Andrea Arfè, biostatistician1, Lorenza Scotti, biostatistician1, Cristina Varas-Lorenzo, epidemiologist2, Federica Nicotra, biostatistician1, Antonella Zambon, biostatistician1, Bianca Kollhorst, biostatistician3, Tania Schink, biostatistician3, Edeltraut Garbe, pharmacoepidemiologist3, Ron Herings, pharmacoepidemiologist4, Huub Straatman, biostatistician4, René Schade, epidemiologist5, Marco Villa, epidemiologist6, Silvia Lucchi, biostatistician6, Vera Valkhoff, epidemiologist5, Silvana Romio, biostatistician5, Frantz Thiessard, medical computer scientist7, Martijn Schuemie, medical computer scientist5, Antoine Pariente, pharmacoepidemiologist7, Miriam Sturkenboom, pharmacoepidemiologist5, Giovanni Corrao, biostatistician1 On behalf of the Safety of Non-steroidal Anti-inflammatory Drugs (SOS) Project Consortium

Abstract

Objectives To investigate the cardiovascular safety of non-steroidal anti-inflammatory drugs (NSAIDs) and estimate the risk of hospital admission for heart failure with use of individual NSAIDs.

Design Nested case-control study.

Setting Five population based healthcare databases from four European countries (the Netherlands, Italy, Germany, and the United Kingdom).

Participants Adult individuals (age ≥18 years) who started NSAID treatment in 2000-10. Overall, 92 163 hospital admissions for heart failure were identified and matched with 8 246 403 controls (matched via risk set sampling according to age, sex, year of cohort entry).

Main outcome measure Association between risk of hospital admission for heart failure and use of 27 individual NSAIDs, including 23 traditional NSAIDs and four selective COX 2 inhibitors. Associations were assessed by multivariable conditional logistic regression models. The dose-response relation between NSAID use and heart failure risk was also assessed.

Results Current use of any NSAID (use in preceding 14 days) was found to be associated with a 19% increase of risk of hospital admission for heart failure (adjusted odds ratio 1.19; 95% confidence interval 1.17 to 1.22), compared with past use of any NSAIDs (use >183 days in the past). Risk of admission for heart failure increased for seven traditional NSAIDs (diclofenac, ibuprofen, indomethacin, ketorolac, naproxen, nimesulide, and piroxicam) and two COX 2 inhibitors (etoricoxib and rofecoxib). Odds ratios ranged from 1.16 (95% confidence interval 1.07 to 1.27) for naproxen to 1.83 (1.66 to 2.02) for ketorolac. Risk of heart failure doubled for diclofenac, etoricoxib, indomethacin, piroxicam, and rofecoxib used at very high doses (≥2 defined daily dose equivalents), although some confidence intervals were wide. Even medium doses (0.9-1.2 defined daily dose equivalents) of indomethacin and etoricoxib were associated with increased risk. There was no evidence that celecoxib increased the risk of admission for heart failure at commonly used doses.

Conclusions The risk of hospital admission for heart failure associated with current use of NSAIDs appears to vary between individual NSAIDs, and this effect is dose dependent. This risk is associated with the use of a large number of individual NSAIDs reported by this study, which could help to inform both clinicians and health regulators.

BMJ