Cox selectivity and chemical subgroup of non-steroidal anti-inflammatory drugs and frequency of spontaneous reporting of hypersensitivity reactions

Background/Introduction: Use of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with many adverse events, including hypersensitivity reactions (HSRs), such as angioedema and urticaria. However, no studies have investigated whether cyclooxygenase (COX) enzyme selectivity and/or chemical subgroups are associated with a difference in HSRs. Objective/Aim: to describe and compare the frequency of HSRs among NSAIDs based on cyclooxygenase selectivity and chemical subgroups. Methods: A case/non-case study was performed using data from the World Health Organization global database of Individual Case Safety Report (ICSR), VigiBase, containing over 13 million ICSRs submitted by the participating member states enrolled under WHO's international drug monitoring program by June 2016. This study was nested among ICSRs where NSAIDs were a suspected drug. Cases were ICSRs mentioning HSRs (urticaria, angioedema, anaphylactic shock, anaphylactic reaction, anaphylactoid shock, and anaphylactoid reaction), whereas non-cases were all ICSRs without HSRs. Based on the ratio of inhibitory concentration 80% of COX-1/COX-2, NSAIDs were categorized into coxibs, non-coxib NSAIDs with COX-2 preference, NSAIDs with poor selectivity, and NSAIDs with unknown selectivity. Only ICSRs with complete information on age and sex, and NSAIDs with first market authorization from 1978 onward were included. RORs and 95% confidence intervals (95% CIs) to assess the association between NSAIDs and the reporting of HSRs were calculated using logistic regression analysis. Results: We identified 16,289 HSR cases and 160,319 non-cases among ICSRs involving NSAIDs. Non-coxib NSAIDs with COX-2 preference, NSAIDs with poor selectivity, and NSAIDs with unknown selectivity were all associated with an increased reporting of HSRs (age- and sexadjusted ROR 1.70, 95% CI 1.61-1.79, age- and sex-adjusted 2.19, 95% CI 2.11-2.77, and age- and sex-adjusted 1.26, 95% CI: 1.03-1.54, respectively) compared to coxibs. Conclusion: HSRs were more often reported for NSAIDs with poor selectivity, non-coxib NSAID with COX-2 preference, and NSAIDs with unknown selectivity compared to coxibs

Heterogeneity after harmonisation: a retrospective cohort study of bleeding and stroke risk after the introduction of direct oral anticoagulants in four Western European countries

Purpose: Database heterogeneity can impact effect estimates. Harmonisation provided by common protocols and common data models (CDMs) can increase the validity of pharmacoepidemiologic research. In a case study measuring the changes in the safety and effectiveness of stroke prevention therapy after the introduction of direct oral anticoagulants (DOACs), we performed an international comparison. Methods: Using data from Stockholm, Denmark, Scotland and Norway, harmonised with a common protocol and CDM, two calendar-based cohorts were created: 2012 and 2017. Patients with a diagnosis code of atrial fibrillation 5 years preceding the 1-year cohort window were included. DOAC, vitamin K antagonist and aspirin treatment were assessed in the 6 months prior to the start of each year while strokes and bleeds were assessed during the year. A Poisson regression generated incidence rate ratios (IRRs) to compare outcomes from 2017 to 2012 adjusted for changes in individual-level baseline characteristics. Results: In 280 359 patients in the 2012 cohort and 356 779 in the 2017 cohort, treatment with OACs increased on average from 45% to 65%, while treatment with aspirin decreased from 30% to 10%. In all countries except Scotland, there were decreases in the risk of stroke and no changes in bleeding risk, after adjustment for changes in baseline characteristics. In Scotland, major bleeding (IRR 1.09, 95% confidence interval [CI] [1.00; 1.18]) and intracranial haemorrhage (IRR 1.31, 95% CI [1.13; 1.52]) increased from 2012 to 2017. Conclusions: Stroke prevention therapy improved from 2012 to 2017 with a corresponding reduction in stroke risk without increasing the risk of bleeding in all countries, except Scotland. The heterogeneity that remains after methodological harmonisation can be informative of the underlying population and database

Bias in observational studies on the effectiveness of in hospital use of hydroxychloroquine in COVID-19

Purpose: During the first waves of the coronavirus pandemic, evidence on potential effective treatments was urgently needed. Results from observational studies on the effectiveness of hydroxychloroquine (HCQ) were conflicting, potentially due to biases. We aimed to assess the quality of observational studies on HCQ and its relation to effect sizes. Methods: PubMed was searched on 15 March 2021 for observational studies on the effectiveness of in-hospital use of HCQ in COVID-19 patients, published between 01/01/2020 and 01/03/2021 on. Study quality was assessed using the ROBINS-I tool. Association between study quality and study characteristics (journal ranking, publication date, and time between submission and publication) and differences between effects sizes found in observational studies compared to those found in RCTs, were assessed using Spearman's correlation. Results: Eighteen of the 33 (55%) included observational studies were scored as critical risk of bias, eleven (33%) as serious risk and only four (12%) as moderate risk of bias. Biases were most often scored as critical in the domains related to selection of participants (n = 13, 39%) and bias due to confounding (n = 8, 24%). There were no significant associations found between the study quality and the characteristics nor between the study quality and the effect estimates. Discussion: Overall, the quality of observational HCQ studies was heterogeneous. Synthesis of evidence of effectiveness of HCQ in COVID-19 should focus on RCTs and carefully consider the added value and quality of observational evidence

Recruitment of participants through community pharmacies for a pharmacogenetic study of antihypertensive drug treatment

Objective To describe the design, recruitment and baseline characteristics of participants in a community pharmacy based pharmacogenetic study of antihypertensive drug treatment. Setting: Participants enrolled from the population-based Pharmaco-Morbidity Record Linkage System. Method We designed a nested case-control study in which we will assess whether specific genetic polymorphisms modify the effect of antihypertensive drugs on the risk of myocardial infarction. In this study, cases (myocardial infarction) and controls were recruited through community pharmacies that participate in PHARMO. The PHARMO database comprises drug dispensing histories of about 2,000,000 subjects from a representative sample of Dutch community pharmacies linked to the national registrations of hospital discharges. Results In total we selected 31010 patients (2777 cases and 28233 controls) from the PHARMO database, of whom 15973 (1871 cases, 14102 controls) were approached through their community pharmacy. Overall response rate was 36.3% (n = 5791, 794 cases, 4997 controls), whereas 32.1% (n = 5126, 701 cases, 4425 controls) gave informed consent to genotype their DNA. As expected, several cardiovascular risk factors such as smoking, body mass index, hypercholesterolemia, and diabetes mellitus were more common in cases than in controls. Conclusion Furthermore, cases more often used beta-blockers and calcium-antagonists, whereas controls more often used thiazide diuretics, ACE-inhibitors, and angiotensin-II receptor blockers. We have demonstrated that it is feasible to select patients from a coded database for a pharmacogenetic study and to approach them through community pharmacies, achieving reasonable response rates and without violating privacy rules

Rivaroxaban was found to be noninferior to warfarin in routine clinical care: A retrospective noninferiority cohort replication study

Purpose: To compare the effectiveness and safety of a drug in daily practice with the outcomes of a target non-inferiority trial by rigorously mimickingin an observational study the trial's design features. Methods: This cohort study was conducted using the British Clinical Practice Research Datalink (CPRD) to emulate the ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial. Patients with atrial fibrillation who were newly prescribed (>=12 months of no use) either rivaroxaban or warfarinfrom October 2008 to December 2017 were included. Non-inferiority of rivaroxaban to warfarin in the prevention of stroke or systemic embolism was assessed in different analysis populations (intention-to-treat [ITT], per-protocol [PP], and as-treated populations) using a hazardratio (HR) of 1.46 as the non-inferiority margin. Major bleeding (safety outcome) was also assessed and compared to that of the target trial. All outcomes were analyzed using Cox-proportional hazard analyses. Results: We included 25,473 incident users of rivaroxaban (n=4,008) or warfarin(n=21,465). Similar to the trial, non-inferiority in the primary out come was demonstrated in all three analysis populations: HR=1.04 (95%CI 0.84 to 1.30) (ITT), HR=0.98 (95%CI 0.70 to 1.38) (PP), and HR=1.11 (95%CI 0.86 to 1.42) (as-treated). Risk of major bleeding was also similar to the target trial. Conclusion: The results of this study provide supportive evidence to the effectiveness of rivaroxaban and adds knowledge on the usefulness of emulating a non-inferiority trial to assess drug effectiveness

Rivaroxaban was found to be noninferior to warfarin in routine clinical care: A retrospective noninferiority cohort replication study

PURPOSE: To compare the effectiveness and safety of a drug in daily practice with the outcomes of a target non-inferiority trial by rigorously mimickingin an observational study the trial's design features. METHODS: This cohort study was conducted using the British Clinical Practice Research Datalink (CPRD) to emulate the ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial. Patients with atrial fibrillation who were newly prescribed (>=12 months of no use) either rivaroxaban or warfarinfrom October 2008 to December 2017 were included. Non-inferiority of rivaroxaban to warfarin in the prevention of stroke or systemic embolism was assessed in different analysis populations (intention-to-treat [ITT], per-protocol [PP], and as-treated populations) using a hazardratio (HR) of 1.46 as the non-inferiority margin. Major bleeding (safety outcome) was also assessed and compared to that of the target trial. All outcomes were analyzed using Cox-proportional hazard analyses. RESULTS: We included 25,473 incident users of rivaroxaban (n=4,008) or warfarin(n=21,465). Similar to the trial, non-inferiority in the primary out come was demonstrated in all three analysis populations: HR=1.04 (95%CI 0.84 to 1.30) (ITT), HR=0.98 (95%CI 0.70 to 1.38) (PP), and HR=1.11 (95%CI 0.86 to 1.42) (as-treated). Risk of major bleeding was also similar to the target trial. CONCLUSION: The results of this study provide supportive evidence to the effectiveness of rivaroxaban and adds knowledge on the usefulness of emulating a non-inferiority trial to assess drug effectiveness

The reporting of studies conducted using observational routinely collected health data statement for pharmacoepidemiology (RECORD-PE).

In pharmacoepidemiology, routinely collected data from electronic health records (including primary care databases, registries, and administrative healthcare claims) are a resource for research evaluating the real world effectiveness and safety of medicines. Currently available guidelines for the reporting of research using non-randomised, routinely collected data—specifically the REporting of studies Conducted using Observational Routinely collected health Data (RECORD) and the Strengthening the Reporting of OBservational studies in Epidemiology (STROBE) statements—do not capture the complexity of pharmacoepidemiological research. We have therefore extended the RECORD statement to include reporting guidelines specific to pharmacoepidemiological research (RECORD-PE). This article includes the RECORD-PE checklist (also available on www.record-statement.org) and explains each checklist item with examples of good reporting. We anticipate that increasing use of the RECORD-PE guidelines by researchers and endorsement and adherence by journal editors will improve the standards of reporting of pharmacoepidemiological research undertaken using routinely collected data. This improved transparency will benefit the research community, patient care, and ultimately improve public health

Determinants of DNA yield and purity collected with buccal cell samples

Buccal cells are an important source of DNA in epidemiological studies, but little is known about factors that influence amount and purity of DNA. We assessed these factors in a self-administered buccal cell collection procedure, obtained with three cotton swabs. In 2,451 patients DNA yield and in 1,033 patients DNA purity was assessed. Total DNA yield ranged from 0.08 to 1078.0 μg (median 54.3 μg; mean 82.2 μg ± SD 92.6). The median UV 260:280 ratio, was 1.95. Samples from men yielded significantly more DNA (median 58.7 μg) than those from women (median 44.2 μg). Diuretic drug users had significantly lower purity (median 1.92) compared to other antihypertensive drug users (1.95). One technician obtained significantly lower DNA yields. Older age was associated with lower DNA purity. In conclusion, DNA yield from buccal swabs was higher in men and DNA purity was associated with age and the use of diuretics