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The first LC–HRMS method for quantification of bisoprolol, ramipril and simvastatin in dried blood spots developed.A micro-analytical method for monitoring medication adherence.Validation showed good linearity, accuracy and precision for the three target drugs.Drug recoveries, sample stability and matrix effects were investigated.The validated method successfully identified control volunteers who were known to be either adherent or non-adherent.The use of dried blood spot (DBS) collection cards was investigated for the quantification of three therapeutic drugs used in cardiovascular therapy for assessing medication adherence. A liquid chromatography–high resolution mass spectrometry (LC–HRMS) method was developed and validated for the determination of bisoprolol, ramipril and simvastatin. Whole blood spiked with target analytes was used to produce 30 μl blood spots on specimen collection cards. An 8 mm disc was cut from the dried blood spot and extracted using methanol: water (70:30, v/v) containing the internal standard, atenolol. Extracts were vortexed, sonicated and then centrifuged. Gradient chromatographic elution was achieved using a Zorbax Eclipse C18 HD 100 mm × 2.1 mm, 1.8 μm pore size column and a mobile phase flow rate of 0.6 ml/min and the column oven temperature at 40 °C with a run time of 3 min. MS detection was carried out in electrospray positive ion mode for the three target drugs and for the IS. Drug recoveries from spiked blood spots were ≥92% for bisoprolol and ramipril and ˜43% for simvastatin and the drugs were stable in DBS for at least 12 weeks. Validation of the LC–HRMS method showed good linearity and the accuracy (relative error) and precision (coefficient of variation) values were within the pre-defined limits of ≤15% at all concentrations. Matrix effects and the effects of different volumes of blood applied to the collection card were investigated. The LC–HRMS method successfully identified control volunteers who were known to be either adherent or non-adherent. There were no false positives from volunteers taking other cardiovascular drugs or from volunteers receiving no medication.