Arfè A, Scotti L, Varas-Lorenzo C, et al.
BMJ 2016; 354:i4857

Background

COX2 inhibitors and some traditional non-steroidal anti-inflammatory drugs (NSAIDs: diclofenac, ibuprofen, naproxen) are associated with an increased risk of atherothrombotic vascular events [1]. NSAID use has been described to be associated with an increased risk of heart failure (HF) in both randomised trials and observational studies [2-4]. Guidelines include limitations for the use of these medicines in patients with HF [5]. However, the dose-response relationships between COX2 inhibitors and traditional NSAIDs on one hand, and the risk of HF on the other hand, are not clear.
The European Commission-funded multinational Safety of Non-Steroidal Anti-Inflammatory (SOS) Project is a CV and gastrointestinal risk evaluation of individual NSAIDs, which included heart failure as outcome of interest. It is a nested case-control study based on five electronic healthcare databases from four European countries (the Netherlands, Italy, Germany, and the United Kingdom), based on real-world data on over 7.5 million NSAID users. Adults who received at least one prescription or dispensation of an NSAID during 2000-10 were considered eligible to enter the cohort, unless they received NSAIDs in the preceding year, or had a diagnosis of malignant cancer, or were admitted to hospital with a primary diagnosis of HF in the year before cohort entry. 24 555 063 person years of follow-up were accumulated in the cohort. 92163 cases of HF were admitted to hospital during follow-up.

Main results

• According to the pooled analysis, current (in previous 14 days) users of any NSAID had a 20% higher risk of HF hospitalisation compared with past users (OR: 1.19; 95% CI: 1.17 - 1.22).
• There was a significantly higher risk of HF hospitalisation in association with the current use of seven NSAIDs and two COX2 inhibitors compared with past use of any NSAIDs (ketorolac, etoricoxib, indomethacin, rofecoxib, piroxicam, diclofenac, ibuprofen, nimesulide, and naproxen). The associations were independent of HF diagnosis and gender. ORs ranged from 1.16 (95% CI: 1.07-1.27) for naproxen to 1.83 (95% CI: 1.66-2.02) for ketorolac.
• Other less frequently used NSAIDs (sulindac, acemethacin, and dexibuprofen) were also associated with an increased risk of HF, but not in a statistically significant way.
• Compared with current use of celecoxib, current use of other individual NSAIDs was not associated with a significant decrease in HF risk. ORs ranged from 0.83 (95% CI: 0.57 - 1.20) for oxaprozin to 1.84 (95% CI: 1.67 - 2.04) for ketorolac.
• Current users of very high doses of diclofenac, etoricoxib, indomethacin, piroxicam, and rofecoxib had more than a 2-fold higher HF risk compared with past users.
• The OR associated with current high dose use of ibuprofen was also compatible with an increased HF risk, despite the wide CI.
• There was no evidence that celecoxib at commonly used doses increased the risk of hospital admission for HF compared with past use of any NSAIDs.

Conclusion

The most frequently used individual traditional NSAIDs and selective COX2 inhibitors are associated with an increased risk of hospital admission for HF. The risk seems to vary between drugs and according to the dose, up to double risk.  

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References

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