OP0019 HPR A SYSTEMATIC REVIEW AND META-ANALYSIS ASSESSING GASTROINTESTINAL, LIVER, RENAL AND CARDIOVASCULAR ADVERSE EVENTS OF PARACETAMOL

Abstract

Background Despite its modest efficacy, guidelines consistently recommend paracetamol as a first-line analgesic for osteoarthritis (OA) based on its perceived safety. However, there is growing controversy, highlighted in the National Institute for Health and Care Excellence OA (NICE) 2014 guidance on OA, that paracetamol is not as safe as previously thought, especially at the highest therapeutic dose of 4gm/day. Objectives To investigate the association between paracetamol and gastrointestinal, liver, renal and cardiovascular adverse events both in randomised controlled trials (RCTs) and observational studies. Methods We systematically searched MEDLINE, EMBASE, PUBMED, AHMED, CINAHL, Web of Science, and Google Scholar for published literature in any language to the end of November 2018 for (1) RCTs of paracetamol in symptomatic OA, and (2) observational studies irrespective of any underlying condition, to determine the risk of gastrointestinal, liver, renal and cardiovascular adverse events. We included studies assessing oral paracetamol in people aged ≥18 years and reporting on clinically relevant adverse effects. Risk ratio (RR) and 95% confidence interval (CI) were estimated for RCT and cohort studies, whereas odds ratio (OR) and 95% CI were used for case-control studies. Results were pooled as appropriate using random effects model. The risk of bias was assessed using modified Cochrane tool for RCTS and Newcastle Ottawa scale for observational studies. Results We reviewed titles and abstracts of 3,622 records in the systematic search (1,997 RCTs and 1,635 observational studies). After examining full papers 23 RCTs (7,863 participants), 15 cohort studies (2,262,517 participants) and 34 case-control studies (441,638 participants) met inclusion criteria. Compared to placebo, paracetamol was associated with increased incidence of treatment-related adverse events (RR 1.35, 95% CI 1.04 to 1.75), especially diarrhoea (RR 2.14, 95% CI 1.35 to 3.37) and abnormal liver function (RR 3.99, 95% CI 2.05 to 7.77). The pooled OR from twelve age and gender matched case-control studies (7894 participants) was 1.36 (95% CI 1.13 to 1.64) for upper gastrointestinal bleeding. In addition, a dose response relationship was observed in a cohort study (382,404 participants) for this outcome. The RR was 1.11 (95% CI 1.04 to 1.21) with low dose paracetamol (measured as medication possession rate) and 1.49 (95% CI 1.29 to 1.71) with high dose paracetamol. Paracetamol was not associated with cardiovascular events in two RCTs (775 participants) (RR 1.27, 95% CI 0.06 to 27.77) and three case-control studies (42,180 participants) (OR 0.97, 95% CI 0.77 to 1.21), but in three cohort studies (208,926 participants) (RR 1.35, 95% CI 1.14 to 1.59). There were insufficient data in RCTs and case-control studies for renal adverse events. However, three cohort studies (7,360 participants) demonstrated a dose response relationship between paracetamol and renal function impairment (defined as ≥30 percentage decrease in estimated glomerular filtration rate). The data of these three cohort studies could not be pooled due to different doses of paracetamol. One cohort study (1697 participants) reported RR of 1.40 (95% CI 0.79 to 2.48) for renal impairment for paracetamol 100-499g, and 2.19 (95% CI 1.4 to 3.43) for paracetamol >3000g. Conclusion Paracetamol is associated with diarrhoea and abnormal liver function in short-term trial data, and with upper GI bleeding and renal impairment in long-term observational data. Methodological limitations of observational data, such as channelling bias, may confound the results. Large-scale well-designed prospective studies are needed to ascertain the long-term safety of paracetamol. Disclosure of Interests Jaspreet Kaur: None declared, Burak Kundaki: None declared, Georgina Nakafero: None declared, Abhishek Abhishek Grant/research support from: AstraZeneca and OxfordImmunotech, Grant/research support from: AstraZeneca and Oxford Immunotech, Speakers bureau: Menarini pharmaceuticals, Speakers bureau: Menarini pharmaceuticals, Michael Doherty Grant/research support from: AstraZeneca funded the Nottingham Sons of Gout study, Consultant for: Advisory Boards on Grunenthal and Mallinckrodt, Weiya Zhang Consultant for: Grunenthal for advice on gout management, Speakers bureau: Bioiberica as an invited speaker for EULAR 2016 satellite symposium