Colchicine reduces extracellular vesicle NLRP3 inflammasome protein levels in chronic coronary disease: A LoDoCo2 biomarker substudy.

BACKGROUND AND AIMS: Colchicine reduces the risk of cardiovascular events in patients with coronary disease. Colchicine has broad anti-inflammatory effects and part of the atheroprotective effects have been suggested to be the result of NLRP3 inflammasome inhibition. We studied the effect of colchicine on extracellular vesicle (EV) NLRP3 protein levels and inflammatory markers, high sensitivity-CRP (hs-CRP) and interleukin (IL)-6, in patients with chronic coronary disease. METHODS: In vitro, the NLRP3 inflammasome was stimulated in PMA-differentiated- and undifferentiated THP-1 cells. In vivo, measurements were performed in serum obtained from 278 participants of the LoDoCo2 trial, one year after randomization to colchicine 0.5 mg once daily or placebo. EVs were isolated using precipitation. NLRP3 protein presence in EVs was confirmed using iodixanol density gradient centrifugation. Levels of NLRP3 protein, hs-CRP and IL-6 were measured using ELISA. RESULTS: In vitro, NLRP3 inflammasome stimulation showed an increase of EV NLRP3 protein levels. EV NLRP3 protein levels were lower in patients treated with colchicine (median 1.38 ng/mL), compared to placebo (median 1.58 ng/mL) (p = 0.025). No difference was observed in serum NLRP3 protein levels. Serum hs-CRP levels were lower in patients treated with colchicine (median 0.80 mg/L) compared to placebo (median 1.34 mg/L) (p < 0.005). IL-6 levels were lower in patients treated with colchicine (median 2.07 ng/L) compared to placebo (median 2.59 ng/L), although this was not statistically significant (p = 0.076). CONCLUSIONS: Colchicine leads to a reduction of EV NLRP3 protein levels. This indicates that inhibitory effects on the NLRP3 inflammasome might contribute to the atheroprotective effects of colchicine in coronary disease.

Colchicine in Patients With Chronic Coronary Disease in Relation to Prior Acute Coronary Syndrome.

BACKGROUND: Colchicine reduces risk of cardiovascular events in patients post-myocardial infarction and in patients with chronic coronary disease. It remains unclear whether this effect is related to the time of onset of treatment following an acute coronary syndrome (ACS). OBJECTIVES: This study investigates risk for major adverse cardiovascular events in relation to history and timing of prior ACS, to determine whether the benefits of colchicine are consistent independent of prior ACS status. METHODS: The LoDoCo2 (Low-Dose Colchicine 2) trial randomly allocated patients with chronic coronary disease to colchicine 0.5 mg once daily or placebo. The rate of the composite of cardiovascular death, spontaneous myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization was compared between patients with no prior, recent (6-24 months), remote (2-7 years), or very remote (>7 years) ACS; interaction between ACS status and colchicine treatment effect was assessed. RESULTS: In 5,522 randomized patients, risk of the primary endpoint was independent of prior ACS status. Colchicine consistently reduced the primary endpoint in patients with no prior ACS (incidence: 2.8 vs 3.4 events per 100 person-years; hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.52-1.27), recent ACS (incidence: 2.4 vs 3.3 events per 100 person-years; HR: 0.75; 95% CI: 0.51-1.10), remote ACS (incidence: 1.8 vs 3.2 events per 100 person-years, HR: 0.55; 95% CI: 0.37-0.82), and very remote ACS (incidence: 3.0 vs 4.3 events per 100 person-years, HR: 0.70; 95% CI: 0.51-0.96) (P for interaction = 0.59). CONCLUSIONS: The benefits of colchicine are consistent irrespective of history and timing of prior ACS. (The LoDoCo2 Trial: Low Dose Colchicine for secondary prevention of cardiovascular disease [LoDoCo2] ACTRN12614000093684).

A mandatory indication-registration tool in hospital electronic medical records enabling systematic evaluation and benchmarking of the quality of antimicrobial use: a feasibility study.

OBJECTIVES: Evaluation of the extent and appropriateness of antimicrobial use is a cornerstone of antibiotic stewardship programs, but it is time-consuming. Documentation of the indication at the moment of prescription might be more time-efficient. We investigated the real-life feasibility of mandatory documentation of the indication for all hospital antibiotic prescriptions for quality evaluation purposes. METHODS: A mandatory prescription-indication format was implemented in the Electronic Medical Record (EMR) of three hospitals using EPIC or ChipSoft HIX software. We evaluated the retrieved data of all antibiotics (J01) prescribed as empiric therapy in adult patients with respiratory tract infections (RTI) or urinary tract infections (UTI), from January through December 2017 in Hospital A, June through October 2019 in Hospital B and May 2019 through June 2020 in Hospital C. Endpoints were the accuracy of the data, defined as agreement between selected indication for the prescription and the documented indication in the EMR, as assessed by manually screening a representative sample of eligible patient records in the EMR of the three hospitals, and appropriateness of the prescriptions, defined as the prescriptions being in accordance with the national guidelines. RESULTS: The datasets of hospitals A, B and C contained 9588, 338 and 5816 empiric antibiotic prescriptions indicated for RTI or UTI, respectively. The selected indication was in accordance with the documented indication in 96.7% (error rate: 10/300), 78.2% (error rate: 53/243), and 86.9% (error rate: 39/298), respectively. A considerable variation in guideline adherence was seen between the hospitals for severe community acquired pneumonia (adherence rate ranged from 35.4 to 53.0%), complicated UTI (40.0-67.1%) and cystitis (5.6-45.3%). CONCLUSIONS: After local validation of the datasets to verify and optimize accuracy of the data, mandatory documentation of the indication for antibiotics enables a reliable and time-efficient method for systematic registration of the extent and appropriateness of empiric antimicrobial use, which might enable benchmarking both in-hospital and between hospitals.

Association between workarounds and medication administration errors in bar-code-assisted medication administration in hospitals.

Objective: To study the association of workarounds with medication administration errors using barcode-assisted medication administration (BCMA), and to determine the frequency and types of workarounds and medication administration errors. Materials and Methods: A prospective observational study in Dutch hospitals using BCMA to administer medication. Direct observation was used to collect data. Primary outcome measure was the proportion of medication administrations with one or more medication administration errors. Secondary outcome was the frequency and types of workarounds and medication administration errors. Univariate and multivariate multilevel logistic regression analysis were used to assess the association between workarounds and medication administration errors. Descriptive statistics were used for the secondary outcomes. Results: We included 5793 medication administrations for 1230 inpatients. Workarounds were associated with medication administration errors (adjusted odds ratio 3.06 [95% CI: 2.49-3.78]). Most commonly, procedural workarounds were observed, such as not scanning at all (36%), not scanning patients because they did not wear a wristband (28%), incorrect medication scanning, multiple medication scanning, and ignoring alert signals (11%). Common types of medication administration errors were omissions (78%), administration of non-ordered drugs (8.0%), and wrong doses given (6.0%). Discussion: Workarounds are associated with medication administration errors in hospitals using BCMA. These data suggest that BCMA needs more post-implementation evaluation if it is to achieve the intended benefits for medication safety. Conclusion: In hospitals using barcode-assisted medication administration, workarounds occurred in 66% of medication administrations and were associated with large numbers of medication administration errors.

[Oral better than parenteral supplementation of vitamin B12]. / Vitamine B12-suppletie liever oraal dan parenteraal.

Vitamin B12 deficiency occurs in 5-10% of the Dutch population. Serum vitamin B12 levels should be determined in patients with haematological or neurological disorders such as megaloblastic anaemia or neuropathy, and in patients with risk factors for vitamin B12 deficiency such as atrophic gastritis or intrinsic factor-deficiency. The aim of this article was to explicate the data from the literature on the efficacy of oral versus parenteral vitamin B12 supplementation. Two randomised, controlled trials have shown that oral supplementation of 1000-2000 microg/day of vitamin B12 is equally effective in raising serum vitamin B12 levels as a standard parenteral dosing schedule. Moreover, the effects on clinical endpoints were comparable. Several dose-finding studies have been performed, showing that the minimal effective oral dose is 647-1032 microg/day. It is recommended that patients with vitamin B12 deficiency be prescribed 1000 microg/day vitamin B12 orally, unless they have problems with swallowing or treatment compliance or have severe clinical symptoms. In that case parenteral administration is indicated.

Thalidomide-associated thrombocytopenia.

OBJECTIVE: To report thrombocytopenia in a patient prescribed thalidomide for multiple myeloma (MM). CASE SUMMARY: A 70-year-old woman was diagnosed in 2003 with MM. At diagnosis, melphalan 0.25 mg/kg/day and prednisolone 2 mg/kg/day were started; however, the patient became refractory to therapy. Melphalan and prednisolone were discontinued, and monotherapy with dexamethasone 40 mg for 12 days per month was started. The patient's hematologic condition deteriorated again after about one year; dexamethasone was discontinued, and treatment with oral thalidomide 200 mg/day was initiated. About 2 weeks after thalidomide administration, the woman developed disabling adverse effects (flu-like symptoms, swollen fingers, rash and hematoma on her legs, shortness of breath, dry mouth, multiple petechiae). Laboratory testing showed neutropenia (neutrophils 0.4 x 10(9)/L) and thrombocytopenia (platelets 58 x 10(9)/L). Thalidomide was promptly discontinued; within 3 weeks, the laboratory values returned to pretreatment levels (1.3 x 10(9)/L and 267 x 10(9)/L, respectively) and her symptoms disappeared. DISCUSSION: Thrombocytopenia is a rarely reported hematologic adverse consequence of thalidomide therapy. A recent report identified 5 patients who developed thrombocytopenia while undergoing monotherapy with thalidomide for MM. According to the Naranjo probability scale, thalidomide was classified as the probable cause of thrombocytopenia in our patient. CONCLUSIONS: Unlike other antineoplastic drugs, thalidomide is rarely reported to cause severe hematologic toxicity. We present this case to increase clinicians' awareness for the potential of thalidomide to adversely affect platelet counts, particularly because its effectiveness in MM will likely result in expansion of its clinical use.