Drug Safety

, Volume 42, Issue 1, pp 67–75 | Cite as

Nonsteroidal Anti-Inflammatory Drugs and Risk of First Hospitalization for Heart Failure in Patients with No History of Heart Failure: A Population-Based Case-Crossover Study

  • Sung-Po Huang
  • Yao-Chun Wen
  • Shih-Tsung Huang
  • Chih-Wan Lin
  • Tzung-Dau Wang
  • Fei-Yuan HsiaoEmail author
Original Research Article



Traditional nonselective, nonsteroidal anti-inflammatory drugs (NSAIDs) are known to cause salt and fluid retention and should thus be used cautiously in patients with documented heart failure. Recent studies have found that some NSAIDs, including cyclooxygenase (COX)-2 inhibitors, are associated with an increased risk of incident heart failure regardless of the related medical history of the patient.


This study aimed to investigate the potential link between NSAIDs (both COX-2 inhibitors and traditional nonselective NSAIDs) and heart failure in patients without a history of heart failure.


We conducted a case-crossover study using the National Health Insurance Research Database (NHIRD) in Taiwan. A total of 5615 subjects with a first hospitalization for heart failure between 2005 and 2013 were identified from the NHIRD. Exposure to individual NSAIDs between the case period (1–30 days before the index date) and control period (121–150 days before the index date) were retrieved. Multivariable conditional logistic regression models were used to estimate the adjusted odds ratios (aORs) of the incident heart failure associated with NSAID use after adjustments for potential confounders. Multiple sensitivity analyses, including the case-time-control analysis, were performed to test the robustness of the study results.


Overall, NSAID use was associated with a 1.58-fold risk [aOR 1.58; 95% confidence interval (CI) 1.40–1.79] of heart failure leading to hospitalization in the main analysis, and similar results were obtained in the case-time-control analysis [aOR 1.40 (95% CI 1.18–1.67)]. The increased risks of heart failure were comparable between traditional NSAIDs [aOR 1.53 (95% CI 1.35–1.74)] and COX-2 inhibitors [aOR 1.74 (95% CI 1.25–2.44)]. Among all NSAIDs, ketorolac was associated with the highest risk of heart failure [aOR 1.98 (95% CI 1.37–2.86)].


Both traditional NSAIDs and COX-2 inhibitors were associated with an increased risk of heart failure leading to hospitalization in patients without a related history of heart failure.



We thank the National Health Insurance Administration (NHIA) and National Health Research Institutes (NHRI) for making the databases used in this study available. However, the content of this article does not represent any official position of the NHIA or NHRI. The authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Compliance with Ethical Standards


This work was supported by the Ministry of Science and Technology, Taiwan (Grant No. MOST104-2410-H-002-225-MY3). The funding source had no role in conducting this study, including the study design, data collection and analysis, manuscript preparation and review, or decision to submit the manuscript for publication.

Ethical Approval

The identification numbers for all of the entries in the NHIRD are encrypted to ensure privacy. The study protocol was approved by the Research Ethics Committee of the National Taiwan University Hospital (NTUH-REC-201403069 W).

Conflicts of Interest

Sung-Po Huang, Yao-Chun Wen, Shih-Tsung Huang, Chih-Wan Lin, Tzung-Dau Wang, and Fei-Yuan Hsiao have no conflicts of interest that are directly relevant to the content of this study.

Supplementary material

40264_2018_720_MOESM1_ESM.pdf (294 kb)
Supplementary material 1 (PDF 294 kb)


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Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.School of Pharmacy, College of MedicineNational Taiwan UniversityTaipeiTaiwan
  2. 2.Health Data Research CenterNational Taiwan UniversityTaipeiTaiwan
  3. 3.Graduate Institute of Clinical Pharmacy, College of MedicineNational Taiwan UniversityTaipeiTaiwan
  4. 4.College of MedicineNational Taiwan UniversityTaipeiTaiwan
  5. 5.Cardiovascular Center and Division of Cardiology, Department of Internal MedicineNational Taiwan University HospitalTaipeiTaiwan
  6. 6.Department of PharmacyNational Taiwan University HospitalTaipeiTaiwan

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