Scientific
publications

PURPOSE: After regulatory restrictions for terfenadine and astemizole in '90s, only scarce evidence on proarrhythmic potential of antihistamines has been published. We evaluate the risk of ventricular tachyarrhythmia (VA) related to the use of individual antihistamines. METHODS: A matched case-control study nested in a cohort of new users of antihistamines was conducted within the EU-funded ARITMO project. Data on 1997-2010 were retrieved from seven healthcare databases: AARHUS (Denmark), GEPARD (Germany), HSD and ERD (Italy), PHARMO and IPCI (Netherlands) and THIN (UK). Cases of VA were selected and up to 100 controls were matched to each case. The odds ratio (OR) of current use for individual antihistamines (AHs) was estimated using conditional logistic regression. RESULTS: For agents largely used to prevent allergic symptoms, such as cetirizine, levocetirizine, loratadine, desloratadine and fexofenadine, we found no VA risk. A statistically significant, increased risk of VA was found only for current use of cyclizine in the pooled analysis (ORadj, 5.3; 3.6-7.6) and in THIN (ORadj, 5.3; 95% CI, 3.7-7.6), for dimetindene in GEPARD (ORadj, 3.9; 1.1-14.7) and for ebastine in GEPARD (ORadj, 3.3; 1.1-10.8) and PHARMO (ORadj, 4.6; 1.3-16.2). CONCLUSIONS: The risk of VA associated with a few specific antihistamines could be ascribable to heterogeneity in pattern of use or in receptor binding profile.

PURPOSE: Newly approved novel drugs in Europe receive a black triangle label to promote pharmacovigilance. With growing momentum for earlier drug approvals and reliance on real-world evidence, we studied if the black triangle label promotes more judicious prescribing. METHODS: We examined whether general practitioners prescribed escitalopram, tadalafil, and vardenafil with a black triangle more cautiously than the same or similar drugs without a black triangle in The Health Improvement Network (UK). We performed interrupted time-series analyses to estimate changes in new prescription rates and nested case-control studies to compare characteristics of new users before and after removal of a black triangle. RESULTS: Prescribing rates to the 33 441 new users of these new drugs were highest shortly after initial approval and declined subsequently; there were no increases in rates of new prescriptions after a black triangle's removal (new prescriptions/million/month postlabel: escitalopram -1.5 [95% CI, -1.9 to -1.2]; tadalafil and vardenafil: -0.1 [95% CI, -0.6 to 0.4]). Among drugs in the same class, loss of a patent had more impact on prescribing rates than loss of a black triangle. People who began taking black triangle drugs were less likely to be young or to have multiple comorbidities or recent hospitalization compared with those starting the same drugs after the label's removal. However, these differences generally reflected secular trends seen also in similar, unlabeled medicines. CONCLUSIONS: Accelerated drug approvals could cause more uncertainty about drug effectiveness and safety, but specific labeling of newly approved medicines is unlikely to promote more judicious prescribing.

BACKGROUND: Hydroxychloroquine and chloroquine may reduce the risk of cancer as they inhibit autophagy, in particular, in people with connective tissue diseases. METHODS: The hazard ratios of cancers, metastases, and death were assessed in adults with connective tissue diseases prescribed hydroxychloroquine/chloroquine for at least 1 year in comparison with unexposed individuals with the same underlying conditions. A competing risk survival regression analysis was performed. Data were extracted from the Health Improvement Network UK primary care database. RESULTS: Eight thousand nine hundred and ninety-nine individuals exposed to hydroxychloroquine (98.6%) or chloroquine (1.4%) and 24,118 unexposed individuals were included in the study (median age: 56 [45-66] years, women: 76.8%). When compared to the unexposed group, individuals exposed to hydroxychloroquine/chloroquine were not at lower risk of non-skin cancers (adjusted sub-distribution hazard ratio [sHR]: 1.04 [0.92-1.18], =0.54), hematological malignancies (adjusted sHR: 1.00 [0.73-1.38], =0.99), or skin cancers (adjusted sHR: 0.92 [0.78-1.07], =0.26). The risk of metastasis was not significantly different between the two groups. However, it was significantly lower during the exposure period when compared with the unexposed (adjusted sHR: 0.64 [0.44-0.95] for the overall population and 0.61 [0.38-1.00] for those diagnosed with incident cancers). The risk of death was also significantly lower in those exposed to hydroxychloroquine/chloroquine (adjusted HR: 0.90 [0.81-1.00] in the overall population and 0.78 [0.64-0.96] in those diagnosed with incident cancer). CONCLUSION: Individuals on long-term exposure to hydroxychloroquine/chloroquine are not at lower risk of cancer. However, hydroxychloroquine/chloroquine may lower the risk of metastatic cancer and death.

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OBJECTIVES: Recent studies have shown an increase in both cardiovascular and all-cause mortality in ankylosing spondylitis (AS). We examined the potential survival benefit of statin use in AS within a general population context. METHODS: We performed an incident user cohort study with time-stratified propensity score matching using a UK general population database between 1 January 2000 and 31 December 2014. To account for potential confounders, we compared propensity score-matched cohorts of statin initiators and non-initiators using 1-year cohort accrual blocks. The variables used to create the propensity score model included disease duration, body mass index, lifestyle factors, comorbidities and medication use. RESULTS: Using unmatched AS cohorts, statin initiators (n=1430) showed a 43% higher risk of mortality than non-initiators (n=1430) (HR=1.43; 95% CI 1.12 to 1.84). After propensity score matching, patients with AS who initiated statins (n=1108) had 96 deaths, and matched non-initiators (n=1108) had 134 deaths over a mean follow-up of 5.3 and 5.1 years, respectively. This corresponded to mortality rates of 16.5 and 23.8 per 1000 person-years (PY), respectively, resulting in an HR of 0.63 (95% CI 0.46 to 0.85) and an absolute mortality rate difference of 7.3 deaths per 1000 PY (95% CI 2.1 to 12.5). CONCLUSION: This general population-based cohort study suggests that statin initiation is associated with a substantially lower risk of mortality among patients with AS. The magnitude of the inverse association appears to be larger than that observed in randomised trials of the general population and in population-based cohort studies of patients with rheumatoid arthritis.

OBJECTIVE: To determine whether patients with paroxysmal atrial fibrillation (AF) are less likely to be treated with anticoagulants than patients with persistent/permanent AF and to investigate trends in treatment between 2000 and 2015. UK and European guidelines recommend that anticoagulants are offered to all patients with AF at increased risk of stroke, irrespective of AF type. METHODS: Sixteen sequential cross-sectional analyses from 2000 to 2015 were carried out with index dates on 1st of May each year. The data source was primary care data from 648 practices across the UK contributing to The Health Improvement Network database. All patients with a diagnosis of AF aged ≥35 years and registered for at least 1 year were included. The main outcome measure was prescription of anticoagulant medication. RESULTS: The proportion of patients with AF with a diagnosis of paroxysmal AF increased from 7.4% (95% CI 7.0 to 7.8) in 2000 to 14.0% (95% CI 13.7 to 14.3) in 2015. Among patients with a CHADS score of ≥1, between 2000 and 2015 the proportion prescribed anticoagulants increased from 18.8% (95% CI 16.4 to 21.4) to 56.2% (95% CI 55.0 to 57.3) and from 34.2% (95% CI 33.3 to 35.0) to 69.4% (95% CI 68.9 to 69.8) in patients with paroxysmal and other (persistent/permanent) AF, respectively; RR for treatment of patients with paroxysmal AF compared with patients with other AF increased from 0.48 (95% CI 0.42 to 0.55) to 0.76 (95% CI 0.74 to 0.77). Adjusting for age, sex, Townsend score and presence or absence of contraindications had little effect on the results. CONCLUSIONS: In 2000, eligible patients with paroxysmal AF were half as likely to be treated with anticoagulants as patients with other AF; this has improved over time, but in 2015, eligible patients with paroxysmal AF were still around 20% less likely to be prescribed anticoagulant medication.

Pulmonary rehabilitation is recommended for patients with COPD to improve physical function, breathlessness and quality of life. Using The Health Information Network (THIN) primary care database in UK, we compared the demographic and clinical parameters of patients with COPD in relation to coding of pulmonary rehabilitation, and to investigate whether there is a survival benefit from pulmonary rehabilitation. We identified patients with COPD, diagnosed from 2004 and extracted information on demographics, pulmonary rehabilitation and clinical parameters using the relevant Read codes. Thirty six thousand one hundred and eighty nine patients diagnosed with COPD were included with a mean (SD) age of 67 (11) years, 53% were male and only 9.8% had a code related to either being assessed, referred, or completing pulmonary rehabilitation ever. Younger age at diagnosis, better socioeconomic status, worse dyspnoea score, current smoking, and higher comorbidities level are more likely to have a record of pulmonary rehabilitation. Of those with a recorded MRC of 3 or worse, only 2057 (21%) had a code of pulmonary rehabilitation. Survival analysis revealed that patients with coding for pulmonary rehabilitation were 22% (95% CI 0.69-0.88) less likely to die than those who had no coding. In UK THIN records, a substantial proportion of eligible patients with COPD have not had a coded pulmonary rehabilitation record. Survival was improved in those with PR record but coding for other COPD treatments were also better in this group. GP practices need to improve the coding for PR to highlight any unmet need locally. CHRONIC LUNG DISEASE: ROLLING OUT THE REHAB: Analysis of recent UK data suggests that more patients with chronic lung disease could benefit from lung rehabilitation programmes. During pulmonary rehabilitation (PR), patients with chronic obstructive pulmonary disease (COPD) work with specialists to learn exercises and optimise breathing techniques. The programmes are recommended under current guidelines, particularly for patients with a high breathlessness score. Despite this, when Charlotte Bolton and co-workers at the University of Nottingham analysed 36,189 patient primary care records gathered since 2004, they found only 9.8% of COPD patients had ever had a coded record of being assessed, referred for, or undertaken PR. Those patients who completed PR were 22% less likely to die that those who didn't, although appeared they had also received better overall COPD care. Current smokers, those suffering from co-morbidities and younger patients were more likely to receive PR than other patient groups.