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

Contemporary radiation doses in interventional cardiology: a nationwide study of patient doses in Finland

The amount of interventional procedures such as percutaneous coronary intervention (PCI), transcatheter aortic valve implantation (TAVI), pacemaker implantation (PI) and ablations has increased within the previous decade. Simultaneously, novel fluoroscopy mainframes enable lower radiation doses for patients and operators. Therefore, there is a need to update the existing diagnostic reference levels (DRLs) and propose new ones for common or recently introduced procedures. We sought to assess patient radiation doses in interventional cardiology in a large sample from seven hospitals across Finland between 2014 and 2016. Data were used to set updated national DRLs for coronary angiographies (kerma-air product (KAP) 30 Gycm2) and PCIs (KAP 75 cm2), and novel levels for PIs (KAP 3.5 Gycm2), atrial fibrillation ablation procedures (KAP 25 Gycm2) and TAVI (KAP 90 Gycm2). Tentative KAP values were set for implantations of cardiac resynchronization therapy devices (CRT, KAP 22 Gycm2), electrophysiological treatment of atrioventricular nodal re-entry tachycardia (6 Gycm2) and atrial flutter procedures (KAP 16 Gycm2). The values for TAVI and CRT device implantation are published for the first time on national level. Dose from image acquisition (cine) constitutes the major part of the total dose in coronary and atrial fibrillation ablation procedures. For TAVI, patient weight is a good predictor of patient dose.</p

Unintended impact of pharmacovigilance regulatory interventions: a systematic review. Supplementary material.

Additional data and other material related to our systematic review of the unintended impact of pharmacovigilance regulatory intervention

Higher persistence with valsartan compared with enalapril in daily practice

Satu J Siiskonen1, Nancy S Breekveldt-Postma1, G&aacute;bor Vincze2, Zeba M Khan3, Jo&euml;lle A Erkens1, Ron MC Herings11PHARMO Institute for Drug Outcomes Research, Utrecht, The Netherlands; 2Novartis Pharma AG, Basel, Switzerland; 3Novartis Pharmaceuticals Corporation, East Hanover, NJ, USAObjective: 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 &ge;2 million subjects in the Netherlands. Patients newly treated with valsartan or enalapril in the period of 1999&ndash;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 RRadj: 1.23, 95% CI: 1.16&ndash;1.32; 2 years RRadj: 1.16, 95% CI: 1.11&ndash;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.Keywords: persistence, antihypertensive, valsartan, enalapril, angiotensin-converting enzyme inhibitors, angiotensin-2-receptor blocker

Alcohol Intake is Associated with Increased Risk of Squamous Cell Carcinoma of the Skin: Three US Prospective Cohort Studies

The association between alcohol intake and cutaneous squamous cell carcinoma (cSCC) is unclear. We studied the association between alcohol intake and incident invasive cSCC in three cohorts of women and men with repeated assessments of alcohol intake in the US. Information on alcohol intake was collected repeatedly during follow-up. Cumulative average of alcohol intakes was used. Multivariable Cox proportional hazards models with time-dependent exposure were used to estimate relative risks (RRs) and 95% confidence intervals, followed by a meta-analysis. During a follow-up of 4,234,416 person-years, 2,938 cSCC were identified. Alcohol intake was associated with an increased risk of cSCC with a dose-response relationship. Each additional drink (12.8 gram of alcohol) per day was associated with a 22% increased risk of cSCC (RR 1.22, 95% confidence interval: 1.13–1.31). White wine consumption of ≥5 times/wk was associated with an increased risk of cSCC (RR 1.31, 95% confidence interval: 1.09–1.59). We found no increased risk of cSCC with other alcoholic beverages. The population-attributable risk associated with alcohol intake of ≥20 grams/d was 3% of cSCCs. In conclusion, alcohol intake was associated with an elevated risk of cSCC. Among alcoholic beverages, white wine was associated with cSCC

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 ≥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 RRadj: 1.23, 95% CI: 1.16-1.32; 2 years RRadj: 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

A genome-wide association study of cutaneous squamous cell carcinoma among european descendants

Background: NoGWASon 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 r2 < 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

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

Background: NoGWASon 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 r2 < 0.4) for replication. Results: Rs8063761 in the DEF8 gene on chromosome 16 showed the strongest association with SCC (P = 1.7 \xc3\x97 10-9 in the combined set; P = 1.0 \xc3\x97 10-6 in the discovery set and P = 4.1 \xc3\x97 10-4 in the replication set). The variant allele of rs8063761 (T allele) was associated with a decreased expression of DEF8 (P=1.2\xc3\x9710-6). Besides, we validated four other SNPs associated with SCC in the replication set, including rs9689649 in PARK2 gene (P = 2.7 \xc3\x97 10-6 in combined set; P = 3.2 \xc3\x97 10-5 in the discovery; and P = 0.02 in the replication), rs754626 in the SRC gene (P = 1.1 \xc3\x97 10-6 in combined set; P = 1.4 \xc3\x97 10-5 in the discovery and P=0.02 in the replication), rs9643297 in ST3GAL1 gene (P = 8.2 \xc3\x97 10-6 in combined set; P = 3.3 \xc3\x97 10-5 in the discovery; and P = 0.04 in the replication), and rs17247181 in ERBB2IP gene (P=4.2\xc3\x9710-6 in combined set; P= 3.1\xc3\x9710-5 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