Non-aspirin Nonsteriodal Anti-inflammatory Drug (NSAID) Safety Concerns Regarding Potential Cardiovascular Events

Date: 
07/27/2015

By R.L. Wynn

Using nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen after a heart attack can increase the risk of death, recurrent heart attack, stroke and bleeding in patients taking antithrombotic medications. A study published in the Journal of the American Medical Association (JAMA) in February of 2015 said that any NSAID increases those risks, even when purchased over the counter and used for a short period of time, in those heart patients on antithrombotic agents. The antithrombotic therapy included aspirin, clopidogrel (Plavix), warfarin, or a combination of them.

A special alert for ibuprofen (July 2015) has been added to the Lexicomp core drug informationdatabase and reads as follows:

The FDA has strengthened an existing label warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) increase the risk of a heart attack or stroke. The FDA is requiring updates to the labels of all prescription NSAIDs, including over-the-counter non-aspirin NSAID Drug Facts labels. Prescription NSAID labels will be revised to reflect the following information:

  • The risk of heart attack or stroke can occur as early as the first weeks of NSAID use. The risk may increase with longer use of the NSAID.
  • The risk appears to be greater at higher doses.
  • It was previously thought that all NSAIDs may have a similar risk. Newer information makes it less clear that the risk of heart attack or stroke is similar for all NSAIDs; however, this newer information is not sufficient to determine that the risk of any particular NSAID is definitely higher or lower than that of any other particular NSAID.
  • NSAIDs can increase the risk of heart attack or stroke in patients with or without heart disease or risk factors for heart disease. A large number of studies support this finding, with varying estimates of how much the risk is increased, depending on the drugs and the doses studied.
  • In general, patients with heart disease or risk factors for heart disease have a greater likelihood of heart attack or stroke following NSAID use than patients without these risk factors (due to a higher baseline risk).
  • Patients treated with NSAIDs following a first heart attack were more likely to die in the first year after the heart attack compared with patients who were not treated with NSAIDs after their first heart attack.
  • There is an increased risk of heart failure with NSAID use.

There was also a special alert issued from Health Canada (April 2015): Health Canada is working with Canadian manufacturers of prescription oral ibuprofen to include safety information about the risk of serious cardiovascular side effects (e.g., heart attack, stroke) when taken at high doses (2,400 mg/day).  The risk increases with dose and duration of use. The safety information now recommends that doses of 2,400 mg/day should not be given to patients with ischemic heart disease, cerebrovascular disease or congestive heart failure, or in those with risk factors for cardiovascular disease.

Also, the following “Alert: US Boxed Warning” has been added to the Lexicomp ibuprofen monograph: Nonsteroidal anti-inflammatory agents (NSAIDs) may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk.

This warning excludes NeoProfen.

The JAMA report examined the risk of bleeding and cardiovascular events among patients with prior heart attack taking antithrombotic drugs and for whom NSAID therapy as then prescribed. In essence, the report concluded that the use of NSAIDs in these patients was associated with increased risk of bleeding and excess thrombotic events, even after short term treatment.

JAMA study: Purpose and methods         

The JAMA report can be accessed at:

Schjerning-Olsen, A.M., et al. “Association of NSAID use with risk of bleeding and cardiovascular events in patients receiving antithrombotic therapy after myocardial infarction.” JAMA 2015; 313(8):807-14.

The stated importance of the study was that antithrombotic therapy is indicated for use in myocardial infarct survivors, and that concomitant NSAID use could pose safety concerns. The objective of the study was to examine the risk of bleeding and cardiovascular events among those patients with prior myocardial infarction taking antithrombotic drugs and for whom NSAID therapy was then prescribed.

The investigators used nationwide administrative registries in Denmark from 2002 to 2011 to study patients 30 years or older admitted with first-time myocardial infarction (MI) and alive 30 days after discharge. Prescription drug claims were used to classify patients into groups based on the treatment after discharge: monotherapy with aspirin, clopidogrel (Plavix), or a vitamin K antagonist (e.g., warfarin); dual therapy with any of those drugs; or triple therapy. Exposure to concomitant NSAIDs was determined using the drug claims database, because most NSAIDs are dispensed in Denmark by prescription only. Patients were followed up until occurrence of an adverse event – defined as bleeding requiring hospitalization, death, recurrent MI, stroke or arterial embolism – or until study completion.  Bleeding was defined as intracranial, gastrointestinal (bleeding ulcer, unspecified gastrointestinal bleeding), bleeding from the respiratory or urinary tract, and anemia caused by bleeding.

In summary the outcome measures in those individuals taking ongoing NSAID and antithrombotic treatment included:

  1. Risk of bleeding that required hospitalization and/or
  2. A cardiovascular outcome which included death, nonfatal recurrent MI, stroke or arterial embolism

JAMA study results

  • 61,971 patients were evaluated
  • Mean age was 67.7 years and 63.2% were men
  • The distribution of the type of antithrombotic drug treatment at study inception was similar among NSAID users and non-NSAID users
  • 5288 bleeding events (8.5%) were counted. From those 5288 bleeding events, fatal bleeds comprised 799 events

Bleeding complications

Bleeding incidence rates (events per 100 person-years) were 4.2 events in the NSAID-antithrombotic group and 2.2 events in the antithrombotic group without NSAIDs. Further interpretation of the data showed that the risk of bleeding associated with NSAID-antithrombotic group was twice that of the group not using NSAIDs. The combinations of aspirin plus clopidogrel with NSAIDs showed a 141% increase in bleeding risk, and the combination of the warfarin anticoagulant plus a single antiplatelet drug with NSAIDs showed a 166% increase in bleeding risk, both compared with antithrombotic treatment without NSAID.

All types of NSAIDs were associated with the increased bleeding risk. These included ibuprofen, naproxen, celecoxib, rofecoxib, and diclofenac. 

The use of any NSAID was associated with a marked risk of bleeding from the beginning of NSAID treatment day (day 0-3), and the risk persisted up through day 90 of NSAID use. 

Cardiovascular events

The risk for a cardiovascular event increased by 40% with any NSAID use compared with no NSAID treatment. The greatest increase for cardiovascular events was in those patients taking combination of aspirin plus clopidogrel with concomitant NSAID, which showed a 159% increased risk. In those patients taking aspirin alone, there was an increased risk of 58% for cardiovascular events in the NSAID group.          

Important points from the JAMA report

  1. This was the first to investigate the bleeding risk associated with NSAIDs prescribed concomitantly with antithrombotic therapy in heart attack survivors.
  2. The association with increased risk was observed for all antithrombotic treatments.
  3. The association with increased risk was apparent with all NSAIDs regardless of whether selective COX-2 inhibitor (celecoxib) or nonselective COX inhibitors (ibuprofen, naproxen and diclofenac) were involved.
  4. There was no safe duration of concomitant NSAID use, since even short-term treatment (fewer than 3 days) was associated with increased risk of bleeding compared with no NSAID use.
  5. The study results have considerable public health relevance since NSAIDs are among the most commonly used medications worldwide. In many countries, ibuprofen is available without prescription in retail outlets, with no restrictions on the amounts that may be purchased.
  6. Studies are needed to determine if concomitant use of NSAIDs with new oral anticoagulants (i.e., dabigatran, rivaroxaban, and others) will interact similarly with antithrombotics in heart attack survivors.
  7. Clinicians are encouraged to consider the balance of benefits and risks before prescribing or recommending NSAIDs in patients with a history of a cardiovascular event on antithrombotic therapy. 

JAMA editorial on NSAID risks

Campbell, C.L.; Moliterno, D.J. “Potential hazards of adding nonsteroidal anti-inflammatory drugs to antithrombotic therapy after myocardial infarction. Time for more than a gut check.” JAMA 2015; 313(8):801-2.

The editorial noted that associated bleeding risk with NSAID therapy was elevated regardless of the type or extent of concomitant antithrombotic therapy. And even among rare cases in which patients received no antithrombotic therapy, NSAID therapy alone was associated with an increased risk of bleeding compared with patients not receiving NSAID. Most surprising, according to the editorial, was that even short-term therapy with NSAIDs was associated with a substantially increased bleeding risk. That risk was found to be markedly elevated with the first 3 days after the initiation of NSAID therapy.

The editorial stated that bleeding events are strongly related to subsequent adverse cardiovascular events among patients with acute coronary syndromes. The mechanism may be that bleeding results in a heightened inflammatory state as well as an interruption of the antithrombotic therapies.

The editorial concluded that, although NSAIDs can be helpful and at times necessary medications for satisfactory quality of life, use of these medications among patients with a history of a recent myocardial infarction is likely to be associated with significant bleeding and ischemic risks.

Finally, consider this quote from the editorial:

“Practitioners would do well to advise patients with cardiovascular disease against all NSAID use (except low dose aspirin), especially patients with a recent acute coronary syndrome.”

Richard L. Wynn, PhD, is Professor of Pharmacology at the Baltimore College of Dental Surgery, Dental School, University of Maryland Baltimore.

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