2.3.1. Adherence to Medication Measures

Adherence to medication was evaluated according to the extent to which a patient’s actual dosing corresponded to the prescribed dosing regimen (i.e., omissions of single or consecutive doses, delays in medication taking, or self-initiated dose changes, such as a reduction or increase in dosing, are considered non-adherence). The poor regularity of immunosuppressive treatment refers to dosing discrepancies of ± 2 h [11,39]. Non-persistence was defined as the early discontinuation of the medication [40]. Adherence was recorded at T_0, T₁ and T_2, combining qualitative and quantitative methods. These methods were selected to facilitate generalizability to large populations and simplicity in use and scoring.

Three questionnaires were used as qualitative methods to measure adherence to immunosuppressive treatment: the Spanish Version of the SMAQ (Simplified Medication Adherence Questionnaire) [41], the IMTS (Immunosuppressive Medication Timing Scale) and the BAASIS (Basel Assessment of Adherence to Immunosuppressive Medications Scale) [42]. The SMAQ and the IMTS were performed during the interview by the pharmacist and the BAASIS was patient reported. The SMAQ questionnaire is a 6-item scale validated in transplant population that measures patients’ medication habits [41]. The IMTS is a 2-item self-reported, semi-quantitative questionnaire created for the study. We asked the patients about how often they modified their immunosuppressant timetable in the last week and since the last scheduled visit. If the answer was “Never” for both questions, the patient is considered to be adherent. The BAASIS has been validated in transplant recipients and measures patients’ medication taking, omission, timing and dose reduction of immunosuppressive medication [42]. BAASIS includes the visual analog scale (VAS), which is an overall score ranging from 0 (never took medications as prescribed) to 100 (always took medications as prescribed). Adherence to other co-medications was assessed at T_0, T₁ and T₂ visits, using the Haynes-Sackett questionnaire (Spanish version) [43]. This is a 1-item scale that asks patients the question: “Most patients have difficulty taking all their tablets, do you have difficulties taking all of yours?” A patient is considered to be non-adherent if he or she responds affirmatively to the question.

Quantitative methods to measure adherence included immunosuppressive medication blood levels and compliance with visits. Variability for tacrolimus and cyclosporine blood levels was assessed by the coefficient of variation of concentrations (CV% = (SD/µ) × 100) and the standard deviation (SD) for each patient. Patients with SD > 2.5 or with CV% > 30% were interpreted as non-adherent [11]. Trough blood levels (ng/mL) were assessed using Fluorescence Polarization Immunoassay at T₀, T₁ and T_2. The therapeutic range for each drug was the range recommended in the ISHLT guidelines [44]. The number and percentage of patients with missing visits at T₀, T₁ and T₂ were recorded by retrospective review of hospital electronic health records (EHR). The SMAQ score at T₀, T₁ and T₂, compliance with the scheduled visits and global CV% were combined to develop a composite adherence score. If any of the 3 variables reflected MNA, the patient was classified as non-adherent.