Hydroxychloroquine safety in Covid-19 vs non-Covid-19 patients: analysis of differences and potential interactions.

BACKGROUND: The use of hydroxychloroquine (HCQ) in the first COVID-19 epidemic wave raised safety concerns. RESEARCH DESIGN AND METHODS: Adverse reactions (ADR) suspected to be induced by HCQ and submitted to the Spanish Pharmacovigilance Database were studied. A disproportionality analysis was performed to determine adverse effects reported in non-Covid and Covid patients. To explore potential drug-drug interactions, Omega (Ω) statistics was calculated. RESULTS: More severe cases were reported when used in COVID-19. Main differences in frequency were observed in hepatobiliary, skin, gastrointestinal, eye, nervous system and heart ADRs. During the COVID-19 pandemic, high disproportionality in reports was found for Torsade de Pointes/QT prolongation with a ROR (-ROR) of 132.8 (76.7); severe hepatotoxicity, 18.7 (14.7); dyslipidaemias, 12.1 (6.1); shock, 9.5 (6.9) and ischemic colitis, 8.9 (2.6). Myopathies, hemolytic disorders and suicidal behavior increased their disproportionality during the pandemic. Disproportionality was observed for neoplasms, hematopoietic cytopaenias and interstitial lung disease in the pre-COVID-19 period. Potential interactions were showed between HCQ and azithromycin, ceftriaxone, lopinavir and tocilizumab. CONCLUSIONS: The use of HCQ during the Covid-19 pandemic changed its ADRs reporting profile. Of particular concern during the pandemic were arrhythmias, hepatotoxicity, severe skin reactions and suicide, but not ocular disorders. Some signals identified would require more detailed analyses.

Análisis y evaluación del riesgo cardiovascular y gastrointestinal de los antiinflamatorios no esteroideos inhibidores selectivos y no selectivos de ciclooxigenasa / Analysis and evaluation of cardiovascular and gastrointestinal risk of nonsteroidal anti-inflammatory drugs selective and non-selective cyclooxygenase inhibitors

Objetivos: revisar la evidencia publicada sobre el uso de AINE (coxibs y clásicos) y evaluar el riesgo cardiovascular (RCV) y gastrointestinal (RGI) asociado. Material y métodos: fueron seleccionados los estudios de cohorte y caso-control que mostraban el RCV o RGI de los AINE versus no expuestos. Se calculó el RR ponderado y el intervalo de confianza 95% para todos los AINE conjuntamente y de forma individual. Resultados: se observó un RCV significativo tanto con coxibs [RR= 1.24 (1.19-1.31)] como con AINE clásicos [RR= 1.18 (1.13-1.24)]. Para los coxibs sería elevado incluso a dosis bajas y en sujetos con RCV basal bajo. Por fármaco individual, rofecoxib [RR= 1.41 (1.33-1.50)] junto con diclofenaco [RR= 1.36 (1.27-1.47)] y etoricoxib [RR= 1.26 (1.08-1.48)] son los AINE con mayor RCV. El metaanálisis sobre el RGI mostró riesgo con los coxibs [RR 1.64 (95% CI 1.44-1.86)]. Por fármaco individual, etoricoxib [RR 4.48 (95% CI 2.98-6.75)] presentó mayor riesgo seguido de rofecoxib [RR 2.02 (95% CI 1.56-2.61)] y celecoxib [RR 1.62 (95% CI 1.46-1.78)]. El riesgo también fue elevado para dosis bajas y edad <65 años. Conclusión: según nuestro estudio, el uso de AINE (coxibs y clásicos) está relacionado con un incremento similar del RCV, incluso a dosis bajas y en pacientes con un RCV bajo-medio. Por otro lado, el uso de coxibs se relacionaría con un incremento del RGI, siendo elevado incluso para dosis bajas y edad <65 años. El riesgo para etoricoxib podría ser superior que para celecoxib y rofecoxib.(AU)

Introduction: the aim of this study is to review the current evidence on the clinical use of NSAIDs, coxibs and nonselective, and to evaluate its cardiovascular (CVR) and gastrointestinal risk (GIR) by means of a meta-analytic procedure. Materials and methods: cohort and case-control studies showing CVR and GIR associated with NSAIDs versus no treatment were selected. We estimated the pooled RR and the 95% confidence interval (CI) for all NSAIDs as a whole and individually. Results: both coxibs (RR, 1.22 [95%CI, 1.17-1.28]) and nonselective NSAIDs (RR 1.18 [95%CI, 1.12-1.24]) were associated with an increased CVR. The coxibs CVR remained even for low-dose and low-baseline CVR subgroups. Analysis by drug disclosed that rofecoxib (RR 1.39 [95%CI, 1.31- 1.47]), along with diclofenac (RR, 1.34 [95%CI, 1.26-1.42]) and etoricoxib (RR 1.27 [95%CI, 1.12-1.43]) were the NSAIDs associated with the highest CVR. Gastrointestinal risk meta-analysis showed that coxibs were associated with a GIR increment [RR1.64 (95% CI 1.44-1.86)]. Analysis by drug disclosed that etoricoxib [RR 4.48 (95% CI 2.98-6.75)]presented the highest GIR followed by rofecoxib [RR 2.02 (95% CI 1.56-2.61)] and celecoxib [RR1.62 (95% CI 1.46-1.78)]. GIR was also high for <65 year-old and low-dose coxibs subgroups. Conclusion: according to our study the use of NSAIDs (coxibs and nonselective) are associated with a similar CVR increment, even for low-dose and low-baseline CVR subgroups. On the other hand, the use of coxibs is associated with a GIR increased, which would be high even for low-dose coxibs and <65-year-old subgroups. The risk would be higher for etoricoxib than for celecoxib and rofecoxib.

Thromboembolism and Oral Contraceptives During the COVID-19 Pandemic: A Disproportionality Analysis Within the Spanish Pharmacovigilance Database.

BACKGROUND: Thromboembolic events (TEs) are known to be a severe complication for COVID-19. They are associated with a systemic inflammatory response syndrome with coagulation cascade activation. OBJECTIVE: The aim of this study was to determine a potential association between the COVID-19 pandemic and the increment of the risk of suspected TEs in women on systemic hormonal contraceptives (SHCs). PATIENTS AND METHODS: This study utilised a case/non-case approach in the Spanish Pharmacovigilance Database, which includes more than 290,000 cases of suspected adverse drug reactions (ADRs). The reporting odds ratio (ROR) was calculated during an initial pandemic period in 2020 compared with a pre-pandemic period in 2019 and an additional control period in 2018. RESULTS: While there was a decreased number of ADR notifications for any medications and for any type of ADR in patients on SHCs during the pandemic period, the TE ROR for all SHCs was higher in the 2020 pandemic period [ROR = 11.8 (5.6-24.7)] relative to the pre-pandemic period in 2019 [ROR = 6.3 (3.2-12.5)] and the additional control period in 2018 [ROR = 4.6. (2.1-9.9)]. In contrast, ROR for progestogen-only contraceptives was lower during the pandemic as compared with the two control periods. CONCLUSION: The reported disproportionality of TEs in women on SHCs rose during the pandemic period. This suggests a potential interaction of the drug (SHC) with COVID-19, which led to an increased risk of TEs in women exposed to both factors. This should be taken into consideration in the context of the COVID-19 pandemic.

Bullous pemphigoid associated with the use of dipeptidil peptidase-4 inhibitors: analysis from studies based on pharmacovigilance databases.

Background Bullous pemphigoid has been associated to dipeptidase-4 inhibitors. Objectives Addressing the potential Bullous pemphigoid-dipeptidase-4 inhibitors association based on pharmacovigilance data currently available in Spain in order to obtain a composite disproportionality estimator from all the data generated by the case-non case studies conducted to this date. Setting The Spanish Pharmacovigilance System for Human Use Drugs database. Method Case-non case study based on the Spanish Pharmacovigilance System for Human Use Drugs notifications submitted between 2007 and 2018 (n = 169,280), using the Medical Dictionary for Regulatory Activities term (Preferred Term) 'pemphigoid' for sitagliptin, vildagliptin, saxagliptin, linagliptin, and alogliptin (n = 1952). As negative control, we used acetaminophen, while furosemide was the positive control. A pooled reported odds ratio analysis in the French, Japanese, and Spanish national pharmacovigilance databases was performed. On The Spanish Pharmacovigilance System for Human Use Drugs, we conducted a bullous pemphigoid-metformin association analysis within the period 1982-2018. Main outcome measure Adverse reaction cases in pharmacovigilance databases and the disproportionality through the reporting odds ratio. Results Within The Spanish Pharmacovigilance System for Human Use Drugs, we found 45 cases of bullous pemphigoid in dipeptidase-4 inhibitors patients. Median age was 77 years (range 72-82). The median latency period was 7 months (range 0.23-86). The Bullous pemphigoid-dipeptidase-4 inhibitors association was established with a reporting odd ratio = 70.0 (95% confidence intervals 49.1-10.1). In the combined analysis of the three aforementioned pharmacovigilance databases, the pooled reporting odd ratio was 81.0 (95% confidence intervals 69.5-94.4). Conclusion The composite estimator for the three national pharmacovigilance databases yields clear evidence of a Bullous pemphigoid-dipeptidase-4 inhibitors association, which was statistically significant for both the pharmacological class as a whole and each of the dipeptidase-4 inhibitors agents under investigation. Metformin's role in the incidence of bullous pemphigoid appeared casual rather than causal. No differences between Caucasian and Asian populations were noted.

Guillain-Barré syndrome and influenza vaccines: current evidence / Síndrome de Guillain-Barré y vacuna antigripal: evidencia actual

PURPUSE: Guillain-Barré Syndrome (GBS) as a consequence of influenza vaccination is a relevant topic, yet to be clarified, which raises concern both amongst health care personnel and the general population. Every study and pharmacovigilance system point to need of further research and the importance of continuous monitoring of safety regarding influenza vaccines. The aim of the present study is to investigate the publication of new data since the realisation of our meta-analysis of GBS and influenza vaccines (published in 2015). METHODS: A systematic revision of PubMed, Embase, and Web of Knowledge (WOS) databases has been carried out. These report observational studies assessing GBS risk after the administration of influenza vaccines from May 2014 up to July 20th, 2017. RESULTS: The research yielded 107 articles. Only three studies met established inclusion criteria and referred to an estimation GBS risk after some influenza vaccine. Two studies investigated GBS risk by the pandemic A/H1N1 vaccine, while only one looked into season vaccines. CONCLUSIONS: The present systematic review, conducted after the publication of our previous meta-analysis, seems to confirm its previous results. Therefore, GBS should be considered an infrequent adverse effect of influenza vaccination, which should not negatively influence its acceptance. Unfortunately, very few of the systematically surveyed studies meeting inclusion criteria. This fact sharply contrasts with the current consensus as to the need of continuously monitoring the safety of influenza vaccines

INTRODUCCIÓN: El síndrome de Guillain-Barré (GBS) después de la administración de la vacuna frente a la gripe es un tema actual que sigue causando preocupación tanto en el personal sanitario como en la población y que permanece sin esclarecer. El objetivo del presente trabajo es investigar la publicación de nuevos datos desde la realización de nuestro metaanálisis sobre el GBS y las vacunas frente a la gripe (publicado en 2015). MÉTODOS: Se ha realizado una revisión sistemática en las bases de datos PubMed, Embase y Web of Science (WOS) de estudios observacionales que evaluarán el riesgo de GBS después de la administración de vacunas influenza, desde mayo de 2014 hasta el 20 de julio de 2017. RESULTADOS: El resultado de las búsquedas fue de 107 artículos. Finalmente, solo 3 estudios cumplían con los criterios de inclusión establecidos y referían una estimación del riesgo de GBS después de alguna de las vacunas antigripales. Dos estudios investigaron el riesgo de GBS con la vacuna pandémica A/H1N1 y un estudio investigó las vacunas estacionales. CONCLUSIONES: Esta revisión sistemática parece confirmar los hallazgos obtenidos en nuestro metaanálisis. El SGB se podría considerar como un posible efecto adverso poco frecuente de las vacuna antigripales, lo cual no debería afectar negativamente en su aceptación. Desafortunadamente, en nuestra revisión sistemática, hemos encontrado muy pocos estudios que cumplieran los criterios de inclusión, este hecho resulta llamativo ya que el consenso actual señala la necesidad de una monitorización continua sobre la seguridad de las vacunas antigripales

Cardiovascular Risk of Nonsteroidal Anti-inflammatory Drugs and Classical and Selective Cyclooxygenase-2 Inhibitors: A Meta-analysis of Observational Studies.

The purpose of this study was to review the published evidence on the clinical use of nonsteroidal anti-inflammatory drugs (NSAIDs) and to assess the cardiovascular risk (CVR) of cyclooxygenase-2 inhibitors (coxibs), excluding aspirin, by means of a meta-analytic procedure. A search was conducted on MEDLINE and EMBASE databases between October 1999 and June 2018. Cohort and case-control studies showing CVR as relative risk (RR), odds ratio, hazard ratio, or incidence rate ratio associated with NSAIDs versus no treatment were selected. We estimated the pooled RR and the 95% confidence interval (CI) for all NSAIDs as a whole and individually. Eighty-seven studies met the inclusion criteria. Overall, NSAIDs were found to be associated with a statistically significantly increased CVR (RR, 1.24 [95%CI, 1.19-1.28]). The risk was slightly higher for coxibs (RR, 1.22 [95%CI, 1.17-1.28]) as compared with nonselective NSAIDs (RR, 1.18 [95%CI, 1.12-1.24]). Data analysis by drug disclosed that rofecoxib (RR, 1.39 [95%CI, 1.31-1.47]), followed by diclofenac (RR, 1.34 [95%CI, 1.26-1.42]) and etoricoxib (RR, 1.27 [95%CI, 1.12-1.43]) were the NSAIDs associated with the highest CVR. Analysis by type of event showed that the highest risk corresponded to vascular events for both coxibs (RR, 2.18 [95%CI, 1.72-2.78]) and nonselective NSAIDs (RR, 2.46 [95%CI, 2.00-3.02]). The meta-analysis results suggest that the use of the marketed coxibs celecoxib and etoricoxib would be related to a statistically significant CVR increase. Etoricoxib CVR could be higher than that for celecoxib. This increment would be similar to classical NSAID CVR.

Gastrointestinal safety of coxibs: systematic review and meta-analysis of observational studies on selective inhibitors of cyclo-oxygenase 2.

Prior meta-analyses have shown a higher gastrointestinal risk of nonselective NSAIDs versus placebo and a lower gastrointestinal risk of coxibs versus nonselective NSAIDs. However, the available data about gastrointestinal risk for coxibs versus placebo are scarce. The aim of this study was to review the current evidence on the use of coxibs and to evaluate the risk of gastrointestinal adverse outcomes (GAO) associated with coxibs versus nonexposed. Search was conducted on PubMed and Embase databases. We selected cohort observational, case-control, nested case-control and case-crossover studies that reported the risk of GAO associated with coxibs versus nonexposed as relative risk (RR), odds ratio (OR), hazard ratio (HR) or incidence rate ratio (IRR). It was estimated the pooled RR and the 95% confidence interval (CI) for coxibs both individually and as a whole by the DerSimonian and Laird method. Twenty-eight studies met inclusion criteria. Overall, coxibs were associated with a significant increment in the risk of GAO [RR 1.64 (95% CI 1.44-1.86)]. The analysis by individual drugs showed that etoricoxib [RR 4.85 (95% CI 2.64-8.93)] presented the highest gastrointestinal risk, followed by rofecoxib [RR 2.02 (95% CI 1.56-2.61)] and celecoxib [RR 1.53 (95% CI 1.19-1.97)]. Gastrointestinal risk was also high for the subgroups aged <65 years and low-dose coxibs. The use of coxibs is associated with a statistically significant increased risk of GAO, which would be high even for low-dose coxibs and <65-year-old subgroups. The risk would be higher for etoricoxib than for celecoxib and rofecoxib.

Cardiovascular and gastrointestinal safety of selective cyclooxygenase-2 inhibitors: a case/non-case study.

Background Coxibs cardiovascular (CV) safety continues being a current issue after rofecoxib worldwide withdrawal in 2004. Objective To evaluate the cardiovascular and gastrointestinal (GI) risk of coxibs through case/non-case study. Setting The Spanish Pharmacovigilance System for Human Use Drugs (FEDRA) and the Uppsala Monitoring Centre (VigiBase) databases. Method We identified adverse drug reactions (ADRs) cases reported under the MedDRA system organ classes of "cardiac disorders", "vascular disorders", "nervous system disorder" and "gastrointestinal disorders". Disproportionality was considered when the following criteria were met simultaneously: proportional reporting ratio (PRR) ≥ 2, 95% confidence interval lower limit of reporting odds ratio (ROR) > 1, Chi square test (χ2) ≥ 4; and number of ADR reports (n rep.) > 3. Main outcome measure Potential disproportionality between cardiovascular and GI ADRs as reported to FEDRA and VigiBase and the use of coxibs. Results We found association between coxibs and CV-ADRs in FEDRA [PRR 2.11 (95% CI 1.97-2.27); ROR 2.53 (95% CI 2.29-2.89); χ2 367.81; n rep., 561] and VigiBase [PRR 2.67 (95% CI 2.64-2.71); ROR 3.26 (95% CI 3.20-3.31); χ2 23,950.93; n rep., 21,047]; and between coxibs and GI-ADRs in VigiBase [PRR 2.91 (95% CI 2.84-2.97); ROR 3.08 (95% CI 3.01-3.16); χ2 8762.82; n rep. 6954]. No association was found between coxibs and GI-ADRs in FEDRA. Conclusion The association found support a potential coxibs class effect in terms of cardiovascular safety. Classical NSAIDs GI risk may be higher than that for coxibs.

Risk excess of mortality and use of antipsychotics: a case-noncase study.

Severe mental disorders are associated with an increased mortality risk and the use of antipsychotic drugs may be one of the causes. In this study, we addressed the potential association of the reported mortality among patients on antipsychotics compared to other drugs from a pharmacovigilance database with the aim of evaluating the drug-induced mortality risk. A database containing 189 441 entries of suspected adverse reactions reported from 1 January 1995 to 31 December 2012 was explored for fatal outcomes. Potential disproportionality was estimated using the reporting odds ratio, proportional reporting ratio, and the χ-test. Two-hundred fatal outcomes were reported in patients on antipsychotics, which indicated the occurrence of disproportionality for this pharmacological class compared with any other drugs. When data were analysed by antipsychotic subclass, disproportionality was found only for atypical but not for typical antipsychotics. When individually analysed by active substances and routes, only a few substances were found to show disproportionality. The disproportionality encountered in this study compared with the mortality associated with other drugs suggests that the active substances under study may be associated with a mortality risk higher than what is assumed currently. Also, it suggests that atypical antipsychotics are likely to have a mortality risk higher than the risk of typical antipsychotics. The disproportionality found for zuclopentixol, in both oral and depot formulations, can be considered to be a drug surveillance signal.