NSAIDS and Heart Failure Risk

Chidozie Ukpabi, Mercer University College of Pharmacy

Non-steroidal anti-inflammatory drugs (NSAIDS) have been described as one of the most commonly used medications due to having both anti-inflammatory and analgesic effects. Their inhibition of cyclooxygenase 2 (COX2) leads to decreased inflammatory mediators and has been stated to contribute to effective pain management. [1] It is stated that NSAIDS are the most common cause of gastroduodenal injury in the United States, a consequence of COX1 inhibition. [2]. Selective COX2 inhibitors, such as Celebrex® (celecoxib), are stated to be advantageous because they circumvent the adverse effects of COX1 inhibition. It has been shown that COX 2 inhibitors lead to cardiovascular adverse effects such as stroke and myocardial infarction. [3]

Non-steroidal anti-inflammatory drugs and risk of heart failure in four European countries: nested case-control study [4]
Design Nested case-control study; N= 8,338,566
Objective To investigate the cardiovascular safety of NSAIDs and estimate the risk of hospital admission for heart failure with use of individual NSAIDs
Study Groups Case patients (n= 92,163); control patients (n= 8,246,403)
Methods This study utilized five electronic health databases from four European countries. Each database longitudinally recorded data on each member of its target population. Data harmonization was performed across all databases. Adults (age ≥18 years) who received at least one NSAID prescription or dispensation during 2000-10 were considered eligible to enter the cohort. A case-control study was nested into the cohort of new users of NSAIDs. Each case study was matched with up to 100 controls within the databases. The risk of heart failure was measured for the use of 27 individual NSAIDs, including 23 non-selective NSAIDs and four selective COX 2 inhibitors.


Duration Data availability between 1999 and 2010
Primary Outcome Measure Association between risk of hospital admission for heart failure as measured by first hospital admission for heart failure identified during follow-up
Baseline Characteristics
Case Patients Controls
Men, n (%) 41,652 (45.2) 3,671,565 (44.5)
Mean age at cohort entry, years (SD) 77 (11) 76 (10)
Comorbidities and other characteristics, n (%)
Acute myocardial infarction 3063 (3.3) 81,222 (1.0)
Alcohol abuse 1942 (2.1) 12,8871 (1.6)
Asthma 1,031 (1.1) 57,079 (0.7)
Atrial fibrillation and flutter 4,606 (5.0) 110,217 (1.3)
Chronic liver disease 1,815 (2.0) 98,762 (1.2)
Chronic respiratory disease 16,190 (17.6) 870,497 (10.6)
Diabetes 17,888 (19.4) 725,320 (8.8)
Heart failure 8,353 (9.1) 209,125 (2.5)
Hyperlipidemia 18,793 (20.4) 1,160,532 (14.1)
Hypertension 19,905 (21.6) 1,515,002 (18.4)
Iron deficiency anemia 2,159 (2.3) 83,926 (1.0)
Ischemic heart 8,406 (9.1) 294,986 (3.6)
Kidney failure 1,445 (1.6) 41,094 (0.5)
Obesity 4,555 (4.9) 181,104 (2.2)
Osteoarthritis 6,916 (7.5) 483,721 (5.9)
Other cardiovascular disease 13,055 (14.2) 463,797 (5.6)
Rheumatoid arthritis and inflammatory polyarthritis 736 (0.8) 40,269 (0.5)
Smoking 164 (0.2) 8,155 (0.1)
Stroke 1,869 (2.0) 85109 (1.0)
Valvular disease and endocarditis 2,383 (2.6) 70,646 (0.9)
NSAID Risk for Heart Failure, Odds Ratio (95% CI)
Ketoralac 1.83 (1.66 – 2.02)
Etoricoxib 1.51 (1.41 – 1.62)
Indomethacin 1.51 (1.33 – 1.71)
Rofecoxib 1.36 (1.28 – 1.44)
Piroxicam 1.27 (1.19 – 1.35)
Diclofenac 1.19 (1.15 – 1.24)
Nimesulide 1.18 (1.14 – 1.23)
Ibuprofen 1.18 (1.12 – 1.23)
Naproxen 1.16 (1.07 – 1.27)
Any NSAID overall 1.19 (1.17 – 1.22)
Adverse Events Common Adverse Events: N/A
Serious Adverse Events: N/A
Percentage that Discontinued due to Adverse Events: N/A
Study Author 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.


The responsibility of organizations like the FDA are to protect public health, by assuring the safety of the drugs that are made available for public use. [5] Trials such as this provide information that can be utilized to make the use of medications safer. Considering the period of time NSAIDS have been available, information regarding hospitalization due to heart failure should have been available before now. The increase in the risk of heart failure at specific dosages in combination with the warnings that are already known such as gastrotoxicity and atherothrombotic events make NSAIDS a class of medications that should be moderated to limit the risk they pose to their consumers. It will be interesting to see what adjustments will be made in the near future to ensure that the public will be able to use these medications in a safe and effective manner.



  1. Ong CK, Lirk P, Tan CH, Seymour RA. An evidence-based update on nonsteroidal anti-inflammatory drugs. Clin Med Res. 2007;5(1):19-34.
  2. Laine L. Approaches to nonsteroidal anti-inflammatory drug use in the high-risk patient. Gastroenterology. 2001;120(3):594-606.
  3. Lenzer J. FDA advisers warn: COX 2 inhibitors increase risk of heart attack and stroke. BMJ. 2005;330(7489):440.
  4. Arfè A, Scotti L, Varas-lorenzo C, et al. Non-steroidal anti-inflammatory drugs and risk of heart failure in four European countries: nested case-control study. BMJ. 2016;354:i4857.
  5. What We Do. Fda.gov. 2016. Available at: http://www.fda.gov/AboutFDA/WhatWeDo/. Accessed October 5, 2016.






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