FDA Strengthens Warnings for NSAIDs Regarding Risk of Heart Attack and Stroke

Raghavendra Rao and Mark Thomas

The FDA announced on 9 July 2015 that it was strengthening an existing warning concerning the risk of heart attack and stroke in the labeling for non aspirin non-steroidal anti-inflammatory drugs (NSAIDs), a class of drugs widely used to provide temporary relief from pain and inflammation. The FDA’s decision was made following careful review of new safety information from a number of sources, which included the published literature, observational studies, and a large combined analysis of clinical trials. In addition, the FDA considered recommendations from a Joint Arthritis Advisory Committee and Drug Safety, and a Risk Management Advisory Committee meeting that was held on February 10-11, 2014 to discuss data and analyses published during or after 2006 with relevance to better understanding the relationship between NSAIDs and cardiovascular thrombotic risk.1

This link to the meeting minutes shows some of the key questions that were considered during the meeting, and how the committee members responded to them.

The FDA’s announcement indicated that the warning language for prescription NSAIDs will be strengthened by incorporating the following specific points. The Marketing Authorization Holder was responsible for submitting revised labeling in accordance with this information for formal FDA review.

The risk of heart attack or stroke:

  • May be present as early as the first weeks of NSAID use
  • May increase with extended use
  • Appears to increase with higher doses
  • May not be the same for all NSAIDs
  • Can be increased by NSAIDs in patients with or without heart disease or risk factors for heart disease
  • Is, in general, higher in patients that do have heart disease or risk factors for heart disease

In addition, the labeling should indicate that NSAID use within one year of suffering the first heart attack is associated with an increased risk of death in the year following the heart attack. The use of NSAIDs is also associated with an increased risk of heart failure.

Similar updates will be made to the labeling for non-aspirin NSAIDs available over the counter (OTC).
Following the FDA’s announcement in July ’15, there has been a lot of effort by Marketing authorization holders of NSAIDs, with a few companies who already have updated labels available online and some who are still in discussions with the FDA.

NSAID-CV Risk Link
The link between NSAIDs and CV risks can be traced back to rofecoxib, a drug developed and eventually sold by Merck under the tradename Vioxx. Rofecoxib’s ability to selectively inhibit the cyclooxygenase 2 (“COX-2”) form of the cyclooxygenase enzyme, which is in contrast to that of traditional NSAIDs, generated much enthusiasm due to its potentially superior safety profile. Nevertheless, even before the FDA granted marketing approval for Vioxx in 1999, the agency expressed some concerns about CV risks in patients that had received the drug. A little less than two years later, concerns were discussed in a meeting of the FDA Arthritis Advisory Committee. A description of CV events from controlled clinical trials was then introduced into the label on April 11, 2002.2

Ultimately, in a move that sent shock waves through the industry, Merck withdrew Vioxx from the market on September 30, 2004, in response to study results showing that rofecoxib treated patients experienced significantly more thromboembolic events than patients treated with placebo.3 With more than 80 million patients receiving treatment, and annual sales exceeding $2.5 billion, it was the largest prescription drug withdrawal in history.2

The situation with Vioxx triggered the FDA to re-examine the NSAIDs-CV risks link.4 A joint meeting with the Arthritis Advisory Committee (AAC) and the Drug Safety and Risk Management Advisory Committee (DSaRM AC) was held in February 2005 to review the emerging evidence of the risks and consider how they could be best mitigated. One outcome of the meeting was the FDA requested that Pfizer withdraw another COX-2 inhibitor, Bextra (valdecoxib), from the market due to an unfavorable benefit/risk profile. With respect to labeling and prescription NSAIDs, the following actions were taken5:

  • Patients should be provided with a Medication Guide when they receive the drug to better inform them about the risks of NSAID use
  • A contraindication was added for use immediately after CABG surgery
  • A boxed warning was added to describe the potential for increased risk of CV events and GI bleeding

Manufacturers of non-prescription OTC NSAIDs were also asked to revise their labeling to include more specific information about potential CV and GI risks.


  1. FDA Drug Safety Communication: FDA strengthens warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or strokes
  2. Topol, E.J. (2004). Failing the public health – rofecoxib, Merck, and the FDA. The New England Journal of Medicine 351 (17): 1707-9.
  3. Bresalier, R.S. et al (2005). Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. The New England Journal of Medicine 352 (11): 1092-102.
  4. FDA Announces Series of Changes to the Class of Marketed Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
  5. Public Health Advisory – FDA Announces Important Changes and Additional Warnings for COX-2 Selective and Non-Selective Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)