Structured pharmaceutical interviews enhance
knowledge and medication adherence in DOAC therapy:
Insights from the EDUC-AOD study

Samuel D Cohen, François Bouvier, Claire-Marie Tissot, Alice Viallet, Caroline Leiterer, Frédéric Tacco, Jean-Marc Dauchot, François Kramp, Catherine Verret, Solenne Martin, et al.

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To cite this version:

Samuel D Cohen, François Bouvier, Claire-Marie Tissot, Alice Viallet, Caroline Leiterer, et al. Structured pharmaceutical interviews enhance knowledge and medication adherence in DOAC therapy: Insights from the EDUC-AOD study. Patient Education and Counseling, 2026, 143, pp.109423. 10.1016/j.pec.2025.109423. hal-05408869

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Structured pharmaceutical interviews enhance knowledge and medication
adherence in DOAC therapy: Insights from the EDUC-AOD study

Samuel D. Cohen<sup>a,b,c,*†</sup>, François Bouvier<sup>d</sup>, Claire-Marie Tissot<sup>e</sup>, Alice Viallet<sup>a</sup>,
Caroline Leiterer<sup>f,g</sup>, Frédéric Tacco<sup>b</sup>, Jean-Marc Dauchot<sup>b</sup>, François Kramp<sup>a</sup>,
Catherine Verret<sup>g,h</sup>, Solenne Martin<sup>g,h</sup>, Hubert Nielly<sup>h</sup>, Albert Boccara<sup>e</sup>

ARTICLE INFO

Keywords:

Factor Xa Inhibitors

Pharmaceutical Interview

Patient medication knowledge

Medication adherence

Therapeutic patient education

A B S T R A C T

**Objective:** Direct oral anticoagulants (DOACs) are first-line therapies for atrial fibrillation and venous thromboembolism. Structured pharmaceutical interviews (SPIs) aim to enhance patient knowledge of DOAC therapy, thereby improving medication adherence and reducing both disease-related and treatment-related complications. The EDUC-AOD study was conducted to assess the impact of SPIs on patient knowledge, medication adherence, and clinical complications.

**Methods:** Patients newly prescribed DOACs were enrolled from two centers, with only one center delivering SPIs. The primary objective was to evaluate the impact of SPIs on patients' knowledge and medication adherence at 3 months, using standardized questionnaires. Secondary objectives included evaluating the impact of SPIs on clinical complications, as well as knowledge and medication adherence at 6 months. Multivariate logistic regression analysis, adjusted for propensity score, was used to identify predictors of improved knowledge and adherence.

**Results:** From January 2021 to June 2023, 145 patients were enrolled: 68 in the intervention group and 77 in the control group. At 3 months, the intervention group demonstrated significantly higher rates of satisfactory knowledge (74% vs. 12%, p < 0.001) and good medication adherence (86% vs. 64%, p = 0.008). SPIs were significant predictors of satisfactory knowledge (OR = 23.6, 95% CI [8.3–81.1], p < 0.001) and good medication adherence (OR = 3.5, 95% CI [1.4–10.0], p = 0.012). Treatment indication (OR = 4.9, 95% CI [1.7–16.3], p = 0.005) and lower HAS-BLED score (OR = 0.4, 95% CI [0.1–1.0], p = 0.039) were also associated with improved outcomes. At 6 months, the intervention group experienced significantly fewer clinical complications (0 vs. 9, p = 0.010).

**Conclusion:** SPIs substantially enhance patients' knowledge and adherence to DOAC therapy and reduce clinical complications. Integrating SPIs into routine care may optimize anticoagulant management. Further randomized trials are needed to confirm these findings.

**Abbreviations:** AF, Atrial Fibrillation; BMI, Body Mass Index; DOAC, Direct Oral Anticoagulant; ESC, European Society of Cardiology; ISCED, International Standard Classification of Education; MTH, Military Teaching Hospital; OR, Odds Ratio; SD, Standard Deviation; SFPC, French Society of Clinical Pharmacy; SPI, Structured Pharmaceutical Interview; VKA, Vitamin K Antagonist; VTE, Venous Thromboembolism.

* Correspondence to: Sorbonne University, CIC 1901, Department of Pharmacology, La Pitié-Salpetrière Hospital, 47-83 Boulevard de l'Hôpital, Paris 75651, France

E-mail address: samuel.cohen.1@etu.sorbonne-universite.fr (S.D. Cohen).

¹ ORCID: 0000-0001-5462-0625

<footnote><sup>a</sup> Hospital Pharmacy, Bégin Military Teaching Hospital, Saint-Mandé 94160, France</footnote>

<footnote>b Hospital Pharmacy, Montreuil Hospital, Montreuil 93100, France</footnote>

<footnote>c Sorbonne University, CIC 1901, Department of Pharmacology, La Pitié-Salpetrière Hospital, Paris 75651, France</footnote>

<footnote>d Department of Cardiology, Bégin Military Teaching Hospital, Saint-Mandé 94160, France</footnote>

<footnote>e Department of Cardiology, Montreuil Hospital, Montreuil 93100, France</footnote>

<footnote>f Clinical Research Unit, Bégin Military Teaching Hospital, Saint-Mandé 94160, France</footnote>

<footnote>g Training, Research, and Innovation Direction of the Health Service of the French armed ministry, Paris 75230, France</footnote>

<footnote>Department of Internal Medicine, Bégin Military Teaching Hospital, Saint-Mandé 94160, France</footnote>
# 1. Introduction

Since their introduction in 2008, direct oral anticoagulants (DOACs) such as Rivaroxaban, Apixaban, and Dabigatran, have transformed the prevention and treatment of thromboembolic conditions. They provide a fixed-dose alternative to vitamin K antagonists (VKAs), with more predictable pharmacokinetics and pharmacodynamics, eliminating the need for routine coagulation monitoring, and are recommended by the European Society of Cardiology (ESC) as the first-line treatment for preventing stroke in atrial fibrillation (AF) due to their superior efficacy and safety profile [1,2]. DOACs are also widely used in the management of venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism [3]. As a result, DOACs have seen a significant global shift from traditional VKA-based treatments. However, despite these advantages, the risks of bleeding and suboptimal adherence continue to pose significant challenges, potentially leading to adverse clinical outcomes such as stroke or systemic embolism [4,5].

Therapeutic patient education (TPE) is pivotal in optimizing clinical outcomes by empowering patients with the knowledge and skills needed to autonomously manage their treatment [6,7]. It is particularly critical for DOAC therapy, where adherence and understanding of the associated risks are essential to avoid complications such as thrombosis and hemorrhage [8,9]. The 2020 ESC guidelines emphasize integrating TPE into AF management to improve patient adherence and early complication recognition [2].

Pharmaceutical interventions, particularly structured pharmaceutical interviews (SPIs), have been increasingly recognized for their positive impact on medication adherence and patient safety. Conducted typically in hospital settings, these interventions help clarify drug administration, potential interactions, adverse effects, and disease-related complications, offering personalized patient support [10]. International studies have highlighted the benefits of such interventions, showing improvements in adherence, patient quality of life, and reductions in hospital readmission rates [11–14]. However, a notable research gap remains regarding the evaluation of these pharmaceutical interventions, particularly their impact on DOAC therapy knowledge and adherence [15,16]. Given the widespread use of anticoagulants and the critical role of patient education in minimizing associated risks, this gap is particularly concerning [17].

To our knowledge, no previous prospective study has assessed the impact of structured pharmaceutical interviews on DOAC therapy using standardized and validated post-discharge assessments. This work addresses a gap identified in both ESC 2020 guidelines and national recommendations by evaluating a replicable intervention in a real-world hospital setting. This study aims to: 1) assess whether SPIs enhance patients’ knowledge and medication adherence to DOAC therapy compared to standard care provided by cardiologists; 2) identify factors associated with improved knowledge retention and medication adherence; and 3) analyze the potential effect of these interviews on the occurrence of clinical complications, such as thromboembolic events and bleeding.

# 2. Methods

## 2.1. Study design and ethical approval

The EDUC-AOD study was a prospective, multicenter, observational cohort study with a non-randomized comparative design, adhering to the STROBE guidelines. Conducted in accordance with the Declaration of Helsinki, the study obtained non-opposition from each participant prior to enrollment. Ethical approval was granted by the Ethics Committee West IV of Nantes (Approval No.: 20.09.15.52204), and the study was registered at ClinicalTrials.gov (NCT04674202).

The study was conducted across two parallel cohorts in the cardiology departments of the Military Teaching Hospital (MTH Bégin) and Montreuil Hospital. The intervention group was at MTH Bégin, which

has systematically implemented SPIs since 2013 for patients newly initiated on DOACs. The control group was at Montreuil Hospital, where therapeutic education was limited to physician consultations without the involvement of dedicated clinical pharmacists or nurses.

Both hospitals followed identical clinical pathways and anti-coagulation protocols, differing only in the implementation of SPIs, ensuring that the primary contrast between groups was the presence or absence of SPIs. Patients were followed for six months, with telephone interviews conducted at three- and six-months post-inclusion to assess outcomes.

## 2.2. Participants

Eligible patients were adults aged 18 years or older, hospitalized for more than 48 h at the study centers, who were newly initiated on DOAC therapy for a clinical indication such as newly diagnosed AF, deep vein thrombosis, or pulmonary embolism. Exclusion criteria included patients receiving DOAC solely for venous thromboembolism prevention, cognitive impairment, prior DOAC use before the study, deprivation of liberty, guardianship, pregnancy, or breastfeeding. Secondary exclusions during follow-up included patients with active cancer (due to altered coagulation profiles and complex anticoagulation management that could confound outcome assessments), antiphospholipid syndrome, or a change in DOAC prescription, including a change to any other anticoagulant therapy.

## 2.3. Data collection

Data were obtained through patient interviews and medical records review. Patient interviews conducted during the first hospital stay focused on education level and self-reported medical history (e.g., prior hospitalizations or cardiovascular events). Education level was based on the International Standard Classification of Education (ISCED) 2011 [18]. Medical records provided clinical and demographic characteristics (age, sex, Body Mass Index (BMI), educational level), biological parameters (creatinine, glomerular filtration rate calculated using the Cockcroft-Gault formula, hemoglobin level), and details of DOAC treatment (start date, indication, drug, regimen). Additionally, prior anticoagulant use, co-prescribed antiplatelet therapy, and clinical risk scores as CHA2DS2-VASc and HAS-BLED were recorded [2,19,20]. Hemorrhagic complications were classified according to the International Society on Thrombosis and Hemostasis (ISTH) criteria, distinguishing between major bleeding, clinically relevant non-major bleeding, and minor bleeding [21]. We collected information on the number of cardiovascular-related hospitalizations and dichotomous variables indicating the presence of ischemic and/or bleeding events within the preceding three months. Upon completion of the six-month follow-up, all patients’ responses were reviewed and validated by the study’s scientific coordinator.

## 2.4. Pharmaceutical interview process

In the intervention group, patients received a SPI lasting between 15 and 30 min, conducted by a pharmacist, pharmacy intern, or pharmacy assistant. Interviewers underwent specialized training in educational techniques [22], delivered by senior pharmacists holding a University Diploma in Therapeutic Patient Education. This academic training provides structured methods in patient communication, motivational interviewing, and chronic disease management. Additionally, all interviewers completed continuing education workshops on structured pharmaceutical interviews organized by hospital education departments and professional societies such as French Society of Clinical Pharmacy (SFPC) and reginal hospital pharmacist associations, ensuring consistent and standardized SPI delivery through a cascaded training approach. These interviews covered key aspects of DOAC therapy, including the drug’s name, indication, mechanism of action, dosing schedule, and
management of missed doses. Patients were counseled on dietary considerations and potential adverse effects, with a focus on recognizing signs of hemorrhage. An informational flyer and a card on DOACs were provided at the end of the interview. The session could take place with the patient alone or with a close relative. Patient understanding was assessed using a standardized checklist rating each key information item as ‘acquired’ or ‘not acquired.’ When an item was not acquired, the information was repeated and clarified until understanding was achieved, ensuring both consistency and comprehension across interviewers. In the control group, patients received standard medical information about their anticoagulant from their cardiologist, without SPI or a formal evaluation of retained knowledge.

## 2.5. Outcomes

The co-primary outcome was the proportion of patients in each group achieving satisfactory scores in both knowledge and medication adherence assessments related to DOAC therapy at 3 months. Secondary outcomes included separate assessments of knowledge and medication adherence at 6 months, as well as the prevalence of clinical complications within six months after enrollment.

To ensure objectivity and reproducibility, two standardized questionnaires were used. The knowledge questionnaire was specifically developed for this study, inspired by established scales such as the Likert scale [23] and guided by recommendations from the French Health Authority [24]. The medication adherence questionnaire was adapted from the validated Girerd adherence questionnaire [25], endorsed by the SFPC, and tailored to direct oral anticoagulant therapy. These questionnaires were designed to separately and accurately measure patient knowledge and medication adherence. Knowledge scores ranged from 0 (no knowledge) to ≥ 3 (satisfactory knowledge), while MA scores ranged from 0 (good medication adherence) to ≥ 3 (poor medication adherence) (Figure S1, Figure S2).

The cut-off scores were validated by a panel of 4 clinical experts (2 cardiologists and 2 internists) using a structured consensus process, ensuring the thresholds were clinically meaningful for assessing knowledge and adherence to DOAC therapy. For analysis, knowledge was categorized as satisfactory (score ≥3) or unsatisfactory (score <3), and medication adherence as good (score = 0) or poor (score ≥1).

## 2.6. Bias

Randomization was not feasible because structured pharmaceutical interviews had been implemented as standard practice at MTH Bégin since 2013. Modifying or withholding this established intervention for research purposes would have been impractical and potentially unethical. A pragmatic, real-world comparative design was therefore chosen to evaluate the impact of SPI under routine conditions, ensuring that findings would be directly applicable to similar healthcare settings.

To address potential confounding biases due to non-randomized group allocation, a propensity score was estimated using multivariable logistic regression. The dependent variable was assignment to the intervention group (SPI vs. control), and covariates included baseline characteristics that could influence group assignment or outcomes, such as age, BMI, HAS-BLED score, treatment indication, study center, and education level. The resulting propensity score was used to create matched groups or to weight observations, thereby enhancing group comparability and mitigating the impact of imbalanced baseline characteristics, including education levels.

Baseline scores at M0 were not collected because the primary aim of this study was to compare post-hospitalization outcomes between two care models, rather than to measure within-patient changes from hospital admission. Pre-discharge pharmaceutical interviews conducted during hospitalization were designed for qualitative, patient-centered education and used a 10-item checklist scored from 0 ("not acquired") to 1 ("acquired"). However, inter-evaluator variability and the absence

of formal psychometric validation made them unsuitable for direct comparison with the standardized, validated questionnaires developed for 3 months and 6 months. This methodological choice was pre-specified in the study protocol to focus on the long-term retention of knowledge and adherence in real-life settings, reflecting the effectiveness of educational interventions beyond the immediate hospitalization period and avoiding contamination from immediate post-education recall.

## 2.7. Sample size calculation

Assuming that the prevalence of patients with satisfactory knowledge would be 25% in the control group (Montreuil Hospital) and 50% in the intervention group (MTH Bégin), and setting the α risk at 5% and the study power at 90%, the required sample size was estimated to be 154 patients (77 per group) [26].

## 2.8. Statistical analysis

Continuous variables were presented as mean (standard deviation) or median (interquartile range) and compared using paired Student's t-tests or Wilcoxon signed-rank tests as appropriate. Categorical variables were presented as frequency (percentage) and compared using Chi-square or Fisher's exact tests. All tests were two-sided, and a p-value < 0.05 was considered statistically significant. Bonferroni correction was applied to adjust for multiple comparisons.

Multivariate logistic regression models were used to evaluate the primary outcomes of satisfactory knowledge and good medication adherence at three and six months. These models were adjusted for baseline covariates to enhance the comparability between groups and minimize selection bias. All statistical analyses were conducted using R® version 4.3.

# 3. Results

From January 2021 to June 2023, 145 patients were enrolled in the study: 68 in the intervention group and 77 in the control group. Among these, 127 patients completed the follow-up and were included in the analysis. Reasons for exclusion from the analysis included withdrawal of consent (n = 4), lost to follow-up (n = 11), and death (n = 3). (Fig. 1). The mean age of patients was 68 [SD = 15] years, with a female-to-male ratio of 1.2 (Table 1). Patients of the control group had a higher mean BMI (30 [SD =7] kg/m² vs 27 [SD =6] kg/m², p = 0.033) and a lower education level (e.g., 47% vs 20% for level 4 education, p < 0.001). Fewer clinical and hemorrhagic complications were observed in the intervention group (0 vs. 9 and 0 vs. 8, respectively, p = 0.010).

At 3 months, the co-primary outcome revealed significant differences between the two groups (Table 2). The proportion of patients achieving a satisfactory knowledge score at 3 months was significantly higher in the intervention group (74% vs 12%, p < 0.001). Medication adherence at 3 months was also significantly different, with 86% of patients in the intervention group reporting good medication adherence compared to 64% in the control group (p = 0.008). In univariate analysis, factors associated with a satisfactory knowledge score at 3 months included (Table S1): SPI (OR = 21.86, 95% CI = [8.93–59.63], p < 0.001), age (OR = 0.97 per year, 95% CI = [0.95–0.99], p = 0.041), higher education level and VTE diagnosis (vs AF) (OR = 2.81, 95% CI = [1.36–5.93], p = 0.005). Specifically, for each incremental increase in education level (e.g., from level 1 to level 2), the odds of achieving a satisfactory knowledge score at 3 months increased by 2.24%. After adjusting for the propensity score, both SPI (aOR = 23.60; 95% CI [8.30–81.10]; p < 0.001) and treatment indication (aOR = 4.90; 95% CI [1.70–16.30]; p = 0.005), remained independently associated with better knowledge at 3 months (Fig. 2). For medication adherence at 3 months, SPI (OR = 3.55, 95% CI = [1.50–9.16], p = 0.003) and lower HAS-BLED score (OR = 0.37, 95% CI = [0.14–
<figure><img src="image_4.png" /><figcaption>Fig. 1. Flow chart of study population. Abbreviation: N for number of patients.</figcaption></figure>

0.96], *p* = 0.042) were significantly associated with good medication adherence in univariate analysis (Table S2). In the adjusted model, SPI (aOR = 3.50; 95 % CI [1.40 – 10.00]; *p* = 0.012) and lower HAS-BLED score (aOR = 0.40; 95 % CI [0.10 – 1.00]; *p* = 0.039), remained significantly associated with good medication adherence at 3 months (Fig. 3).

At 6 months, satisfactory knowledge score remained higher in the intervention group (79 % vs 33 %, *p* < 0.001) (Table S3). Factors associated with satisfactory knowledge scores included (Table S4): SPI (OR = 7.78, 95 % CI = [3.27–20.07], *p* < 0.001), age (OR = 0.95 per year, 95 % CI = [0.92–0.98], *p* = 0.002), lower BMI (OR = 0.93, 95 % CI = [0.87 – 0.99], *p* = 0.026), higher level of education and VTE diagnosis (vs AF) (OR = 2.31, 95 % CI = [1.06–5.13], *p* = 0.034). Specifically, for each incremental increase in education level (e.g., from level 1 to level 2), the odds of achieving a satisfactory knowledge score at 6 months increased by 1.67 %. After adjusting for the propensity score and relevant covariates, SPI, younger age and BMI remained independently associated with knowledge at 6 months (Figure S3). No variables were significantly associated with good medication adherence at 6 months (Table S5).

Correlation analysis showed no significant linear relationship between knowledge and adherence scores at 3 months or 6 months, with coefficients of 0.06 and 0.07, respectively. Similarly, adherence scores and the number of complications at 3 months and 6 months had coefficients of 0.01 and 0.00, respectively, indicating no correlation. Correlation analysis between knowledge and complications was not specified in the study protocol and thus was not conducted.

# 4. Discussion and conclusion

## 4.1. Discussion

The EDUC-AOD study demonstrated that SPIs enhanced patients' knowledge and medication adherence scores related to DOAC therapy at

3 months post-hospitalization. Patients who received SPI were 24 times more likely to achieve satisfactory knowledge scores at 3 months and eight times more likely at 6 months compared to those in the control group. These findings highlight the crucial role of SPIs, suggesting that engaging with patients through these interviews effectively addresses knowledge gaps. These benefits may be mediated by enhanced patient self-efficacy and engagement, key behavioral components in health education models such as the Health Belief Model. Furthermore, at 3 months, patients in the intervention group were four times more likely to demonstrate good adherence compared to the control group. However, this effect was not sustained at 6 months, indicating a potential area for further investigation or intervention reinforcement. The loss of effect at 6 months may reflect the natural decline in behavioral reinforcement over time once patients return to routine care. Regular follow-up or booster educational sessions could help sustain adherence improvements beyond the early post-discharge phase. In doing so, this study fills an evidence gap in the evaluation of structured education for DOAC therapy, where most existing work has been cross-sectional, retrospective, or based on VKAs.

The knowledge questionnaire was developed for this study and underwent expert validation and pilot testing to ensure reliability, whereas the medication adherence questionnaire was adapted from a validated tool (Girerd) endorsed by the SFPC.

In the multivariate analysis, adjusted for propensity scores, SPI and presenting with VTE rather than AF were identified as independent factors associated with better treatment knowledge at 3 months. Interestingly, patients treated for VTE showed higher knowledge gains than those with AF, possibly due to the more acute presentation and tangible symptomatology of VTE, which may increase patient engagement. Among these, SPI had the strongest association, underscoring the critical importance of structured, tailored educational interventions in improving patient outcomes. For patients who completed the knowledge questionnaire at both time points, satisfactory knowledge scores significantly improved from 38 % at 3 months to 53 % at 6 months
<caption>**Table 1**</caption>

Baseline patient demographics, clinical characteristics, medications, and complications at 6 months.

<table><thead><tr><th>Characteristics</th><th>Intervention group (n = 58)</th><th>Control group (n = 69)</th><th>p-value</th></tr></thead><tbody><tr><td>Age (years), mean (SD)</td><td>66 (16)</td><td>69 (14)</td><td>0.308</td></tr><tr><td>Female, n (%)</td><td>21 (36)</td><td>37 (54)</td><td>0.074</td></tr><tr><td>Body Mass Index (kg/m²), mean (SD)</td><td>27 (6)</td><td>30 (7)</td><td><strong>0.033</strong></td></tr><tr><td>Education Level<sup>a</sup>, n (%)</td><td></td><td></td><td><strong>&lt;0.001</strong></td></tr><tr><td>Level 1</td><td>6 (10)</td><td>20 (29)</td><td></td></tr><tr><td>Level 2</td><td>8 (14)</td><td>23 (33)</td><td></td></tr><tr><td>Level 3</td><td>17 (29)</td><td>12 (18)</td><td></td></tr><tr><td>Level 4</td><td>27 (47)</td><td>14 (20)</td><td></td></tr><tr><td>eGFR, mL/min/1.73 m²<sup>b</sup>, mean (SD)</td><td>88 (40)</td><td>90 (43)</td><td>0.864</td></tr><tr><td>Hemoglobin (g/dL), mean (SD)</td><td>14 (2)</td><td>13 (2)</td><td>0.172</td></tr><tr><td>Treatment indication, n (%)</td><td></td><td></td><td>0.717</td></tr><tr><td>AF</td><td>30 (52)</td><td>39 (57)</td><td></td></tr><tr><td>VTE</td><td>28 (48)</td><td>30 (43)</td><td></td></tr><tr><td>Dose Reduction at treatment initiation<sup>c</sup>, n(%)</td><td>4 (7)</td><td>5 (7)</td><td>1.000</td></tr><tr><td>Co-prescription of Antiplatelet, n (%)</td><td>4 (7)</td><td>7 (10)</td><td>0.740</td></tr><tr><td>CHA2DS2-VASc Score (AF patients only), mean (SD)</td><td>3 (2)</td><td>3 (1)</td><td>0.685</td></tr><tr><td>CHA2DS2-VASc ≥ 2 (AF patients only), n (%)</td><td>26/30 (87)</td><td>36/39 (92)</td><td>0.690</td></tr><tr><td>HAS-BLED Score, mean (SD)</td><td>1 (1)</td><td>2 (1)</td><td>0.071</td></tr><tr><td>HAS-BLED ≥ 3, n (%)</td><td>10 (17)</td><td>13 (19)</td><td>0.998</td></tr><tr><td>Prior anticoagulant treatment by VKA or heparin therapy, n (%)</td><td>3 (5)</td><td>4 (6)</td><td>1.000</td></tr><tr><td>Information about DOACs from community pharmacy, n (%)</td><td>7 (12)</td><td>7 (10)</td><td>0.975</td></tr><tr><td>Complications at 6 months, n (%)</td><td>0/48 (0)</td><td>9/64 (14)</td><td><strong>0.010</strong></td></tr><tr><td>Ischemic complication at 6 months</td><td>0/48 (0)</td><td>1/64 (2)</td><td>1.000</td></tr><tr><td>Transient ischemic attack</td><td>0/48 (0)</td><td>1/64 (2)</td><td></td></tr><tr><td>Hemorrhagic complications at 6 months<sup>d</sup></td><td>0/48 (0)</td><td>8/64 (13)</td><td><strong>0.010</strong></td></tr><tr><td>Major bleeding</td><td>0/48 (0)</td><td>3/64 (5)</td><td></td></tr><tr><td>Major gynecological bleeding</td><td>0/48 (0)</td><td>1/64 (2)</td><td></td></tr><tr><td>Macroscopic hematuria</td><td>0/48 (0)</td><td>2/64 (3)</td><td></td></tr><tr><td>Clinically relevant bleeding</td><td>0/48 (0)</td><td>2/64 (3)</td><td></td></tr><tr><td>Non-traumatic hematoma</td><td>0/48 (0)</td><td>1/64 (2)</td><td></td></tr><tr><td>Melena</td><td>0/48 (0)</td><td>1/64 (2)</td><td></td></tr><tr><td>Minor bleeding</td><td>0/48 (0)</td><td>3/64 (5)</td><td></td></tr><tr><td>Epistaxis</td><td>0/48 (0)</td><td>3/64 (5)</td><td></td></tr></tbody></table>

AF: Atrial Fibrillation; DOACs: Direct oral anticoagulants; eGFR: estimated glomerular filtration rate, SD: Standard Deviation, VKA: Vitamin K antagonist, VTE: Venous Thromboembolism.

* No pertinent statistical test due to the very small number of patients receiving dabigatran.

a The education level is based on the International Standard Classification of Education (ISCED) 2011: Level 1 = includes early childhood education and care and primary education, Level 2 = lower secondary education, Level 3 = upper secondary education, Level 4 = post-secondary education. b Glomerular filtration rate calculated according to Cockroft & Gault equation. c Criteria for dose reduction include advanced age (≥ 80 years), impaired renal function (creatinine clearance < 30–50 mL/min), low body weight (< 60 kg), and potential drug interactions with strong P-glycoprotein or CYP3A4 inhibitors. These criteria aim to adjust the dosage to minimize the risk of bleeding while maintaining anticoagulant efficacy, in accordance with clinical guidelines from the ESC and the Summary of Product Characteristics. d Hemorrhagic complications at 6 months, classified according to the International Society on Thrombosis and Hemostasis (ISTH) criteria. Major bleeding is defined as any clinically overt bleeding associated with one or more of the following: a decrease in hemoglobin level of ≥ 2 g/dL, the need for transfusion of ≥ 2 units of red blood cells, bleeding in a critical area or contributing to death. Clinically relevant bleeding includes events that lead to hospitalization or prolongation of hospitalization, or require medical intervention. Minor bleeding includes all other bleeding events that do not meet the criteria for major or clinically relevant bleeding.

(p < 0.001, McNemar test). This observed progression suggests that the effects of SPIs may extend beyond the immediate post-hospitalization period, possibly due to cumulative learning or reinforcement from

follow-up care. Regarding medication adherence, the findings demonstrated consistently good adherence between 3 months and 6 months, which is encouraging for long-term treatment success.

<caption>**Table 2**</caption>

Patients' evaluation at 3 months.

<table><thead><tr><th>Characteristics</th><th>Intervention group (n = 58)</th><th>Control group (n = 69)</th><th>p-value</th></tr></thead><tbody><tr><td><strong>DOACs at 3 months</strong></td><td></td><td></td><td></td></tr><tr><td>Rivaroxaban</td><td>32 (55 %)</td><td>19 (27 %)</td><td>*</td></tr><tr><td>Apixaban</td><td>26 (45 %)</td><td>48 (70 %)</td><td></td></tr><tr><td>Dabigatran</td><td>0 (0.0 %)</td><td>2 (3 %)</td><td></td></tr><tr><td><strong>Patient's Knowledge at 3 months</strong></td><td></td><td></td><td></td></tr><tr><td>Satisfactory<sup>a</sup></td><td>43 (74 %)</td><td>8 (12 %)</td><td><strong>&lt; 0.001</strong></td></tr><tr><td><strong>Patient's Medication Adherence at 3 months</strong></td><td></td><td></td><td></td></tr><tr><td>Good<sup>b</sup></td><td>50 (86 %)</td><td>44 (64 %)</td><td><strong>0.008</strong></td></tr><tr><td><strong>Rehospitalization at 3 months</strong></td><td></td><td></td><td></td></tr><tr><td>Yes</td><td>4 (7 %)</td><td>9 (13 %)</td><td>0.379</td></tr></tbody></table>

DOACs: Direct oral anticoagulants.

* No pertinent statistical test due to the very small number of patients receiving dabigatran.

a For analysis, patient's knowledge was categorized as satisfactory (score ≥3) or unsatisfactory (score <3).

b For analysis, patient's medication adherence was categorized as good (score = 0) or poor (score ≥1).
<figure><img src="image_5.png" /><figcaption>**Fig. 2.** Multivariate logistic regression adjusted for propensity score for patients with a satisfactory knowledge score at 3 months. Patients who have received a pharmaceutical interview on Direct Oral Anticoagulants (DOAC) were 23.6 times more likely to have a satisfactory treatment knowledge score at 3 months. Patients who received a DOAC for venous thromboembolism (VTE) were 4.9 times more likely to have a satisfactory 3-month treatment knowledge score than those who received a DOAC for atrial fibrillation (AF).</figcaption></figure>

<figure><img src="image_6.png" /><figcaption>**Fig. 3.** Multivariate logistic regression adjusted for propensity score for patients with a good medication adherence score at 3 months. Patients who received a pharmaceutical interview on Direct Oral Anticoagulant (DOAC) were 3.5 times more likely to have a good medication adherence score at 3 months. HAS-BLED is related to the 3-month medication adherence score; for each unit increase in HAS-BLED score, the chance of good medication adherence at 3 months is 0.4 times lower.</figcaption></figure>

The absence of correlation between patient knowledge and medication adherence suggests that these outcomes may be driven by distinct cognitive and behavioral mechanisms, warranting further investigation in future studies.

The lower number of clinical complications observed in the intervention group may suggest a potential safety signal associated with SPIs, although causality cannot be established given the study design. In the control group, nine hemorrhagic events were reported — three major, two clinically relevant non-major, and three minor — consistent with

typical annual rates reported in the literature for similar patient populations [27]. Nevertheless, this observation supports the hypothesis that patient education could contribute to safer anticoagulant use, a point that warrants further investigation in randomized studies.

Our study has several limitations that warrant discussion. Despite efforts to minimize biases, attrition bias due to a 7.6 % follow-up loss by 3 months must be considered. However, comparison of baseline characteristics between completers and those lost to follow-up showed no significant differences, suggesting that attrition bias is unlikely to have
affected the main results.

Although the final sample size (145 patients) was slightly below the initially estimated 154 patients, the achieved statistical power (84%) remained sufficient to detect the observed between-group differences in primary outcomes. Patient-reported outcomes, while valuable, are also subject to response bias, particularly when influenced by social desirability or recall limitations. To limit response bias, interviews were conducted by trained pharmacists not involved in the patients' daily care, and anonymity was maintained when collecting follow-up questionnaires. Additionally, our inability to measure long-term adherence beyond 6 months restricts conclusions regarding sustained behavioral changes. The study's relevance may be constrained to specific healthcare settings, such as French hospitals, limiting its broader generalizability without further multi-center validation. An uncontrolled center effect is also a limitation; randomization was not feasible due to the pre-existing implementation of SPIs at MTH Bégin. Both participating centers followed standardized clinical and pharmaceutical procedures for DOAC initiation and monitoring, which helped to minimize center-related variability. However, a potential uncontrolled center effect cannot be completely ruled out. The pragmatic design increases the external validity of our findings and reflects conditions in which many hospitals could feasibly implement SPIs without altering other aspects of care. As this was a non-randomized comparative cohort study, residual confounding cannot be fully excluded despite the use of propensity score adjustment, and causal inference between SPI and clinical outcomes cannot be affirmed.

The Hawthorne effect, where participants alter their behavior due to awareness of being observed, was not addressed in this study and could lead to an overestimation of the intervention's impact due to increased attention from healthcare providers. Future studies should consider strategies to mitigate observation bias, such as using blinded assessors or objective measures of adherence.

The educational level of patients is a critical factor influencing both treatment knowledge and medication adherence, as demonstrated in our study and supported by previous research [28–31]. Patients with higher education levels tend to perform better in treatment knowledge assessments. Education levels were higher in the intervention group, which may explain the differences observed. Despite adjustment using the propensity score, the higher educational level in the intervention group could have partly contributed to better knowledge outcomes. Notably, each additional level of education increased the likelihood of achieving satisfactory knowledge at 3 months. This finding aligns with previous studies that identified lower adherence rates among patients with lower education levels, highlighting the need for tailored educational approaches [28,30]. Future SPIs could be adapted using simplified language, visual aids, and repeated reinforcement to better engage patients with lower literacy or cognitive limitations.

Our findings also align with the broader body of literature that underscores the positive impact of structured education on patient outcomes. Unlike VKA therapy, which require frequent laboratory monitoring and complex dose adjustments, DOAC therapy offers simplified management. This allows SPIs to focus on key safety behaviors and treatment understanding, potentially making education more accessible and effective for patients with lower educational levels. For example, the EDUC'AVK study evaluated the impact of a structured educational program for patients with VKA therapy on the occurrence of hemorrhagic or thromboembolic events and patient knowledge. This study reported a significant cumulative risk reduction in the experimental group, paralleling our observation of lower complication rates among patients who received SPIs during hospitalization [32]. Moreover, studies by Ashjian et al. [9], and Perlman et al. [4] support this perspective by showing improvements in patient knowledge and medication adherence through targeted pharmacist involvement.

## 4.2. Conclusion

To conclude, our study highlights the pivotal role of SPIs in improving patients' knowledge and adherence to DOAC therapy. The successful collaboration between pharmacists and physicians emerges as a 'winning duo' due to the time efficiency gained by pharmacist-led interviews. These interviews alleviate consultation time for physicians and provide a structured format that physicians are unable to accommodate within their schedules. This collaboration also allows time to reformulate information for patients and integrates multisource information from physicians, pharmacists, nurses, and patient resources. Given the scalability of SPIs and their alignment with international guideline priorities, our results have implications beyond the French hospital context and warrant consideration in diverse healthcare systems. Given the standardized yet adaptable nature of SPIs, this approach could be successfully implemented across different healthcare systems and cultural contexts, promoting global optimization of anticoagulant management. Since our follow-up was limited to six months, future studies should investigate whether the benefits of SPIs persist over longer periods.

## 4.3. Practice implications

Our study suggests that incorporating SPIs into routine hospital care for patients on DOACs enhances their knowledge and adherence, leading to improved anticoagulant management. Although the clinical benefit of SPI is supported by improved knowledge and adherence, determining the precise number of patients requiring education would require standardized baseline knowledge assessment and causal evidence from randomized studies. Expanding SPI training to all DOAC prescribers could help standardize patient education and potentially enhance clinical management across medical specialties [33]. To maximize the impact of SPIs, large-scale studies should explore their scalability across diverse healthcare systems and cultural contexts. Such research could help establish universally applicable guidelines for integrating therapeutic education into routine DOAC management, thereby enhancing their utility and effectiveness in different clinical settings.

Furthermore, the significance of interdisciplinary collaboration between pharmacists and physicians warrants further exploration in future studies. The pharmacist–physician partnership was central to the success of the intervention. Physicians were primarily responsible for diagnosis and determining treatment indications, while pharmacists focused on patient education regarding proper medication use, thereby ensuring both efficacy and safety of therapy. This collaborative approach facilitated coherent messaging and shared therapeutic goals across disciplines. The impact of this partnership on patient outcomes could be further evaluated through physician satisfaction surveys or randomized studies assessing perceived improvements in patient adherence to treatment. Modernizing the educational tools used in SPIs, as part of a broader therapeutic education program, could also be key to further enhancing patient knowledge and adherence outcomes.

## Funding

This study was funded by the Training, Research, and Innovation Direction of the Health Service of the French armed ministry (grant ID: 2020PPRC08). The funder played no role in this work.

## CRediT authorship contribution statement

**Albert BOCCARA:** Writing – review & editing, Writing – original draft, Methodology, Investigation, Data curation, Conceptualization.
**Samuel, David COHEN:** Writing – review & editing, Writing – original draft, Supervision, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization.
**Claire-Marie TIS-SOT:** Writing – review & editing, Investigation, Data curation.
**François**
**BOUVIER:** Writing – review & editing, Investigation, Data curation.
**Caroline LEITERER:** Writing – review & editing, Data curation. **Alice VIALLET:** Writing – review & editing, Data curation. **Jean-Marc DAUCHOT:** Writing – review & editing, Methodology, Conceptualization. **Frédéric TACCO:** Writing – review & editing, Methodology, Conceptualization. **Catherine VERRET:** Writing – review & editing, Formal analysis, Data curation. **François KRAMP:** Writing – review & editing, Methodology, Conceptualization. **Hubert NIELLY:** Writing – review & editing, Writing – original draft, Investigation, Data curation. **Solenne MARTIN:** Writing – review & editing, Formal analysis, Data curation.

Declaration of Competing Interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Samuel D. Cohen reports administrative support and travel were provided by French Government Ministry of the Armed Forces. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

The authors and study sponsor are indebted to the patients and their families, as well as the investigators and sites participating in the studies. We would like to express our gratitude to the team at the Department of Vascular Medicine and Therapeutics, Saint-Étienne University Hospital – North Hospital, for their insightful expertise, particularly Pr. L. BERTOLETTI and Dr. G. POENOU. We would also like to thank Dr. Q. FISCHER, from the Cardiology Department at Cochin University Hospital, for his thoughtful guidance and constructive feedback.

Author's contributions

Samuel D. Cohen had access to all the data in the study and had final responsibility for the decision to submit for publication. Samuel D. Cohen, Frédéric Tacco, Jean-Marc Dauchot, François Kramp and Albert Boccara contributed to study concept and design. Samuel D. Cohen, François Bouvier, Claire-Marie Tissot, Caroline Leiterer, Alice Viallet, Hubert Nielly and Albert Boccara contributed to acquisition of data. Samuel D. Cohen, Solenne Martin and Catherine Verret contributed to analysis and interpretation of data, and statistical analysis. Samuel D. Cohen, Hubert Nielly and Albert Boccara drafted the manuscript. All authors revised the manuscript critically and approved the final version before submission and agree to be accountable for all aspects of the work.

Appendix A. Supporting information

Supplementary data associated with this article can be found in the online version at doi:10.1016/j.pec.2025.109423.

Data availability

The data supporting the findings of this study are available from the corresponding author upon reasonable request.

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