This prospective observational study analyzed 60 consecutive patients admitted to the neurology department of Coimbra Hospital and University Center between November 2016 and August 2017 for ischemic stroke associated with non-valvular AF, despite chronic anticoagulation with warfarin, dabigatran, apixaban, rivaroxaban or edoxaban.

Ischemic stroke was diagnosed on the basis of evidence of acute focal neurological deficit lasting longer than 24 hours and cerebral ischemia identified by neuroimaging methods (computed tomography or brain magnetic resonance imaging).17 Stroke was classified in etiological subtypes according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria as (1) large-artery atherosclerosis, (2) cardioembolism, (3) small-vessel occlusion (lacune), (4) stroke of other determined etiology, or (5) stroke of undetermined etiology.17 Severity of neurological damage at admission was assessed by a neurologist using the National Institutes of Health Stroke Scale. The patient selection process is illustrated in Figure 1.

Figure 1.

Flowchart of the patient selection process. AF: atrial fibrillation.

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The study was approved by the ethics committee of the Central Region health authority and was conducted in accordance with the international guidelines for clinical research of the Declaration of Helsinki of the World Medical Association. All patients provided written informed consent.

The following information was collected for each patient: demographic data, socioeconomic status as measured by the Graffar scale, educational level, personal history (hypertension; dyslipidemia; diabetes; sedentary lifestyle; heart failure; thromboembolism, stroke or transient ischemic attack; previous coronary disease or myocardial infarction), CHA2DS2-VASc score, smoking status, alcohol consumption, renal function assessed by the Cockcroft-Gault formula, and medication, including type and dosage of oral anticoagulation, INR if applicable, and other drug therapies. Adequacy of dosage of NOACs was assessed on the basis of the recommended doses for each drug and the renal function, age, weight, and concomitant medication of the individual patient, with dosages being classified as adequate, subtherapeutic, or supratherapeutic. On the basis of the patient's overall medication, their Medication Regimen Complexity Index was calculated. This validated tool assesses the complexity of drug therapy independently of socioeconomic, pharmacological and clinical factors, based on types of prescribed dosage forms, dosing frequency, and additional directions given by the prescriber and that patients need to take into consideration to ensure that the drug is administered correctly.18

Adherence to anticoagulant therapy in each patient was assessed by the application of two instruments, both validated for the Portuguese language: the Brief Medication Questionnaire (BMQ)19 and Medição da Adesão ao Tratamento (Measure of Treatment Adherence, MAT).20

The BMQ consists of three sets of questions that assess treatment adherence by asking patients how they take their medication, their beliefs, and how they remember, classifying adherence as high (no positive responses), probably high (one positive response), probably low (two positive responses), or low (three or more positive responses). For the purposes of this study, two or more positive responses were considered to indicate non-adherence.

The MAT includes seven items assessing patients’ behavior concerning daily drug use, the response to each item being scored on a six-point Likert scale from 1 (always) to 6 (never). The level of adherence is obtained by adding together the scores for each item and dividing by the number of items, giving a total score between 1 and 6, with higher numbers indicating better adherence.

Categorical variables (demographics, clinical characteristics and type of anticoagulant) were expressed as frequency and percentage, and continuous variables were presented as means and standard deviation.

Patients under VKAs were compared to those under NOACs. The MAT score and the BMQ results (dividing the study population into adherers and non-adherers according to the above criteria) were used to identify potential predictors of poor treatment adherence. Dichotomous (categorical) variables were compared with the chi-square test or Fisher's exact test, and continuous variables were compared using the Student's t test or the Mann-Whitney test, depending on normality of distribution.

Spearman's correlation was used to compared the accuracy of the two adherence scores.

A p-value <0.05 was considered statistically significant in all tests. The statistical analysis was performed in IBM SPSS® version 23.

Patients’ mean age was 78.6±8.0 years, and 51.7% were male. Regarding socioeconomic status, 56.6% were middle or upper-middle class and none were upper class. The illiteracy rate was 18.3% and most subjects had only completed primary education; none had an educational level higher than a bachelor's degree. Mean CHA2DS2-VASc score was 4.3±1.4, minimum 1 and maximum 7. Subtherapeutic doses were identified in 43% of patients taking NOACs: 44% of those taking dabigatran, 22% apixaban and 34% rivaroxaban. The overall characteristics of the study population are presented in Table 1.

Eighteen patients (30%) were anticoagulated with VKAs and 42 (70%) with NOACs, of whom 15.0% were taking apixaban, 23.3% dabigatran, 1.7% edoxaban and 30.0% rivaroxaban. In those taking VKAs, all cases of stroke were of cardioembolic etiology. Also in this group, mean INR at admission for stroke was 1.5±0.4, and 91.7% of them presented INR <2. Among patients taking NOACs, 19.5% of cases of stroke were non-cardioembolic in origin (all due to small-vessel disease). In the subgroup of patients taking NOACs who suffered cardioembolic stroke, a large proportion (33.3% of those on NOACs, 14 patients) were taking subtherapeutic doses (five on dabigatran 110 mg instead of 150 mg twice daily, three on apixaban 2.5 mg instead of 5 mg twice daily, and six on rivaroxaban 15 mg instead of 20 mg daily). Among patients with cardioembolic stroke and appropriate NOAC dosage, treatment adherence was poor in 47% (nine patients, 21.4% of those on NOACs) (Figure 2).

Figure 2.

Possible mechanisms for stroke occurrence in patients chronically anticoagulated with NOACs compared to VKAs. NOACs: novel oral anticoagulants; VKAs: vitamin K antagonists.

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No drugs that potentially could interact with oral anticoagulation were recorded. Comparison between patients taking VKAs and those taking NOACs showed differences in the proportions of adherent patients and in those with a history of MI or heart failure, with more in the VKA group (Table 2).

There was excellent correlation between the two scores used to assess treatment adherence (r=-0.955, p<0.001). According to the BMQ, 63.3% of the overall population presented good treatment adherence, while the mean MAT score was 5.6±0.6, minimum 2.4 and maximum 6.0 (Table 1). Of adherent patients, 26.3% were illiterate, in contrast to only 4.5% of non-adherent patients (p=0.012). The CHA2DS2-VASc score was similar in both adherent and non-adherent patients as determined by the BMQ (Figure 3). The characteristics of the study population according to treatment adherence are shown in Table 3.

Figure 3.

Treatment adherence according to CHA2DS2-VASc score.

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Of the 30% of patients taking VKAs, 83.3% were adherent to anticoagulant therapy according to the BMQ (mean MAT score 5.9±0.3), while of the 70% taking NOACs, only 54.8% were adherent (mean MAT score 5.5±0.7) (p=0.035 and p=0.044 for BMQ and MAT, respectively) (Table 2).

Although the proportion of patients taking VKAs with poor treatment adherence was relatively low (30%), most (91.7%) presented subtherapeutic INR at admission.

Among patients taking NOACs, a non-cardioembolic stroke etiology was identified in 19.5% of cases, which may explain why oral anticoagulation was ineffective in preventing these strokes. Furthermore, another 33.3% of patients on NOACs were receiving subtherapeutic doses, and of those with appropriate dosages, almost half (amounting to 21.4% of patients on NOACs) presented poor adherence to the drugs they were prescribed (Figure 2). Thus, among patients who suffered stroke despite chronic therapy with NOACs, a non-cardioembolic etiology and/or subtherapeutic dosages and/or poor treatment adherence were observed in 74.2% of cases.