Unintended impact of pharmacovigilance regulatory interventions: A systematic review.

AIMS: Studies assessing the impact of pharmacovigilance regulatory interventions often focus on the expected (or intended) outcomes, while any possible unintended impact may be overlooked. The update of the Good Pharmacovigilance Practice guideline in 2017 elaborated on impact assessment, emphasizing the need also to assess possible unintended impact. This systematic literature review investigated how often the unintended impact of regulatory interventions was considered in publications of studies investigating pharmacovigilance regulatory interventions in Europe. METHODS: We conducted a systematic review of the literature on MEDLINE and EMBASE from 1 January 2012 to 28 February 2022 to identify publications that investigated the impact of regulatory interventions in Europe. The primary outcome of the study was the number of publications reporting assessments of unintended impact. In addition, we studied the characteristics of these publications, including the type of outcomes assessed, the analytical methods applied and the type of data used. RESULTS: In total, 96 publications were included in the analysis. The unintended impact of pharmacovigilance regulatory interventions was investigated in 23 of 96 publications (24%). The drug classes most frequently studied in the publications assessing unintended impact of regulatory interventions were oral glucose-lowering drugs (n = 6, 26%), opioids (n = 4, 17%), antidepressants (n = 4, 17%) and antipsychotics (n = 3, 13%). The reported methods to assess the unintended impact were interrupted time series (n = 10, 43%) and descriptive statistics with or without significance testing (n = 2 [9%] and n = 9 [39%], respectively). The outcomes selected for unintended impact assessments included the use of other drugs (n = 16, 70%), health outcomes (n = 8, 35%) and behavioural changes (n = 4, 17%). Most of the publications reported on the use of electronic health record databases (n = 13, 57%) or claims databases (n = 13, 57%), while registries were used in 4 publications (17%). CONCLUSION: The unintended impact of pharmacovigilance regulatory interventions was reported in only a quarter of identified publications. There was no apparent increase in attention to unintended impact assessments after the update of the Good Pharmacovigilance Practice guidelines.

COVID-19-related medicine utilization study in pregnancy: The COVI-PREG cohort.

AIM: The objective of this study was to describe the use of COVID-19-related medicines during pregnancy and their evolution between the early/late periods of the pandemic. METHODS: Pregnant women who tested positive for SARS-CoV-2 from March 2020 to July 2021 were included using the COVI-PREG registry. Exposure to the following COVID-19-related medicines was recorded: antibiotics, antivirals, hydroxychloroquine, corticosteroids, anti-interleukin-6 and immunoglobulins. We described the prevalence of medicines used, by trimester of pregnancy, maternal COVID-19 severity level and early/late period of the pandemic (before and after 1 July 2020). FINDINGS: We included 1964 pregnant patients who tested positive for SARS-CoV-2. Overall, 10.4% (205/1964) received at least one COVID-19-related medicine including antibiotics (8.6%; 169/1694), corticosteroids (3.2%; 62/1964), antivirals (2.0%; 39/1964), hydroxychloroquine (1.4%; 27/1964) and anti-interleukin-6 (0.3%; 5/1964). The use of at least one COVID-19-related medicine was 3.1% (12/381) in asymptomatic individuals, 4.2% (52/1233) in outpatients, 19.7% (46/233) in inpatients without oxygen, 72.1% (44/61) in those requiring standard oxygen, 95.7% (22/23) in those requiring high flow oxygen, 96.2% (25/26) in patients who required intubation and 57.1% (4/7) among patients who died. The proportion who received medicines to treat COVID-19 was higher before than after July 2020 (16.7% vs. 7.7%). Antibiotics, antivirals and hydroxychloroquine had lower rates of use during the late period. CONCLUSION: Medicine use in pregnancy increased with disease severity. The trend towards increased use of corticosteroids seems to be aligned with changing guidelines. Evidence is still needed regarding the effectiveness and safety of COVID-19-related medicines in pregnancy.

A Genome-Wide Association Study of Cutaneous Squamous Cell Carcinoma among European Descendants.

BACKGROUND: No GWAS on the risk of cutaneous squamous cell carcinoma (SCC) has been published. We conducted a multistage genome-wide association study (GWAS) to identify novel genetic loci for SCC. METHODS: The study included 745 SCC cases and 12,805 controls of European descent in the discovery stage and 531 SCC cases and 551 controls of European ancestry in the replication stage. We selected 64 independent loci that showed the most significant associations with SCC in the discovery stage (linkage disequilibrium r(2) < 0.4) for replication. RESULTS: Rs8063761 in the DEF8 gene on chromosome 16 showed the strongest association with SCC (P = 1.7 × 10(-9) in the combined set; P = 1.0 × 10(-6) in the discovery set and P = 4.1 × 10(-4) in the replication set). The variant allele of rs8063761 (T allele) was associated with a decreased expression of DEF8 (P = 1.2 × 10(-6)). Besides, we validated four other SNPs associated with SCC in the replication set, including rs9689649 in PARK2 gene (P = 2.7 × 10(-6) in combined set; P = 3.2 × 10(-5) in the discovery; and P = 0.02 in the replication), rs754626 in the SRC gene (P = 1.1 × 10(-6) in combined set; P = 1.4 × 10(-5) in the discovery and P = 0.02 in the replication), rs9643297 in ST3GAL1 gene (P = 8.2 × 10(-6) in combined set; P = 3.3 × 10(-5) in the discovery; and P = 0.04 in the replication), and rs17247181 in ERBB2IP gene (P = 4.2 × 10(-6) in combined set; P = 3.1 × 10(-5) in the discovery; and P = 0.048 in the replication). CONCLUSION: Several genetic variants were associated with risk of SCC in a multistage GWAS of subjects of European ancestry. IMPACT: Further studies are warranted to validate our finding and elucidate the genetic function of these variants. Cancer Epidemiol Biomarkers Prev; 25(4); 714-20. ©2016 AACR.

Exposure to phototoxic NSAIDs and quinolones is associated with an increased risk of melanoma.

PURPOSE: Ultraviolet radiation exposure is the most important exogenous risk factor for cutaneous malignancies. It is possible that phototoxic drugs promote the development of cutaneous melanoma (CM) by intensifying the effect of ultraviolet light on the skin. We investigated the association between the use of common systemic phototoxic drugs and development of CM. METHODS: This study was a case-control study in a Dutch population-based cohort. The drug dispensing data was obtained from PHARMO, a Dutch drug dispensing and hospital admissions registry, and linked to PALGA, the nationwide pathology network of the Netherlands. The cases were patients diagnosed with pathologically confirmed primary CM between 1991 and 2004. Controls were sampled from the PHARMO population. Exposure to systemic phototoxic drugs was measured and included antimicrobial agents, diuretics, antipsychotic drugs, antidiabetic drugs, cardiac drugs, antimalarials and nonsteroidal anti-inflammatory drugs (NSAIDs). A multivariate conditional logistic regression analysis was performed to study the association between exposure to phototoxic drugs and CM. RESULTS: The study population included 1,318 cases and 6,786 controls. Any phototoxic drug during the study period was dispensed for 46 % of the cases and 43 % of the controls (p = 0.012). The use of quinolones [odds ratio (OR) 1.33, 95 % confidence interval (CI) 1.01-1.76] and propionic acid derivative NSAIDs (OR 1.33, 95 % CI 1.14-1.54) had a positive association with CM. CONCLUSIONS: Our study shows that the use of phototoxic drugs is associated with an increased risk of developing CM. Even a short-term use of phototoxic quinolones and propionic acid derivative NSAIDs may increase the risk for CM. Patient education to promote sun-protective behaviour is essential to avoid immediate adverse effects and possible long-term effects of phototoxic drugs.

BclI glucocorticoid receptor polymorphism and smoking in the general population.

We studied the hypothesis that the BclI polymorphism of the glucocorticoid receptor gene is associated with an increased probability of being a (heavy) smoker and a decreased ability to quit smoking. The study cohort consisted of all subjects in the Rotterdam Study, a Dutch population-based cohort of people aged 55 years and older, for whom BclI genotyping and smoking status at baseline were available. In prospective analyses, the smoking status was reassessed during three additional examination rounds. Logistic regression analysis was used to study the association between BclI polymorphism and being a smoker or a heavy smoker at baseline. Furthermore, the relationship between BclI polymorphism and incident smoking cessation was tested with Cox proportional hazards analysis within those who smoked at baseline. In total, 6358 subjects were included in the study. The presence of a G-allele was not associated with current smoking at baseline [odds ratio (OR) = 0.96, 95%confidence interval (CI): 0.85-1.09] or with the incidence of smoking cessation during follow-up [hazard ratio (HR) = 0.98, 95%CI: 0.80-1.19]. Within current smokers, having a G-allele was not significantly associated with the risk of being a heavy smoker when measured by pack-years smoked (OR = 1.07, 95%CI: 0.85-1.35) or daily consumption of tobacco (OR = 1.10, 95%CI: 0.88-1.37). We were not able to replicate the earlier findings indicating that the proportion of current smokers is lower among carriers of the CC-genotype of the BclI glucocorticoid receptor. Furthermore, the BclI glucocorticoid receptor polymorphism did not predict the incidence of smoking cessation in the general elderly population.

Effect of persistent use of antihypertensives on blood pressure goal attainment.

OBJECTIVE: Discontinuation rates with antihypertensive drugs in real life are high. The present study investigates the relationship between persistence with antihypertensive drugs (AHT) and blood pressure (BP) goal attainment in daily clinical practice. METHODS: In the PHARMO Record Linkage System, which includes drug dispensing and hospital records for > 2 million inhabitants in the Netherlands, new users of AHT > or = 18 years were identified for the period 1999-2004. Patients with elevated blood pressure (systolic BP > or = 140 and/or diastolic BP > or = 90 mmHg) within 6 months prior to onset of AHT treatment and a BP measurement within 6-12 months of treatment onset were included in the study cohort. Persistent AHT use was determined by summing the number of days of continuous treatment (gap between dispensings < 30 days) from start of treatment onwards. Patients with a BP below 140/90 mmHg at the first BP measurement within 6-12 months of treatment onset were defined as having attained goal. RESULTS: The study included 1271 patients with a mean systolic BP of 174 +/- 22 mmHg and a mean diastolic BP of 100 +/- 12 mmHg. Persistent AHT use was associated with a 40% increased chance of BP goal attainment (RR(adj) = 1.41; 95% CI: 1.08-1.85) after adjustment for gender, age, systolic blood pressure at start, and time to the BP measurement. CONCLUSION: Persistent use of AHT leads to increased blood pressure goal attainment in daily clinical practice.

The effect of discontinuation of antihypertensives on the risk of acute myocardial infarction and stroke.

OBJECTIVE: Adherence to antihypertensive drug treatment is suboptimal. The present study investigates the effect of early treatment discontinuation with antihypertensive drugs on the risk of acute myocardial infarction (AMI) or stroke in daily clinical practice. METHODS: In the PHARMO Record Linkage System, which includes all records of drug dispensings and hospitalisations for > or = 2 million subjects in the Netherlands, new users of antihypertensive (AHT) drugs > or = 18 years of age were studied during the period 1 January 1993 - 1 October 2002 to determine the risk of AMI or stroke related to persistence with AHT. Patients were initially followed for 2 years to determine persistence with AHT, and then for a further 2 years or until the first hospital admission for AMI or stroke, death, or end of the study period. Patients using AHT for secondary prevention of cardiovascular disease were excluded from the study cohort. RESULTS: The study cohort included 77 193 AHT users. The percentage of non-persistent patients was 55% at 2 years, with the lowest non-persistence rates for angiotensin-receptor blockers (ARBs) and ACE-inhibitors (40%) and the highest rates for beta-blockers, calcium-channel blockers (CCBs) and diuretics (54-61%). Non-persistent AHT use was associated with a 15% increased risk of AMI (RR 1.15; 95% CI 1.00-1.33) and a 28% increased risk of stroke (RR 1.28; 95% CI 1.15-1.45). CONCLUSIONS: The results of this study show that in daily clinical practice early discontinuation of antihypertensive drug treatment in primary prevention increases the risk of subsequent AMI or stroke.

Higher persistence with valsartan compared with enalapril in daily practice.

OBJECTIVE: To compare persistence with valsartan and enalapril in daily practice. METHODS: The PHARMO Record Linkage System includes various data registries including drug dispensing and hospitalizations for > or =2 million subjects in the Netherlands. Patients newly treated with valsartan or enalapril in the period of 1999-2002 were selected. Persistence was calculated by summing up the number of days of continuous treatment. Patients who remained on therapy with valsartan or enalapril for 12 or 24 months were defined as persistent at 1 or 2 years, respectively. RESULTS: 3364 patients received valsartan and 9103 patients received enalapril. About 62% of patients treated with valsartan and 55% of patients treated with enalapril remained on therapy at 12 months after the initial dispensing, while 48% of patients treated with valsartan and 43% of patients treated with enalapril were persistent at 24 months. Patients treated with valsartan were about 20% more likely to stay on treatment than patients treated with enalapril (1 year RR(adj): 1.23, 95% CI: 1.16-1.32; 2 years RR(adj): 1.16, 95% CI: 1.11-1.23). CONCLUSIONS: Real-life persistence is higher with valsartan than with enalapril. The results of this and other studies on persistence in daily practice should be taken into account when deciding upon drug treatment for hypertension.