UNDERSTAND THE CONTEXT

Although nearly two decades of clinical studies have piled up, we are still faced with the NSAIDilemma today. Scroll to review a timeline of important milestones related to nonsteroidal anti-inflammatory drugs (NSAIDs).

The problem hasn’t gone away. If I look back over the past 30 years of my career, I would have anticipated that awareness of dose-related NSAID risks would be a nonissue by now because we’ve understood the problem. Despite the advances, it’s still something I see daily in my practice.

—Byron Cryer, MD
Professor of Medicine, Division of Gastroenterology
University of Texas Southwestern Medical Center

2001

Relative Risk of Upper Gastrointestinal Complications Among Users of Acetaminophen and NSAIDs1

(García Rodríguez and Hernández-Díaz)

A nested, case-controlled analysis is conducted to determine whether all conventional NSAIDs have a similar relative risk for an increase in upper gastrointestinal complications.

The results of the study show that current intake of NSAIDs carries a 104% increase in the risk of having a new upper gastrointestinal complication and that all NSAIDs had a greater relative risk at higher doses.

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2001

VIoxx Gastrointestinal Outcomes Research (VIGOR)2

A clinical trial is designed to compare the efficacy and adverse effect profiles of rofecoxib to those of naproxen.

The trial concludes that the rofecoxib arm had nearly 5 times the number of myocardial infarction events when compared to the naproxen arm.

2005

Adenoma Prevention With Celecoxib (APC)3

A clinical trial is undertaken that aims at studying effectiveness of a COX-2 inhibitor in preventing sporadic colorectal adenoma formation. During the study, reports of increased incidence of cardiovascular events are reported. This, along with the withdrawal of rofecoxib a year earlier, prompts the formation of an independent panel of cardiovascular experts to analyze the cardiovascular events of the trial.

Their investigation finds that there was an increased incidence of cardiovascular outcomes in the celecoxib treatment arms that is statistically significant when compared to the placebo arm.

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2005

FDA Public Health Advisory4

FDA requires manufacturers of all marketed prescription NSAIDs to revise the labeling for their products to include a Boxed Warning and a Medication Guide:

  • The Boxed Warning highlights the potential for increased risk of cardiovascular events with these drugs and the well-described, serious, and potentially life-threatening gastrointestinal bleeding associated with their use
  • The Medication Guide helps better inform patients about the cardiovascular and gastrointestinal risks
  • FDA recommends the lowest effective dose for the shortest duration consistent with individual patient goals
  • FDA requires the manufacturers of all over-the-counter NSAIDs to revise their labels to include more specific information about the potential cardiovascular and gastrointestinal risks as well as information to assist consumers in the safe use of the drugs

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Did you know?

NSAIDs are presumed to possess an analgesic ceiling effect in which additional increases in dose provide no further analgesic benefit.5,6 Add more context to FDA recommendations with FDA FAQs.
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Download FDA FAQs

2005

NSAIDs and Risk of Acute Renal Failure in the General Population7

(Huerta et al)

Researchers design a study to learn more about the effect of dose and duration of NSAID therapy on the risk for acute renal failure.

It is discovered that current NSAID use is associated with a 35% greater risk for acute renal failure compared with non-NSAID use, and that this risk is slightly increased with long-term therapy and high doses of NSAIDs compared with low-medium doses.
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2006

NSAID Use and the Risk of Hospitalization for First MI in the General Population8

(Helin-Salmivaara et al)

A nationwide case-controlled study is designed with the intention of evaluating the risk of first myocardial infarction associated with the use of various NSAIDs.

Results indicate that, in all NSAID categories, current use shows a statistically significant association with myocardial infarction and also that the longer the time from NSAID discontinuation, the weaker the association.

2006

Multinational Etoricoxib and Diclofenac Arthritis Long-Term Trial (MEDAL)9

Published as part of the larger MEDAL program, this is the first program to directly compare COX-2 selective inhibitors to nonselective NSAIDs. Importantly, the MEDAL program demonstrates that patients who were treated with COX-2 inhibitors and nonselective NSAIDs have nearly identical risk for thrombotic cardiovascular events.

2007

Risk of Upper Gastrointestinal Events With the Use of Various NSAIDs10

(Helin-Salmivaara et al)

A case-controlled study in a general population is conducted to examine the risk of upper gastrointestinal events associated with various NSAIDs.

The study reveals that current use of any NSAID is associated with approximately a 3-fold increased risk of upper gastrointestinal events compared with non-NSAID users. Researchers also discover that the risk increases with duration of use.

2008

Role of Dose Potency in the Prediction of Risk of Myocardial Infarction Associated With NSAIDs in the General Population11

(García Rodríguez et al)

A study is conducted to determine the association between the frequency, dose, and duration of different NSAIDs and the risk of myocardial infarction in the general population. The results find that patients taking NSAIDs have a 28% increased risk of myocardial infarction. It is also noted that increasing the daily dose was a clear predictor of the corresponding risk of myocardial infarction.
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2011

Cardiovascular Risk With Non-Steroidal Anti-Inflammatory Drugs12

(McGettigan and Henry)

A review of population-based controlled observational studies is designed to provide estimates of the comparative risks with individual NSAIDs at typical doses in community settings.

The authors find that, across all NSAIDs studied, there is a statistically significant increase in risk for serious cardiovascular events with high doses of NSAIDs compared to low doses.

2012

Individual NSAIDs and Upper Gastrointestinal Complications13

(Castellsague et al)

A systematic review and meta-analysis of observational studies is conducted, aimed at discerning the relative risk of upper gastrointestinal complications associated with the use of NSAIDs.

The authors find that high daily doses of individual NSAIDs were associated with approximately a 2- to 3-fold increase of relative risks of upper gastrointestinal complications compared with the use of low-medium doses.

2013

Coxib and Traditional NSAID Trialists’ (CNT) Collaboration14

A large meta-analysis of 138 randomized trials and observational studies is conducted, showing that coxibs and traditional NSAIDs are associated with an increased risk of cardiovascular disease and upper gastrointestinal complications.
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2015

FDA Drug Safety Communication15

FDA strengthens the Boxed Warning to include statements that non-aspirin NSAIDs increase the chance of a heart attack or stroke. Based on this safety communication, prescription NSAID labels are revised to reflect the following information:

  • The risk of heart attack or stroke can occur as early as the first weeks of using an NSAID
    • The risk may increase with longer use of the NSAID
  • The risk appears greater at higher doses
  • NSAIDs can increase the risk of heart attack or stroke in patients with or without heart disease or risk factors for heart disease

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Did you know?

FDA reviewed data from more than 180 studies while updating this label warning.15,16 Want more details about FDA recommendations and warnings?
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Download FDA FAQs

2016

CDC Guidelines for Nonopioid Treatments for Chronic Pain17

CDC issues recommendations that nonpharmacologic therapy and nonopioid pharmacologic therapy, such as NSAIDs, are preferred for chronic pain. NSAIDs are recommended for first-line treatment for osteoarthritis and low back pain.

2016

FDA Label Update for All Non-aspirin NSAIDs

In 2016, FDA continues to recommend using the lowest effective NSAID dose for the shortest duration consistent with individual patient treatment goals. FDA also requires that all non-aspirin NSAID labels be updated with the following information:

  • Increased CV thrombotic risk has been observed most consistently at higher NSAID doses

  • There is an increased risk of heart failure with NSAIDs

  • There is approximately a 2-fold increase in hospitalizations for heart failure in NSAID-treated patients compared to placebo-treated patients


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References:

1. García Rodríguez LA, Hernández-Díaz S. Relative risk of upper gastrointestinal complications among users of acetaminophen and nonsteroidal anti-inflammatory drugs. Epidemiology. 2001;12(5):570-576. 2. Bombardier C, Laine L, Reicin A, et al; VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med. 2000;343(21):1520-1528. 3. Solomon SD, McMurray JJ, Pfeffer MA, et al; Adenoma Prevention with Celecoxib (APC) Study Investigators. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med. 2005;352(11):1071-1080. 4. US Food and Drug Administration. Public health advisory – FDA announces important changes and additional warnings for COX-2 selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs). http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm150314.htm. Published April 7, 2005. Accessed August 15, 2016. 5. Laska EM, Sunshine A, Marrero I, Olson N, Siegel C, McCormick N. The correlation between blood levels of ibuprofen and clinical analgesic response. Clin Pharma Ther. 1986;40(1):1-7. 6. Eisenberg E, Berkey CS, Carr DB, Mosteller F, Chalmers TC. Efficacy and safety of nonsteroidal anti-inflammatory drugs for cancer pain: a meta-analysis. J Clin Onc. 1994;12(12):2755-2765. 7. Huerta C, Castellsague J, Varas-Lorenzo C, Rodriguez LA. Nonsteroidal anti-inflammatory drugs and risk of ARF in the general population. Am J Kidney Dis. 2005;45(3):531-539. 8. Helin-Salmivaara A, Virtanen A, Vesalainen R, et al. NSAID use and the risk of hospitalization for first myocardial infarction in the general population: a nationwide case-control study from Finland. Eur Heart J. 2006;27(14):1657-1663. 9. Cannon CP, Curtis SP, FitzGerald GA, et al; MEDAL Steering Committee. Cardiovascular outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison. Lancet. 2006;368(9549):1771-1781. 10. Helin-Salmivaara A, Saarelainen S, Grönroos JM, Vesalainen R, Klaukka T, Huupponen R. Risk of upper gastrointestinal events with the use of various NSAIDs: a case-control study in a general population. Scand J Gastroenterol. 2007;42(8):923-932. 11. García Rodríguez LA, Tacconelli S, Patrignani P. Role of dose potency in the prediction of risk of myocardial infraction associated with nonsteroidal anti-inflammatory drugs in the general population. J Am Coll Cardiol. 2008;52(20):1628-1636. 12. McGettigan P, Henry D. Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of population-based controlled observational studies. PLoS Med. 2011;8(9):1-18. 13. Castellsague J, Riera-Guardia N, Calingaert B, et al; on behalf of the investigators of the Safety of Non-Steroidal Anti-Inflammatory Drugs (SOS) Project. Individual NSAIDs and upper gastrointestinal complications: a systematic review and meta-analysis of observational studies (the SOS Project). Drug Saf. 2012;35(12):1127-1146. 14. Coxib and traditional NSAID Trialists’ (CNT) Collaboration, Bhala N, Emberson J, Merhi A, et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet. 2013;382:769-779. 15. US Food and Drug Administration Drug Safety Communication: FDA strengthens warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or strokes. http://www.fda.gov/Drugs/DrugSafety/ucm451800.htm. Published July 9, 2015. Accessed August 15, 2016. 16. US Food and Drug Administration. Joint meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee: nonsteroidal anti-inflammatory drugs and cardiovascular thrombotic risk. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM383180.pdf. Published February 10-11, 2014. Accessed August 15, 2016. 17. Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain–United States, 2016. JAMA. 2016;315(15):1624-1645.