Monotreatment With Conventional Antirheumatic Drugs or Glucocorticoids in Rheumatoid Arthritis: A Network Meta-Analysis.

Importance: This is the first network meta-analysis to assess outcomes associated with multiple conventional synthetic disease-modifying antirheumatic drugs and glucocorticoid. Objective: To analyze clinical outcomes after treatment with conventional synthetic disease-modifying antirheumatic drugs and glucocorticoid among patients with rheumatoid arthritis. Data Sources: With no time restraint, English language articles were searched in MEDLINE, Embase, Cochrane Central, ClinicalTrials.gov, and reference lists of relevant meta-analyses until September 15, 2022. Study Selection: Four reviewers in pairs of 2 independently included controlled studies randomizing patients with rheumatoid arthritis to mono-conventional synthetic disease-modifying antirheumatic drugs, glucocorticoid, placebo, or nonactive treatment that recorded at least 1 outcome of tender joint count, swollen joint count, erythrocyte sedimentation rate, and C-reactive protein level. Of 1098 assessed articles, 130 articles (132 interventions) were included. Data Extraction and Synthesis: The review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline, and data quality was assessed by the Cochrane risk of bias tool RoB 2. Data were extracted by a single author and checked independently by 2 authors. Data were analyzed using a random effect model, and data analysis was conducted from June 2021 to February 2023. Main Outcomes and Measures: A protocol with hypothesis and study plan was registered before data recording. The most complete of recorded outcomes (tender joint count) was used as primary outcome, with imputations based on other outcomes to obtain a full analysis of all studies. Absolute change adjusted for baseline disease activity was assessed. Results: A total of 29 interventions in 275 treatment groups among 132 randomized clinical trials (mean [range], 71.0% [27.0% to 100%] females in studies; mean [range] of ages in studies, 53 [36 to 70] years) were identified, which included 13 260 patients with rheumatoid arthritis. The mean (range) duration of RA was 79 (2 to 243) months, and the mean (range) disease activity score was 6.3 (4.0 to 8.8). Compared with placebo, oral methotrexate was associated with a reduced tender joint count by 5.18 joints (95% credible interval [CrI], 4.07 to 6.28 joints). Compared with methotrexate, glucocorticoid (-2.54 joints; 95% CrI, -5.16 to 0.08 joints) and remaining drugs except cyclophosphamide (6.08 joints; 95% CrI, 0.44 to 11.66 joints) were associated with similar or lower tender joint counts. Conclusions and Relevance: This study's results support the present role of methotrexate as the primary reference conventional synthetic disease-modifying antirheumatic drug.

Effect of Routine Cytochrome P450 2D6 and 2C19 Genotyping on Antipsychotic Drug Persistence in Patients With Schizophrenia: A Randomized Clinical Trial.

Importance: Genetic polymorphism of genes encoding the drug metabolizing enzymes, cytochrome P450 2D6 and 2C19 (CYP2D6 and CYP2C19), is associated with treatment failure of and adverse reactions to psychotropic drugs. The clinical utility of routine CYP2D6 and CYP2C19 genotyping (CYP testing) is unclear. Objective: To estimate whether routine CYP testing effects the persistence of antipsychotic drug treatment. Design, Setting, and Participants: This single-masked, 3-group randomized clinical trial included patients aged 18 years or older who had been diagnosed within the schizophrenic spectrum (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes, F20-F29) and not previously genotyped. A total of 669 of 1406 potentially eligible patients from 12 psychiatric outpatient clinics in Denmark were approached between July 2008 and December 2009. Overall, 528 patients were genotyped and randomly allocated to 1 of 3 study groups or exclusion in a sequence of 1:1:1:3 using a predictive enrichment design, aiming to double the proportion of poor or ultrarapid metabolizers for CYP2D6 or CYP2C19. Outcome measurements were recorded at baseline and 1-year follow-up. Data analysis was performed in December 2012 and updated March 2019. Interventions: The trial included 2 intervention groups, where antipsychotic drug treatment was guided by either CYP test (CYP test-guided [CTG]) or structured clinical monitoring (SCM), in which adverse effects and factors influencing compliance were systematically recorded at least once quarterly, and 1 control group. Main Outcomes and Measures: Primary outcome was antipsychotic drug persistence, ie, days to first modification of the initial treatment. Secondary outcomes were number of drug and dose changes, adverse effects, and psychotic symptoms, ie, hallucinations and delusions. Results: A total of 528 participants were genotyped, and 311 (median [interquartile range {IQR} age, 41 [30-50] years; 139 [45%] women; median [IQR] duration of illness, 6 [3-13] years) were randomly allocated to 1 of 3 study groups. Overall, 61 participants (20%) were extreme metabolizers. There was no difference in antipsychotic drug persistence between the CTG group and the control group (hazard ratio [HR], 1.02; 95% CI, 0.71-1.45) or SCM and the control group (HR, 0.88; 95% CI, 0.61-1.26). Subanalyses among extreme metabolizers showed similar results (CTG: HR, 0.99; 95% CI, 0.48-2.03; SCM: HR, 0.93; 95% CI, 0.44-1.96). Conclusions and Relevance: The results of this randomized clinical trial do not support routine CYP testing in patients with schizophrenia. Trial Registration: ClinicalTrials.gov Identifier: NCT00707382.

A systematic review of observational studies of trifluridine/tipiracil (TAS-102) for metastatic colorectal cancer.

Background: The treatment options for patients with therapy refractory metastatic colorectal cancer (mCRC) are sparse. TAS-102 (FTD/TPI) is a new oral anti-tumour agent composed of a nucleoside analogue, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil, indicated for patients with mCRC who are refractory to standard therapies. This study summarizes published and unpublished experience with FTD/TPI in clinical practice settings. Patients and methods: The Medline/PubMed, Embase and Cochrane Library databases were searched to identify observational studies on FTD/TPI monotherapy for mCRC. Papers describing use of FTD/TPI monotherapy outside clinical trials in series of patients evaluable for effectiveness were eligible. The outcomes of interest were median progression free survival (mPFS), median overall survival (mOS) as well as mean PFS time restricted to six months (PFS6m) and mean OS time restricted to one year (OS1y). Results of the pooled analyses of observational studies were compared to the results of the Japanese phase II trial and the two phase III trials, RECOURSE and TERRA. Results: Seven published and two unpublished studies with 1008 patients from 64 centres were included for analysis. The pooled mPFS was 2.2 months (95% CI 2.1 to 2.3 months), and the pooled mOS was 6.6 months (95% CI 6.1 to 7.1 months). PFS6m was 2.9 months (95% CI 2.6 to 3.1 months) and OS1y was 6.8 (95% CI 6.0 to 7.5) months. While these results all reflect RECOURSE, the pooled mOS is lower than in the phase II trial and the OS1y is inferior to both the phase II trial and TERRA. Conclusion: This systematic review and a meta-analysis indicates that in real life settings, the survival benefit of FTD/TPI monotherapy in patients with therapy refractory mCRC reflects the outcomes in RECOURSE but is inferior to outcomes in the two Asian efficacy trials. What is already known TAS 102 (Lonsurf) is an oral fixed dose combination of trifluridine (FTD) and tipiracil (TPI) indicated as salvage-line treatment in patients with therapy refractory metastatic colorectal cancer (mCRC). A Japanese phase II trial and two phase III trials, RECOURSE and TERRA, demonstrated that FTD/TPI prolonged overall survival. What this study adds This systematic review and meta-analysis of real life data from 64 sites indicates that the effectiveness in daily clinical practice settings of FTD/TPI monotherapy in late stage mCRC reflects the outcomes in RECOURCE but is inferior to the outcomes in the Japanese phase II trial and TERRA.

Clinical Effects of a Pharmacist Intervention in Acute Wards - A Randomized Controlled Trial.

The purpose of the study was to investigate the clinical effect of a clinical pharmacist (CP) intervention upon admission to hospital on inpatient harm and to assess a potential educational bias. Over 16 months, 593 adult patients taking ≥4 medications daily were included from three Danish acute medicine wards. Patients were randomized to either the CP intervention or the usual care (prospective control). To assess a potential educational bias, a retrospective control group was formed by randomization. The CP intervention comprised medication history, medication reconciliation, medication review and entry of proposed prescriptions into the electronic prescribing system. The primary outcome of inpatient harm was identified using triggers from the Institute of Healthcare Improvement Global Trigger Tool. Harms were validated and rated for severity by two independent and blinded outcome panels. Secondary end-points were harms per patient, length of hospital stay, readmissions and 1-year mortality. Harm affected 11% of the patients in the intervention group compared to 17% in the combined control group, odds ratio (OR) 0.57 (CI 0.32-1.02, p = 0.06). The incidence of harm was similar in the intervention and prospective control groups, OR 0.80 (CI 0.40-1.59, p = 0.52) but occurred less frequently in the intervention than in the retrospective control group OR 0.46 (CI 0.25-0.85, p = 0.01). An educational bias from the intervention to the control group might have contributed to this negative outcome. In conclusion, the CP intervention at admission to hospital had no statistically significant effect on inpatient harm.

Does pharmacogenetic testing for CYP450 2D6 and 2C19 among patients with diagnoses within the schizophrenic spectrum reduce treatment costs?

The effect of pharmacogenetic testing for CYP450 2D6 and 2C19 on treatment costs have not yet been documented. This study used Danish patient registers to calculate healthcare costs of treating patients with diagnoses within the schizophrenic spectrum for 1 year with or without pharmacogenetic testing for polymorphisms in the genes for the CYP2D6 and CYP2C19 enzymes. In a randomized, controlled trial, stratified with respect to metabolizer genotype, 104 patients were assigned to treatment based on pharmacogenetic testing and 103 patients to treatment as usual. Random exclusion of extensive and intermediate metabolizers was used to increase the frequency of extreme metabolizers (poor metabolizers and ultrarapid metabolizers for CYP2D6) to 20% in both groups. Cost differences were analysed at several levels including (i) overall healthcare expenditure, (ii) psychiatric hospital cost (iii) nonpsychiatric hospital cost, (iv) primary care spending and (v) pharmaceuticals. Statistically significant differences in costs of psychiatric care dependent on metabolizer status were found between intervention groups. Pharmacogenetic testing significantly reduced costs among the extreme metabolizers (poor metabolizers and ultrarapid metabolizers) to 28%. Use of primary care services and pharmaceuticals was also affected by the intervention.This study confirms earlier findings that extreme metabolizers (poor and ultrarapid metabolizers) incur higher costs than similar patients with a normal metabolizer genotype. However, this study shows that these excess costs can be reduced by pharmacogenetic testing. Pharmacogenetic testing for CYP2D6 and CYP2C19 could thus be considered as a means of curtailing high psychiatric treatment costs among extreme metabolizers.

General practitioners' and hospital physicians' preference for morphine or oxycodone as first-time choice for a strong opioid: a National Register-based study.

The aim of this study was to characterize first-time oxycodone and morphine prescriptions in outpatients by type of prescriber and naivety in regard to strong opioids. All prescriptions for morphine and oxycodone in Denmark reported to the National Register of Medicinal Product Statistics in 2010 were analysed. If a patient had not had a prescription filled for the same drug within the last 2 years, the prescription was defined as a first-time prescription. Patients who had not received a prescription for strong opioids for 6 months prior to the date of redemption were classified as strong opioid naive. The odds ratio (OR) was calculated to investigate whether general practitioners (GPs) and hospital physicians had similar preferences for oxycodone over morphine for strong opioid-naive patients. We included 69,110 first-time prescriptions, of which 59,316 (86%) were for strong opioid-naive patients. Opioid-naive patients received 79% of the first-time prescriptions for morphine and 91% of the prescriptions for oxycodone. Hospital physicians had a greater preference for oxycodone over morphine than GPs (OR 1.34, 95% CI 1.29-1.39). However, GPs were responsible for approximately 61% of all first-time prescriptions for both oxycodone and morphine for strong opioid-naive patients. In conclusion, oxycodone is to a great extent prescribed as the first-choice strong opioid, and both GPs and hospital physicians seem to contribute to this prescribing pattern of strong opioids to outpatients.

Does the medication pattern reflect the CYP2D6 genotype in patients with diagnoses within the schizophrenic spectrum?

BACKGROUND: Cytochrome P450 2D6 enzyme (CYP2D6) is an important metabolic pathway for many antipsychotics. Its genetic polymorphism causes pharmacokinetic variability that might lead to adverse drug reactions or treatment failure unless countered by appropriate dose adjustments or shift to CYP2D6-independent antipsychotics. PURPOSE: To investigate the clinical impact of CYP2D6 genotype in patients with a diagnosis within the schizophrenic spectrum using medication pattern as proxy for therapeutic and side effect. METHODS: The study was conducted in patients genotyped during an inpatient stay (N = 576). Continuous antipsychotic, adjuvant, and anticholinergic drug regimens were registered retrospectively in a cross-sectional manner before genotyping. Antipsychotics were divided into CYP2D6 dependent and independent, and dose equivalents were calculated as chlorpromazine equivalents (CPZEq). RESULTS: Poor metabolizers and ultrarapid metabolizers were treated with significantly higher median CPZEq doses (625.8; inter quartile range [IQR], 460.4-926.7; and 550; IQR, 199.8-1049) than extensive metabolizers (EMs) and intermediate metabolizers (IMs) (384; IQR, 150-698; and 446; IQR, 150-800) (P = 0.018). Logistic regression showed no association between anticholinergic treatment and CYP2D6 genotype or concomitant treatment with CYP2D6 inhibitors (P = 0.79 and P = 0.46, respectively). CONCLUSIONS: Our results indicate that CYP2D6 genotype has no sufficient clinical impact that poor metabolizers and ultrarapid metabolizers are easily clinically identified with.

Hospital admission interviews are time-consuming with several interruptions.

INTRODUCTION: The admission interview is an important procedure to reduce medication errors. Studies indicate that physicians do not spend much time on the interview and that the major obstacles are lack of time and heavy workload. The aim of this study was to measure the time physicians spend on admission interviews and to describe factors that affect time consumption. MATERIAL AND METHODS: This time study was conducted at an acute medicine department. Physicians conducting admission interviews were observed, and time consumption was recorded. RESULTS: Fifty admission interviews were observed; they lasted an average of 45 (range 8-84) minutes. The effective time consumption was 32 (range 7-59) minutes. Fifteen (range 3-41) minutes were spent on actually interviewing and examining the patient and compiling the medication history. It took zero to five (mean 2.2) minutes to collect the medication history. The number of interruptions per interview was zero to nine (mean two); they were mostly caused by phone calls from physicians or nurses or by nurses asking for advice on problems with other patients. The mean duration of an interruption was 7.1 minutes. CONCLUSION: Physicians spend an average of 45 minutes on admission interviews and are interrupted up to nine times. Only a few minutes are spent on collecting the medication history. Though the quality of the interviews and the actual error rate were not assessed, the observed working conditions may imply a high potential for medication errors.

Adherence to national guidelines for initiation of antiretroviral regimens in HIV patients: a Danish nationwide study.

AIM: To determine the adherence to the national guidelines for start of highly active antiretroviral treatment (HAART) in HIV infected patients. METHODS: We used a Danish nationwide cohort of HIV infected patients to calculate the fraction of patients who in the period 1997-2006 started HAART according to the guidelines from The Danish Society of Infectious Diseases. We used Kaplan-Meier tables to estimate time from fulfilling the criteria for start of HAART to initiation of the treatment. Cox regression and logistic regression was used to identify risk factors for delayed initiation of treatment and chance of being included in clinical trials. RESULTS: The study included 3223 patients, 74% of whom initiated HAART in the study period. Ninety-four% fulfilled the criteria for start of HAART, with minor differences over calendar periods. Ninety-four% initiated a recommended regimen or were included in a clinical trial. Intravenous drug use predicted initiation of a non-recommended regimen and delay in start of HAART, while non-Caucasians were less likely to be included in clinical trials. CONCLUSIONS: In a Western world setting, the adherence to national guidelines for start of HAART can be high. We suggest that simplicity of the guidelines, centralization of treatment and involvement of local clinicians in the development of guidelines are of major importance for high adherence to treatment guidelines.