Non-steroidal anti-inflammatory drugs and risk of heart failure in four European countries: nested case-control study.
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.



Nested case-control study.



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



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).



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.



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.



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.
Unit of Biostatistics, Epidemiology, and Public Health, Department of Statistics and Quantitative Methods, University of Milano-Bicocca, 20126 Milan, Italy.
Andrea
A
Arfè
Unit of Biostatistics, Epidemiology, and Public Health, Department of Statistics and Quantitative Methods, University of Milano-Bicocca, 20126 Milan, Italy.
Lorenza
L
Scotti
RTI Health Solutions, Barcelona, Spain.
Cristina
C
Varas-Lorenzo
Unit of Biostatistics, Epidemiology, and Public Health, Department of Statistics and Quantitative Methods, University of Milano-Bicocca, 20126 Milan, Italy.
Federica
F
Nicotra
Unit of Biostatistics, Epidemiology, and Public Health, Department of Statistics and Quantitative Methods, University of Milano-Bicocca, 20126 Milan, Italy.
Antonella
A
Zambon
Leibniz Institute of Prevention Research and Epidemiology, Bremen, Germany.
Bianca
B
Kollhorst
Leibniz Institute of Prevention Research and Epidemiology, Bremen, Germany.
Tania
T
Schink
Leibniz Institute of Prevention Research and Epidemiology, Bremen, Germany.
Edeltraut
E
Garbe
PHARMO Institute, Utrecht, Netherlands.
Ron
R
Herings
PHARMO Institute, Utrecht, Netherlands.
Huub
H
Straatman
Department of Medical Informatics, Erasmus University Medical Centre, Rotterdam, Netherlands.
René
R
Schade
Local Health Authority ASL Cremona, Cremona, Italy.
Marco
M
Villa
Local Health Authority ASL Cremona, Cremona, Italy.
Silvia
S
Lucchi
Department of Medical Informatics, Erasmus University Medical Centre, Rotterdam, Netherlands.
Vera
V
Valkhoff
Department of Medical Informatics, Erasmus University Medical Centre, Rotterdam, Netherlands.
Silvana
S
Romio
University of Bordeaux Segalen, Bordeaux, France.
Frantz
F
Thiessard
Department of Medical Informatics, Erasmus University Medical Centre, Rotterdam, Netherlands.
Martijn
M
Schuemie
University of Bordeaux Segalen, Bordeaux, France.
Antoine
A
Pariente
Department of Medical Informatics, Erasmus University Medical Centre, Rotterdam, Netherlands.
Miriam
M
Sturkenboom
Unit of Biostatistics, Epidemiology, and Public Health, Department of Statistics and Quantitative Methods, University of Milano-Bicocca, 20126 Milan, Italy giovanni.corrao@unimib.it.
Giovanni
G
Corrao
D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D016022:Case-Control Studies; D016208:Databases, Factual; D005260:Female; D005858:Germany; D006333:Heart Failure / Q000139:chemically induced* / Q000453:epidemiology; D006760:Hospitalization / Q000706:statistics & numerical data*; D006801:Humans; D007558:Italy; D016015:Logistic Models; D008297:Male; D009426:Netherlands; D012307:Risk Factors; D006113:United Kingdom
D000894:Anti-Inflammatory Agents, Non-Steroidal