Study design

A cross-sectional study was conducted to compare therapeutic adherence in asymptomatic patients with >50% carotid artery stenosis who underwent CEA or received BMT-only and were followed up as outpatients in our Vascular Surgery department at Centro Hospitalar Vila Nova de Gaia/Espinho in Portugal from January 2017 to December 2021. Two vascular surgeons (FB and PC) administered a survey by telephone from May 1^st to May 31^st, 2023. Sociodemographic and risk factor data were obtained from patient clinical records.

Participants and Recruitment

Asymptomatic was defined as patients without history of neurologic symptoms in the past six months, and >50% carotid artery stenosis was defined by the NASCET method.¹

The CEA group was selected from our surgery records, and the BMT-only group was selected from our duplex ultrasound database. Patients were eligible if they presented with a >50% stenosis.

Duplicated duplex ultrasound records for the same patient were excluded. Patients with previous history of carotid revascularization were deemed ineligible for inclusion in the BMT-only group.

After the initial selection process, patients were contacted by telephone and informed of the study, purposes, and funding. Confidentiality and voluntary participation were assured. Informed and clear verbal consent was obtained from patients who agreed to participate in the study in accordance with the Helsinki Declaration and the Oviedo Convention. Their data was subsequently collected, and questionnaires were administered.

Exclusion criteria were as follows: patients dependent on daily living, who couldn't manage their medication, who did not answer the call after multiple attempts, or uncontactable for other reasons.

Measures and Instruments

BMT was defined according to the European Society of Vascular Surgery Carotid Atherosclerotic Disease 2023 guidelines: 1 healthy diet (based on grilled and boiled food with restriction of fried food), smoking abstinence, 30 minutes of exercise five times a week, lower-dose aspirin or 75 mg clopidogrel, high-dose statin (with or without ezetimibe), antihypertensive treatment, and optimal glycemic control.

A questionnaire was specifically developed for this study. The questionnaire was based on existing literature on the subject, adapted to the local context. Adherence to medication was the primary outcome. This was defined as those who obtain a score ≥3 in the adapted MMAS-4 score, consisting of four questions (translated to Portuguese, 1 point per positive answer): Have you ever forgotten to take medication for carotid stenosis? (Alguma vez esqueceu-se de tomar a medicação para a estenose carotídea?); Did you ever need help remembering to take the medication for carotid stenosis, or do you always take it around the same time? (Alguma vez precisou de ajuda para lembrar-se de tomar a medicação para a estenose carotídea, ou toma sempre por volta da mesma hora?); Have you stopped taking you medication for carotid stenosis when you feel well or healthy? (Quando se sente bem/saudável, já deixou de tomar a medicação para a estenose carotídea nesse contexto?); Have you stopped taking your medication for carotid stenosis when you feel it is making you feel ill? (Quando sente que a medicação para a estenose carotídea está a causar mau estar, já deixou de a tomar nesse contexto?).

The MMAS-4 (4-items) is a universal assessment tool for self-reported medication adherence that can be tailored to various health conditions such as high blood pressure, diabetes mellitus, elevated cholesterol, human immunodeficiency virus, contraception, and others. The scale comprises four questions that are answered with either "Yes" or "No," and each "Yes" response is scored as 0 while each "No" response is scored as 1. By adding up the individual scores of the four items, a total score ranging from 0 to 4 is obtained, indicating the degree of adherence to medication. The value of Cronbach’s α of our Portuguese MMAS-4 in our study was 0.79, indicating an acceptable value for internal consistency. The MMAS-4 has a Cronbach’s alpha of 0.61.^8-10

To use this survey, we have obtained permission for both the utilization and translation of the MMAS-4, along with certification from a specialized company attesting to the accuracy and quality of the translation. MMAS-4 was chosen in detriment of the MMAS-8 because of practically; too many questions over the phone could be inconvenient and limit patient’s willingness to participate. We also implemented three additional questions to independently evaluate adherence to healthy diet, physical exercise, and smoking cessation.

Secondary outcomes included comprehension and knowledge of their own medication, which was assessed by eight questions created by our investigation group to inquire if patients knew the name and purpose of the antiplatelet, anti-diabetic, statin, or anti-hypertensive medication. We also assessed the percentage of patients that were prescribed with statin and antiplatelet by the attending physician. The remaining other secondary outcome was the assessment (by phone interview) if patients reported any of the 3-point MACE - excluding death from a cardiovascular cause (nonfatal stroke or nonfatal myocardial infarction) since the procedure for the CEA group or since the doppler exam for the only BMT group.

The questionnaires were conducted by phone because of the target population characteristics (advanced age with multiple comorbidities), and we also believed that it was the most accessible and reliable way to obtain accurate information without misinterpretations from patients; any doubts could be immediately clarified.

A pilot survey was carried out in which the questionnaires were administered to 20 patients (10 from CEA and 10 from BMT-only group) of both sexes to identify and exclude interpretation biases.

Data Analysis

Data analysis was performed using SPSS Statistics (V.27.0; SPSS). Categorical variables were described using absolute and relative frequencies, n (%), and normally distributed quantitative variables were summarized using means and standard deviation (SD). The normality of the distributions was assessed by resorting to the Kolmogorov-Smirnov and Shapiro-wilk tests. To analyze the association between categorical variables, the χ2 test was used. To compare distributions between two independent continuous samples, an independent sample T Test was performed. A level of significance of 0.05 was considered.

Sample Characteristics

From 1720 records (1586 Carotid Doppler ultrasound records and 134 surgical records), a total of 1420 was excluded because of duplicates, or due to previous history of carotid revascularization, which was an ineligibility criterion. A pool of 320 (186 BMT-only; 134 CEA) patients qualified for inclusion in the study.

When we started the contact stage, we excluded 44 patients (37 BMT-only; 7 CEA) who were deceased, 11 (2 BMT-only; 9 CEA) who were dependent on daily living, 28 (17 BMT-only; 11 CEA) who did not manage their medication, 86 (51 BMT-only; 35 CEA) who did not answer the call, 10 (9 BMT-only; 1 CEA) for unavailable phone contact, and 2 (1 BMT-only; 1 CEA) refused to participate in the study.

Of the 320 eligible patients, 240 (75%) were male and the mean age was 70.84±7.9, 264 (82.5%) were hypertensive, 143 (44.7%) were diabetic, 89 (27.8%) were smokers, 221 (69.1%) were dyslipidemic. Furthermore, 278 (86.9%) were prescribed antiplatelets and 287 (89.7%) were prescribed statins.

The characteristics of the sample are summarized in Table 1.

Outcomes and Comparative Analysis of the Groups (BMT-only VS CEA)

Of all 139 respondents (70 BMT-only; 69 CEA), 64.7% (n=90) patients obtained a score ≥3 in the MMAS-4 questionnaire (adherence), 14.4 % (n=20) were current smokers, 61.2% (n=85) reported have a healthy diet, and 39.6% (n=55) practiced 30 minutes of exercise every day. Moreover, 136 were taking statins, of whom 87.5% (n=119) knew what it was for and 53.7% (n=73) knew the name of the medication. Similarly, 137 were taking antiplatelets, of whom 83.2% (n=114) knew what it was for and 57.7% (n=79) knew the name of the medication. Additionally, 126 were taking antihypertensives, of whom 76.2% (n=96) knew what it was for and 36.5% (n=46) knew the name of the antihypertensive, and 88 were taking antidiabetic medication, of whom 68.2% (n=60) knew what it was for, 38.6% (n=34) knew the name of the antidiabetic. Finally, 5.8% (n=8) reported a 3-point MACE up to the date of contact.

Comparing both groups of patients (CEA vs BMT-only) we found differences respect to smoking (51.4% CEA vs 15.9% BMT-only, p<0.001) antiplatelet prescription (80.0% CEA vs. 92.8% BMT-only, p=0.029) and statin prescription (78.6% CEA vs. 94.2% BMT-only, p=0.007). The remaining data is specified in Table 1.

Significant differences were also found between the BMT-only and CEA groups in terms of BMT compliance (40.3% vs. 24.5%, p<0.001, respectively).

The complete data of adherence are described in Tables 2 and 3. Furthermore, statin nomination (35.3% CEA vs. 18.4% BMT-only, p<0.001), antiplatelet nomination (37.2% CEA vs. 20.4% BMT-only, p<0.001), anti-hypertensive nomination (28.6% CEA vs. 7.9% BMT-only, p<0.001), and not knowing the purpose of antidiabetic medication (27.3% CEA vs. 4.5% BMT-only, p<0.001) were also found to have significant differences. Age difference and the remaining non-significant data are specified in Table 4.

Strengths and Limitations of the study

Study limitations include a relatively small sample size, the monocentric nature, the cross-sectional design, and the absence of a formal validation of the questionnaires in Portuguese. Another potential weakness was the social desirability bias. As doctors were calling the patients, they may have given socially acceptable answers, which could overestimate the medical adherence. Additionally, a selection bias may have played a role as patients who did not respond to the surveys may have had lower or higher adherence to BMT with resulting under or overestimation of certain factors.