Is There an Increased Risk of Hepatotoxicity with Metamizole? A Comparative Cohort Study in Incident Users.

INTRODUCTION: The analgesic metamizole, which has been withdrawn from the market in several countries due to the risk of agranulocytosis but is still available on the market in Germany and some other countries, has been associated with liver injury in published case reports; however, epidemiological studies on the risk of liver injury are limited. OBJECTIVE: The aim of this study was to compare the risk of liver injury up to 270 days after the first start of treatment with metamizole with the corresponding risk in patients starting treatment with paracetamol, using a retrospective cohort incident user design. METHODS: The first prescription for either metamizole or paracetamol in the Intercontinental Medical Statistics (IMS)® Disease Analyzer Germany database during the study period (2009-2018) was identified in patients with at least 365 days of observation and no prior diagnosis of liver events, cancer or HIV, or treatment within the last 6 months with hepatotoxic drugs typically administered for chronic conditions. Each patient was followed for specific liver events for 90 days after the prescription. In case of a new prescription within 90 days, a new 90-day observation period started, up to a maximum of 270 days. Cox regression was used to compare the risk of liver injury in the two groups. RESULTS: Metamizole was associated with a higher risk of liver injury compared with paracetamol (adjusted hazard ratio 1.69, 95% confidence interval 1.46-1.97). Sensitivity analyses were performed to evaluate the robustness of these findings. In all the sensitivity analyses, metamizole was still associated with a higher risk of liver injury, including an analysis where naproxen was used as a comparator instead of paracetamol. CONCLUSIONS: Results from this study support previous studies suggesting that metamizole is associated with a significant risk of liver injury. Nevertheless, a possible impact of residual confounding cannot be excluded.

External validation of ADO, DOSE, COTE and CODEX at predicting death in primary care patients with COPD using standard and machine learning approaches.

BACKGROUND: Several models for predicting the risk of death in people with chronic obstructive pulmonary disease (COPD) exist but have not undergone large scale validation in primary care. The objective of this study was to externally validate these models using statistical and machine learning approaches. METHODS: We used a primary care COPD cohort identified using data from the UK Clinical Practice Research Datalink. Age-standardised mortality rates were calculated for the population by gender and discrimination of ADO (age, dyspnoea, airflow obstruction), COTE (COPD-specific comorbidity test), DOSE (dyspnoea, airflow obstruction, smoking, exacerbations) and CODEX (comorbidity, dyspnoea, airflow obstruction, exacerbations) at predicting death over 1-3 years measured using logistic regression and a support vector machine learning (SVM) method of analysis. RESULTS: The age-standardised mortality rate was 32.8 (95%CI 32.5-33.1) and 25.2 (95%CI 25.4-25.7) per 1000 person years for men and women respectively. Complete data were available for 54879 patients to predict 1-year mortality. ADO performed the best (c-statistic of 0.730) compared with DOSE (c-statistic 0.645), COTE (c-statistic 0.655) and CODEX (c-statistic 0.649) at predicting 1-year mortality. Discrimination of ADO and DOSE improved at predicting 1-year mortality when combined with COTE comorbidities (c-statistic 0.780 ADO + COTE; c-statistic 0.727 DOSE + COTE). Discrimination did not change significantly over 1-3 years. Comparable results were observed using SVM. CONCLUSION: In primary care, ADO appears superior at predicting death in COPD. Performance of ADO and DOSE improved when combined with COTE comorbidities suggesting better models may be generated with additional data facilitated using novel approaches.

Investigating Real-World Clopidogrel Pharmacogenetics in Stroke Using a Bioresource Linked to Electronic Medical Records.

Clopidogrel efficacy is influenced by genetic variation of cytochrome P450 (CYP)2C19, however, few studies have considered patients who have a stroke. We used electronic medical records (EMRs) linked to a bioresource to examine real-world implications of clopidogrel pharmacogenetics in stroke. Patients hospitalized for any arterial thrombo-occlusive (ATO) event who subsequently redeemed clopidogrel prescriptions in the community were entered into the study (n = 651). During 24-month follow-up, the primary endpoint of recurrent ATO or death occurred in 299 patients (46%). CYP2C19*2 loss-of-function allele carriers had an increased risk (hazard ratio (HR) = 1.29; 95% confidence interval (CI) = 1.04-1.59; P = 0.019). In the ischemic stroke subgroup (n = 94), the estimate of risk was greater (HR = 2.23; 95% CI = 1.17-4.24; P = 0.015), which was further supported by a meta-analysis of available studies. In conclusion, we have demonstrated the clinical impact of CYP2C19*2 on clopidogrel efficacy using a purely EMR approach. This suggests that the risk in the ischemic stroke population may be particularly high.

Quantifying the real life risk profile of inhaled corticosteroids in COPD by record linkage analysis.

BACKGROUND: Inhaled corticosteroids (ICS), especially when prescribed in combination with long-acting ß2 agonists have been shown to improve COPD outcomes. Although there is consistent evidence linking ICS with adverse effects such as pneumonia, the complete risk profile is unclear with conflicting evidence on any association between ICS and the incidence or worsening of existing diabetes, cataracts and fractures. We investigated this using record linkage in a Dundee COPD population. METHODS: A record linkage study linking COPD and diabetes datasets with prescription, hospitalisation and mortality data via a unique Community Health Index (CHI) number. A Cox regression model was used to determine the association between ICS use and new diabetes or worsening of existing diabetes and hospitalisations for pneumonia, fractures or cataracts after adjusting for potential confounders. A time dependent analysis of exposure comparing time on versus off ICS was used to take into account patients changing their exposure status during follow-up and to prevent immortal time bias. RESULTS: 4305 subjects (3243 exposed to ICS, total of 17,229 person-years of exposure and 1062 non exposed, with a follow-up of 4,508 patient-years) were eligible for the study. There were 239 cases of new diabetes (DM) and 265 cases of worsening DM, 550 admissions for pneumonia, 288 hospitalisations for fracture and 505 cataract related admissions. The hazard ratio for the association between cumulative ICS and outcomes were 0.70 (0.43-1.12), 0.57 (0.24-1.37), 1.38 (1.09-1.74), 1.08 (0.73-1.59) and 1.42 (1.07-1.88) after multivariate analysis respectively. CONCLUSION: The use of ICS in our cohort was not associated with new onset of diabetes, worsening of existing diabetes or fracture hospitalisation. There was however an association with increased cataracts and pneumonia hospitalisations.

Up-titration of allopurinol in patients with gout.

OBJECTIVES: European League against Rheumatism (EULAR) gout management guidelines recommend achieving a target urate level <6.0 mg/dL (<357 µmol/L). Allopurinol is the most widely used urate-lowering therapy; however, many gout patients who are prescribed allopurinol do not have urate levels optimally controlled. The objective of this analysis was to review the efficacy and tolerability of allopurinol up-titration in achieving the EULAR target levels. METHOD: The Febuxostat versus Allopurinol Streamlined Trial (FAST) is an ongoing multi-centre study comparing the cardiovascular safety of febuxostat and allopurinol (target recruitment: 5706 patients). Recruited patients were already taking allopurinol and the protocol required up-titration of daily allopurinol dose, in 100 mg increments, to achieve the EULAR urate target level prior to randomisation. We reviewed pre-randomisation data from the first 400 recruited and subsequently randomised FAST patients. RESULTS: Of 400 patients, 144 (36%) had urate levels ≥357 µmol/L at screening and required allopurinol up-titration. Higher urate levels were significantly associated with lower allopurinol dose, male sex, increased BMI, increased alcohol intake and diuretic use. Mean fall in urate levels after a single 100-mg dose increase was 71 µmol/L. The number of up-titrations required ranged from one to five (median = 1) with 65% of patients controlled after one 100-mg up-titration. Overall, 97% of up-titrated patients achieved target urate levels with median final allopurinol dose of 300 mg daily. Side effects and complications of up-titration were minimal. CONCLUSION: Overall, 36% of FAST patients were not at target urate levels and required up-titration. Allopurinol up-titration was effective in achieving urate target levels and was generally well tolerated by patients.

Fasciola hepatica is associated with the failure to detect bovine tuberculosis in dairy cattle.

Bovine tuberculosis (BTB) is a significant and intractable disease of cattle caused by Mycobacterium bovis. In the United Kingdom, despite an aggressive eradication programme, the prevalence of BTB is increasing with an unexplained, exponential rise in cases year on year. Here we show in a study involving 3,026 dairy herds in England and Wales that there is a significant negative association between exposure to the common, ubiquitous helminth parasite, Fasciola hepatica and diagnosis of BTB. The magnitude of the single intradermal comparative cervical tuberculin test used to diagnose BTB is reduced in cattle experimentally co-infected with M. bovis and F. hepatica. We estimate an under-ascertainment rate of about one-third (95% confidence interval 27-38%) among our study farms, in the hypothetical situation of no exposure to F. hepatica. This finding may in part explain the continuing spread of BTB and the failure of the current eradication programme in the United Kingdom.

Tacit and encoded knowledge in the use of standardised outcome measures in multidisciplinary team decision making: a case study of in-patient neurorehabilitation.

This paper explores how multidisciplinary teams (MDTs) balance encoded knowledge, in the form of standardised outcome measurement, with tacit knowledge, in the form of intuitive judgement, clinical experience and expertise, in the process of clinical decision making. The paper is based on findings from a qualitative case study of a multidisciplinary in-patient neurorehabilitation team in one UK NHS trust who routinely collected standardised outcome measures. Data were collected using non-participant observation of 16 MDT meetings and semi-structured interviews with 11 practitioners representing different professional groups. Our analysis suggests that clinicians drew on tacit knowledge to supplement, adjust or dismiss 'the scores' in making judgements about a patients' likely progress in rehabilitation, their change (or lack of) during therapy and their need for support on discharge. In many cases, the scores accorded with clinicians' tacit knowledge of the patient, and were used to reinforce this opinion, rather than determine it. In other cases, the scores, in particular the Barthel Index, provided a partial picture of the patient and in these circumstances, clinicians employed tacit knowledge to fill in the gaps. In some cases, the scores and tacit knowledge diverged and clinicians preferred to rely on their clinical experience and intuition and adjusted or downplayed the accuracy of the scores. We conclude that there are limits to the advantages of quantifying and standardising assessments of health within routine clinical practice and that standardised outcome measures can support, rather than determine clinical judgement. Tacit knowledge is essential to produce and interpret this form of encoded knowledge and to balance its significance against other information about the patient in making decisions about patient care.

The use of patient reported outcome measures in routine clinical practice: lack of impact or lack of theory?

This paper applies a theory-driven approach to explore why the use of patient-reported outcome (PRO) measures in clinical practice, in particular, health-related quality of life (HRQoL) instruments, has little or no apparent influence on clinical decision making. A theory-driven approach involves combining knowledge of whether and how an intervention works. It is argued that such an approach is currently lacking within the literature evaluating the effectiveness of feeding back HRQoL information to clinicians. The paper identifies a number of mechanisms that might give rise to the expected outcomes that are currently implicit within the design of the intervention and hypotheses specified within the trials evaluating the use of HRQoL measures in clinical practice. It then examines how far current clinical practice matches these mechanisms and in doing so, a number of possible explanations for the lack of impact of HRQoL on clinical decision making are reviewed. The influence of HRQoL information on clinical decision making depends on a large number of factors related to the design of the intervention, patients' and clinicians' desire to discuss HRQoL issues within the consultation and the legitimacy that clinicians give to HRQoL instruments. To date, knowledge of how the feedback of HRQoL information to clinicians might improve doctor-patient communication or clinical decision making has yet to sufficiently inform an assessment of whether these aspects of patient care are improved. The paper concludes by specifying how the feedback of HRQoL information to clinicians might be modified to maximise its impact on clinical decision making.