence (proportion of doses taken within the grace interval, absolute value), (iii) overall taking adherence (proportion of doses taken, absolute value), (iv) occurrence of predefined clinical events of interest (recurrent ischaemic stroke, transient ischaemic attacks (TIA), intracranial haemorrhage, major extracranial haemorrhage, myocardial infarction, venous thromboembolism, death), (v) patient satisfaction with the reminder (questionnaire, 5-point Likert-Scale).

Data processing
We used secuTrial® (version 6.3.2.7) to capture electronic case report forms.The adherence monitoring data were cleaned, and metrics were calculated with Microsoft Excel® 2016 according to an internal standard operating procedure [20,21].Patients without sufficient electronic monitoring data records (less than one-third of the expected records was available) were excluded from the analysis.

Sample size and randomisation
The sample size calculation was based on the following assumptions, informed by our previous experience with this patient population [15,22]: (i) a 20% adherence-enhancing effect of the reminder on 100%-timing adherence; and (ii) a 45% rate of timing adherence below 100% in the control group.The required sample size to achieve a power of 0.9 at an alpha error of 0.05 was 114 participants.In addition, a 12% drop-out rate was estimated.We therefore aimed to recruit 130 participants.Patients were randomly allocated to group 1 or group 2 in a 1:1 ratio.Randomisation was performed by a central computer during visit 1 over the webbased secuTrial® system with minimisation for sex, age, NIHSS and prior pillbox use at visit 0.

Statistical analysis
The predefined statistical analysis plan dictated the use of mixed logistic models to assess the effect of reminders on timing and taking adherence, with reminder use ("with reminder" vs "without reminder") as fixed and subject identifier as a random effect.Due to the prohibitively small number of participants reaching the prespecified primary outcome of 100%-timing adherence, we analysed the effect of reminders on the primary outcome using an exact McNemar's test for paired nominal data instead and explored the alternative thresholds of 90% and 80%-timing and taking adherence using the planned mixed-effects analysis.For all analyses, we report two-sided p-values and present modelbased odds ratio (OR) estimates with 95%-confidence intervals (CI).Subgroup analyses were done by (i) DOAC type (oncedaily vs twice daily), (ii) stroke location (right vs left hemisphere), (iii) Fazekas score (0-3) and (iv) MoCA score (0-30).Analyses were done on an intention-to-treat basis as prespecified in the statistical plan and were repeated in the per-protocol population (including only patients who used the reminder according to randomisation).We investigated time-trend and carry-over effects in sensitivity analyses.The effect of the counselling session and pillbox was assessed by comparing overall adherence during the observational phase and the first half of the interventional phase without the reminder (group 2).We present clinical events of interest and patient satisfaction with the reminder descriptively.All analyses were performed in R (version 4.1.2).Study outcomes were reported according to the CONSORT guideline [23].

Ethics statement
The MAAESTRO study was approved by the Ethics Committee of Northwest/Central Switzerland (EKNZ 2017-01552) and registered at ClinicalTrials.gov(NCT03344146).All participants gave written informed consent; study participation was voluntary.For patients initially consenting to study participation but withdrawing their consent during the course of the study, the use of their study data up to the timepoint of consent withdrawal was allowed according to the signed informed consent.To accelerate the initiation of the interventional study phase, the study protocol was amended on April 28, 2020, to shorten the observational phase from 6 to 3 months for participants who entered the study after April 28, 2020.

Subgroup, per-protocol, and sensitivity analyses
The adherence-enhancing effect of reminders on 90%-timing adherence did not differ in any of the predefined subgroups (Supplement C).The exclusion of 18 patients due to participants not using the reminder (9 participants per randomisation group) resulted in 66 participants eligible for the per-protocol analysis.Consistent with the intention-to-treat analysis, the effect of the reminder on 90%-timing adherence was preserved by the per-protocol analysis (OR 2.53; 95% CI 0.86-7.41;p = 0.091).No carry-over effect (p = 0.950) or time-trend (p = 0.366) was observed between both interventional phases.There was no evidence that the delivery of a counselling session plus pillbox affected the number of patients reaching 90%-timing adherence (Supplement C).
As a higher number of patients dropped out before randomisation, the evaluable sample in MAAESTRO fell short of the planned 114 full patient sets, despite the recruitment of the planned 130 patients.As a post hoc analysis, we calculated scenarios if our main outcome would have changed if 114 participants could have been included in the analysis.In the most likely scenario, our main outcome would remain unchanged (Supplement D.1).

Clinical events of interest
A total of 21 clinical events of interest occurred throughout the study in 16 patients: recurrent ischaemic stroke (8), major extracranial haemorrhage (5), intracranial haemorrhage (4), myocardial infarction (2) and death (2).Fourteen clinical events occurred during the observational study phase (67%), five during the interventional phase without the reminder (24%), and two during the interventional phase with reminder (9%, see also Supplement D. 2

and D.3).
A trend towards lower overall adherence was observed in patients with ischaemic events compared to patients without events (Table 3).

Satisfaction with the reminder
The satisfaction with the reminder differed considerably among participants (Fig. 5).About half of the participants found the reminder impractical and denied benefitting from it.Regarding the integration of the reminder into their daily  routine, 81% of the participants felt no restriction (Supplement E).

Discussion
The MAAESTRO study investigated the intake behaviour of patients with stroke attributable to atrial fibrillation, who are prescribed DOAC for the prevention of recurrent stroke.Specifically, we tested the effect of an intake reminder on adherence to DOAC.The primary outcome (100%-timing adherence) was almost solely achieved when participants used a reminder (p = 0.002).Although the numbers were too small for the mixed-model analysis (N = 10 with reminder, N = 0 without reminder), they are consistent with the findings from our alternative outcomes (90% and 80%-timing adherence) and the Nemar's test where we found strong evidence that the use of reminders increase adherence.The effect of reminders on adherence was shown in patients using long-term medication [13,24], but the effectiveness of this approach in stroke patients in particular those with AF-related stroke has been unclear so far.The few studies that investigated the effect of reminders on adherence to DOAC have yielded discrepant results [25][26][27][28][29].Some studies investigated only a single DOAC agent [28,29] or they assessed adherence by self-report [26] or dispensing data [28].These assessment methods are prone to manipulation by the patients [9], potentially explaining the discrepant findings of these studies.Notably, the behaviour of AF patients in general and not explicitly of stroke survivors was investigated in these previous studies.This is important because stroke-induced cognitive deficits might interfere with adherence.Therefore, our study contributes more detailed data on DOAC intake behaviours in the previously unexplored population of stroke survivors and confirms the effectiveness of reminders in this population.
Adherence to DOAC of the MAAESTRO population was already high at about 90%.Other studies that measured adherence to DOAC with electronic monitoring have reported comparable outcomes, although these studies did not specify if participants took DOAC for primary or secondary prevention, nor did they include all four DOAC agents [2,[29][30][31].An a priori selection bias not amenable to randomisation procedures might explain these high adherence levels, with patients who opt to participate in an adherence study being more health-aware and thus potentially more prone to high adherence, a phenomenon termed "healthy-adherer effect" [32].In addition, the MAAESTRO study was conducted in a comprehensive stroke centre with high expertise in stroke prevention and education.This might have resulted in overall higher adherence rates and limited the generalizability of our results.
Sensitivity analyses showed that the chronology in which patients used the reminder did not influence the adherenceenhancing effect of the reminder.In other words, patients who stopped the use of the reminder after 3 months (group 1) and returned to usual settings also returned to a lower level of adherence in the following 3 months.Thus, the adherence-enhancing effect did not persist when the reminder was removed, which is in agreement with previous findings [33].Lee et al. investigated the effect of multicompartment punch cards and a pharmaceutical care service on adherence to polypharmacy in hypertensive patients.The intervention was highly effective and adherence increased significantly, but after removing the intervention, adherence returned almost to baseline values.
We investigated the clinical relevance of the study outcomes by means of descriptive statistics because our study was not powered to statistically analyse the effect of improved adherence on ischemic events.We observed that adherence to DOAC was not associated with the occurrence of any clinical vascular event or death.At least, higher adherence seems to be associated with numerically fewer ischemic events, including recurrent ischemic strokes.This observation is in line with other studies that have provided evidence of the positive impact of high adherence on less clinical events in AF patients [2,7].
Because participants of the MAAESTRO study had experienced mild strokes, they might have presented with hidden dysfunctions that remained undetected with the scales commonly used in clinical practice, such as NIHSS.Nevertheless, patients' ability to manage their medication might be negatively affected by a stroke, independently of its severity [14].Barrett et al. observed that stroke survivors overestimated their capability to self-administer medication shortly after the stroke, which was associated with memory deficits [34].Therefore, we recommend adherence support to be offered also to patients who seemingly recover well from mild strokes.Providing adherence support could be realised in cooperation with community pharmacies [35].

Strengths and limitations
This study has several strengths.First, the cross-over design of our study enabled each patient to serve as their own control.When investigating individual behaviours, this design delivers more robust results than inter-individual comparisons because the risk of confounders is negligible.We observed no time trends or carry-over effects between the cross-over phases, which supports the appropriateness of our design.Second, our study population was a well-described and homogeneous sample of patients treated with DOAC for secondary prevention due to a recent ischaemic stroke attributable to atrial fibrillation.Reminders increased adherence in this specific sample and should therefore be offered to these patients after suffering a stroke.Third, we used electronic monitoring to assess adherence, which is considered the gold standard when investigating the implementation of a medicine.The Smart cards delivered accurate information on intake times, which was crucial to judging the impact of reminders on timely DOAC intakes.
There were also limitations to this study.First, the primary outcome (100%-timing adherence) proved to be overambitious.When transposed into practice, this threshold means that one single delayed dose in 3 months suffices to disqualify for 100%-timing adherence.Thus, the use of a theory-based approach to developing our study yielded an unrealisable goal for individuals with some active life.It is likely that applying realist research would have provided a different primary outcome.In any case, evidence on a more appropriate threshold for timing adherence to DOAC was limited in the literature.Hence, the alternative outcome of 90%-timing adherence that we used in our secondary analysis is exploratory in nature.Second, the drop-out rate of 36% was considerably higher than the 12% that were estimated from the literature.This number must be put in light of the evolving character of a recent stroke.Drop-outs occurred mainly during the first weeks following study inclusion and concerned older participants with poorer cognitive and functional outcomes.Although this selection bias is difficult to prevent, it reduces the generalizability of our results.We assume that the recruitment timing was inadequate, as patients had just experienced a stroke, which can be considered a rather disturbing situation.Some patients might have overestimated their ability to pursue the study procedures in view of the unusual circumstances.In addition, some inclusion criteria for participation (e.g.self-administration of medication) were subject to changes after discharge, which increased the drop-out rate.However, the calculation of 'worst case' scenarios showed no change in the main outcome if the planned patient number would have completed the trial.Third, we experienced technical issues with the electronic devices.Participants regularly reported Smart cards that stopped beeping when registering the DOAC intake.We systematically documented these defects and excluded these periods from the calculation.Nevertheless, we cannot exclude that some adherence gaps were in reality device malfunctions.

Conclusion
An intake reminder significantly increased timing adherence to DOAC and reduced the number of missed intakes in stroke patients.Offering reminders to stroke patients who

Fine
Dietrich, Alexandros A. Polymeris have equally contributed as first authors.Philippe A. Lyrer, Isabelle Arnet have equally contributed as senior authors.

Fig. 1 Fig. 2
Fig.1Flow chart of the MAAESTRO study[15].At study inclusion (visit 0), patients received the Smart card to monitor DOAC intakes for 12 months.After six months (visit 1), all patients received a

Fig. 4
Fig. 4 Boxplot of the median overall timing adherence (left) and taking adherence (right) of 84 participants per study phase

Fig. 5
Fig. 5 Answers to eight items regarding the satisfaction with the reminder from 84 patients.A value near the centre (0%) indicates poor agreement with the statement (see Supplement E for all values)

Table 1
Characteristics of patients at study entry in the full analysis set per randomisation group DOAC direct oral anticoagulant, IQR interquartile range, MoCA Montreal Cognitive Assessment Score, mRS modified Rankin Scale, NIHSS National Institutes of Health Stroke Scale, SD standard deviation, SMD standardised mean difference

Table 3
Overall adherence during the observational study phase from all recruited participants, of whom 16 experienced clinical events of interest during the study Haemorrhagic events include intracranial haemorrhage and major extracranial haemorrhage; ischaemic events include stroke, TIA, and myocardial infarction IQR interquartile range, TIA transient ischaemic attack a Two patients with clinical events, who died shortly after entering the study, are not included in this table because no adherence data were available.