Background: Drug nonadherence is one of the major challenges faced by resistant hypertension patients, and identification of this problem is needed for optimizing pharmacotherapy. Dried blood spot (DBS) sampling is a minimally invasive method designed to detect and determine the degree of nonadherence. In this study, a DBS method for qualifying 8 antihypertensive drugs (AHDs) and 4 active metabolites was developed and validated using ultra highperformance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Method: The DBS assay was validated analytically and clinically, in accordance with FDA requirements. Analytical validation was accomplished using UHPLC-MS/MS. For clinical validation, paired peak and trough levels of DBS and plasma samples were simultaneously collected and comparatively analyzed using Deming regression and Bland-Altman analyses. All concentrations below the set lower limit were excluded. Deming regression analysis was used to predict comparison bias between the collected plasma and DBS samples, with DBS concentrations corrected accordingly. Results: The UHPLC-MS/MS method for simultaneously measuring 8 AHDs and their metabolites in DBS, was successfully validated. With Deming regression no bias was observed in N = 1; constant bias was seen in N = 6 and proportional bias in N = 11 of the AHDs and metabolites. After correction for bias, only one metabolite (canrenone) met the 20% acceptance limit for quantification, after Bland-Altman analyses. In addition, amlodipine, valsartan, and [enalaprilate] met the 25% acceptance limit. Conclusions: A novel DBS assay for simultaneously qualifying and quantifying 8 AHDs and their metabolites, has been successfully developed and validated. The DBS assay is therefore a suitable method to detect drug nonadherence. However, with the exception of canrenone, the interchangeable use of plasma and DBS sampling to interpret drug quantities should be avoided.

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PurposeCyclosporine A (CsA) is the most widely used immunosuppressive agent after a hematopoietic stem cell transplantation (HSCT). Although recommendations for CsA dose conversion from intravenous to oral administration differ from 1:1 to 1:3, most studies did not consider the role of azole antifungals as an important confounder. Therefore, we assess the optimal conversion rate of CsA from intravenous to oral administration in HSCT recipients, taking into account the concomitant use of azole antifungals.MethodsWe retrospectively included patients from a large database of 483 patients who underwent a HSCT and received intravenous CsA as part of the conditioning regimen and peritransplant immunosuppression. All patients were converted from intravenous to oral administration in a 1:1 conversion rate. We collected for each patient three CsA trough concentrations during intravenous and oral administration, directly before and after conversion to oral administration.ResultsWe included 71 patients; 50 patients co-treated with fluconazole, 10 with voriconazole, and 11 without azole co-medication. In patients with voriconazole, the dose-corrected CsA concentration (CsA concentration divided by CsA dosage) was not different between intravenous and oral administration (2.6% difference, p = 0.754), suggesting a CsA oral bioavailability of nearly 100%. In patients with fluconazole and without azole co-medication, the dose-corrected CsA concentration was respectively 21.5% (p < 0.001) and 25.2% (p = 0.069) lower during oral administration.ConclusionsIn patients with voriconazole, CsA should be converted 1:1 from intravenous to oral administration. In patients with fluconazole and without azole co-medication, a 1:1.3 substitution is advised to prevent subtherapeutic CsA concentrations.

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Background Cardiac resynchronization therapy (CRT) is used in selected heart failure patients with electrical cardiac dyssynchrony with a prolonged QRS duration and a left ventricle ejection fraction (LVEF) ≤35%. QRS duration post CRT implantation can probably predict responders and survivors. The aim of our study is to investigate the effect of QRS change on long-term survival post CRT implantation. Methods We performed a retrospective cohort study in patients receiving a CRT device in our tertiary referral center between January 2009 and January 2018. Clinical and electrocardiographic (ECG) data were collected at baseline, one week after CRT implantation, six months, and yearly during follow-up. The primary endpoint was death, left ventricle assisting device implantation, or heart transplantation. At the end, the cohort was dichotomized to the cut-off value of ≥15ms according current literature. Results The study population consisted of 219 patients of whom 145 (66%) patients were survivors and 74 (34%) non-survivors. Non-survivors were significantly older (63 vs. 68 years, p=0.001), male gender (67% vs. 82%, p=0.015), had more often diabetes mellitus (20% vs. 39%, p=0.002), chronic obstructive pulmonary disease (12% vs. 28%, p=0.003), an ischemic etiology of heart failure (42% vs. 61%, p=0.009) with previous myocardial infarction (29% vs 53%, p=0.001), previous revascularization (32% vs. 49%, p=0.019), atrial fibrillation (21% vs. 39%, p=0.004), worser NYHA class (p=0.008), and amiodarone use (10% vs. 22%, p=0.024). Blood urea nitrogen (BUN) (8.1 mmol/L vs. 10.4 mmol/L, p<0.001) and creatinine levels (96 μmol/L vs. 114 μmol/L, p=0.001) were also higher in the non-survivors group. Median QRS duration (168 ms IQR [154 to 182]) at baseline was comparable between survivors and non-survivors (170 ms vs. 166 ms, p=0.17). However, median QRS change one week after CRT implantation was significantly better in the survivors (−19 ms IQR [−30 to −2] vs. −6 ms IQR [−24 to +12], p=0.004). The QRS change at the last FU (median 5.1 years IQR [2.9 to 7.8] was consistently higher in the survivor group (−16 ms IQR [−29 to 0] vs. +1 ms IQR [−27 to +20], p=0.004). Dichotomized to ΔQRS narrowing of ≥15 ms after CRT implantation showed significantly better long-term survival (figure). Kaplan-Meier curve Conclusion QRS narrowing cut-off of ≥15 ms post CRT implantation is strongly associated with the long term survival in chronic heart failure patients with reduced LVEF.