A new design for external quality assessment for the analysis of thiopurine drugs reveals major differences between laboratories

ObjectiveThe aim of the study was to compare analytical results of 6-TGN and 6-MMPR blood level estimations between laboratories.Design and methodsParticipating laboratories were asked to select patient samples from their routine analysis and exchange these with another assigned laboratory. Because of large differences in results between laboratories, all standard operating procedures were reviewed, revealing that the origin of these differences could lie in the method of hydrolysis and the preparation of calibrator samples. To investigate the contribution of the calibrators to these differences, one participating laboratory was asked to prepare a batch of calibrators to be shipped to the participating laboratories for analysis.ResultsFor 6-TGN and 6-MMPR 43% and 24% of the results were outside of the 80-120% range. When correcting the results from the exchange of the patient samples with the results of the calibrators, the mean absolute difference for 6-TGN improved from 24.8% to 16.3% (P < 0.001), whereas the mean absolute difference for 6-MMPR slightly increased from 17.3% to 20% (P = 0.02).ConclusionThis first EQAS for thiopurine drugs shows that there is a difference between laboratories in the analysis of 6-TGN, and to a lesser extent of 6-MMPR. This difference for 6-TGN can partially be explained by the use of in-house prepared calibrators that differ among the participants

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

A design for external quality assessment for the analysis of thiopurine drugs: pitfalls and opportunities

Background: For the analysis of 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine ribonucleotides (6-MMPR), no external quality assessment scheme (EQAS) is currently available and no quality control samples can be made because of the absence of pure substances. An experimental design is tested to compare laboratory analytical results. Methods: In this EQAS, participating laboratories were asked to select patient samples from their routine analysis and exchange these with a coupled laboratory. Because of large differences in results between laboratories, all standard operating procedures were reviewed, revealing that the origin of these differences could be in the method of hydrolysis and the preparation of calibrators. To investigate the contribution of the calibrators to these differences, one participating laboratory was asked to prepare a batch of calibrators to be shipped to the participating laboratories for analysis. Results: Results for 6-TGN differed more between laboratories, compared with results for 6-MMPR. For 6-TGN and 6-MMPR 43% and 24% of the results, respectively, were out of the 80%-120% range. When correcting the results from the exchange of the patient samples with the results of the calibrators, the mean absolute difference for 6-TGN improved from 24.8% to 16.3% (p <0.001), while the results for 6-MMPR worsened from 17.3% to 20.0% (p = 0.020). Conclusions: This first EQAS for thiopurine drugs shows that there is a difference between laboratories in the analysis of 6-TGN, and to a lesser extent in the analysis of 6-MMPR. This difference for 6-TGN can partially be explained by the use of in-house-prepared calibrators that differ among the participants

Commutability of proficiency testing material containing amitriptyline and nortriptyline:A study within the framework of the Dutch Calibration 2.000 project

BACKGROUND: External quality assessment schemes (EQAS) can provide important information regarding accuracy and comparability of different measurement methods if the sample matrices are composed of commutable material. The aim of this study was to assess the commutability of different matrices for the material used in an EQAS for amitriptyline and nortriptyline. METHODS: Proficiency testing material (PTM) and patient samples containing amitriptyline and nortriptyline were prepared, collected, pooled, and distributed to participating laboratories for analysis. Low, medium and high concentrations of both drugs in liquid pooled human, lyophilized human and lyophilized bovine serum were tested in this study. The measurement deviation of the PTM results to the patient serum regression line were normalized by dividing trough the average within-laboratory SD (SDwl) derived from the results reported in the official EQAS, resulting in a relative residual. The commutability decision limit was set at 3 SDwl. RESULTS: With 10 laboratories participating in this study, 45 laboratory couples were formed. All matrix types delivered several relative residuals outside the commutability decision limit. The number and the magnitude of relative residuals for both drugs were lower for liquid human sera as compared to lyophilized human and bovine sera. CONCLUSIONS: The PTM used for amitriptyline and nortriptyline is preferably prepared with human serum, although not all relative residuals are within the commutability decision limit

Commutability of proficiency testing material containing amitriptyline and nortriptyline: A study within the framework of the Dutch Calibration 2.000 project

Background: External quality assessment schemes (EQAS) can provide important information regarding accuracy and comparability of different measurement methods if the sample matrices are composed of commutable material. The aim of this study was to assess the commutability of different matrices for the material used in an EQAS for amitriptyline and nortriptyline. Methods: Proficiency testing material (PTM) and patient samples containing amitriptyline and nortriptyline were prepared, collected, pooled, and distributed to participating laboratories for analysis. Low, medium and high concentrations of both drugs in liquid pooled human, lyophilized human and lyophilized bovine serum were tested in this study. The measurement deviation of the PTM results to the patient serum regression line were normalized by dividing trough the average within-laboratory SD (SDwl) derived from the results reported in the official EQAS, resulting in a relative residual. The commutability decision limit was set at 3 SDwl. Results: With 10 laboratories participating in this study, 45 laboratory couples were formed. All matrix types delivered several relative residuals outside the commutability decision limit. The number and the magnitude of relative residuals for both drugs were lower for liquid human sera as compared to lyophilized human and bovine sera. Conclusions: The PTM used for amitriptyline and nortriptyline is preferably prepared with human serum, although not all relative residuals are within the commutability decision limit

A Multilaboratory Commutability Evaluation of Proficiency Testing Material for Carbamazepine and Valproic Acid:A Study Within the Framework of the Dutch Calibration 2000 Project

Background: Medical laboratories are required to participate in interlaboratory comparisons of the analyses they perform. The materials used in these comparisons need to be of sufficient quality so that the comparison provides a picture of the performances. One of the main characteristics of the testing material is commutability, which is the ability of a material to yield the same numerical relationships between results of measurements as those relationships obtained when the same procedures are applied to patient samples. The aim of this study was to assess the commutability of 3 different matrices for the preparation of proficiency testing material (PTM) for the analysis of carbamazepine and valproic acid. Methods: Patient samples and PTM containing various concentrations of carbamazepine and valproic acid were collected, prepared, and shipped to different laboratories for analysis. Reported results for patient samples from each laboratory were plotted against results for patient samples of each of the other laboratories, and the corresponding regression line was calculated. The distance of results from PTM to the regression line is a measure for commutability. The distance is expressed as a multiple of the SDwl (average within-laboratory SD as calculated from external quality assessment scheme results) and referred to as relative residual. A commutability decision limit of 2 SDwl was set. Results: For carbamazepine and valproic acid, a total of 78 and 105 laboratory couples respectively could be formed. The number of relative residuals for liquid human serum outside the commutability decision limit was 1, 4, and 0 for low, medium, and high concentrations of carbamazepine, respectively and 3, 1, and 0 for low, medium, and high concentrations of valproic acid, respectively. In both liquid and lyophilized bovine sera, the number of relative residuals outside the commutability decision limit was between 2 and 15 and between 6 and 21 for carbamazepine and valproic acid, respectively. Conclusions: Although not all results for PTM with carbamazepine and valproic acid are within the commutability decision limits, a preference for human serum can be seen