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.

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.