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Adding NSAIDS or Aspirin to Anticoagulants Increases Bleeding Danger

Worst Pills, Best Pills Newsletter article December, 2014

Millions of patients in the U.S. take anticoagulants (blood thinners) on a long-term basis to prevent the formation of potentially harmful clots in the heart, veins or arteries. These drugs offer great benefit by preventing devastating consequences of undesired clot formation, such as strokes, lung damage, limb loss and, in some cases, death.

However, the benefits of anticoagulants come at the price of an increased risk of potentially life-threatening bleeding. Thus, treatment with...

Millions of patients in the U.S. take anticoagulants (blood thinners) on a long-term basis to prevent the formation of potentially harmful clots in the heart, veins or arteries. These drugs offer great benefit by preventing devastating consequences of undesired clot formation, such as strokes, lung damage, limb loss and, in some cases, death.

However, the benefits of anticoagulants come at the price of an increased risk of potentially life-threatening bleeding. Thus, treatment with these drugs always involves a delicate balance between preventing harmful clots and avoiding dangerous bleeding. Many factors, including a number of drugs that interact with anticoagulants, can tilt this balance in one direction or the other.

A recent study in JAMA Internal Medicine adds to the growing body of evidence showing that combining either aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) with anticoagulants can tip this benefit-risk balance unfavorably toward serious bleeding.

Two ways to block clotting

The ability to form blood clots is essential for life. Two components of blood are necessary for clot formation. The first is a family of proteins called clotting factors that are made in the liver. When activated, these factors come together to form the basic building blocks and supporting framework of a clot.

The second component is a group of cell-like structures called platelets that are produced in the bone marrow. Platelets clump together with activated clotting factors to form a clot when a blood vessel is damaged.

Blocking either component can inhibit clot formation. Not surprisingly, blocking both provides the most potent means for preventing clot formation, but also the greatest bleeding risk.

Anticoagulant drugs work by interfering in various ways with one or more of the clotting factors. Warfarin (COUMADIN, JANTOVEN) is one of the oldest and most widely prescribed blood thinners, having been used in medical practice for more than half a century. Public Citizen’s Health Research Group recommends warfarin over the many new anticoagulant drugs that have come on the market over the past several years, such as apixaban (ELIQUIS), dabigatran (PRADAXA) and rivaroxaban (XARELTO).

Other drugs can interfere with clot formation by blocking platelet function. Aspirin is one of the most commonly used antiplatelet medications for prevention of clots that could lead to heart attacks or strokes. Another is clopidogrel (PLAVIX).

One adverse effect of all NSAIDs, which are used to treat pain and inflammation, is that they too block platelet function (for a list of available NSAIDs, see table below).

Oral NSAIDS[1]

Generic Name Brand Name(s)
celecoxib* CELEBREX
etodolac** Available in generic form only
fenoprofen** NALFON
flurbiprofen ANSAID
indomethacin* INDOCIN, TIVORBEX
ketoprofen NEXCEDE
ketorolac* Available in generic form only
meclofenamate** Available in generic form only
mefenamic acid** PONSTEL
meloxicam* MOBIC
nabumetone** Available in generic form only
oxaprozin** DAYPRO
piroxicam* FELDENE
sulindac** CLINORIL
tolmetin Available in generic form only

*Designated as Do Not Use
**Designated as Limited Use
***Combination medication that includes an NSAID as one of the active ingredients

New study highlights bleeding risk

Many previous studies have shown that use of aspirin is associated with as much as a 2.5-fold increase in the risk of bleeding in patients treated with anticoagulants for atrial fibrillation, coronary artery disease or mechanical heart valves. A few studies also have suggested a similar heightened risk of bleeding when cardiac disease patients take NSAIDs in combination with anticoagulants.[2]

The most recent study to assess the risk of bleeding when combining an anticoagulant with NSAIDs or aspirin was published in June in JAMA Internal Medicine.[3] For this well-designed observational study, a team of international researchers analyzed data from a large randomized trial that compared two anticoagulants in patients who had a clot in one or more of their large veins, mainly in the legs or the lungs. The data covered 8,246 patients in 39 countries who were tracked from 2007 to 2009. Patients were randomly assigned to receive either rivaroxaban or enoxaparin (LOVENOX) for three, six or 12 months. Rivaroxaban was administered as a pill, and enoxaparin was injected under the skin.

Throughout the trial, any exposure to an NSAID or aspirin was recorded for each day during the period when patients took the anticoagulant. Likewise, any episode of major bleeding or other clinically relevant bleeding was recorded throughout the course of the study. Bleeding was categorized as major if it was fatal, involved a significant drop in the red blood cell count on a blood test, occurred at a critical site (such as bleeding into the brain) or required a transfusion of two or more units of blood.

Clinically relevant bleeding included major bleeding and other bleeding episodes that were associated with a medical treatment, unscheduled follow-up with a physician, temporary stopping of the anticoagulant or significant patient discomfort causing pain or interfering with daily activities. The researchers compared the rate of bleeding episodes during time periods when subjects used an NSAID or aspirin to rates when they were not using these drugs.

The study’s major strength lay in the real-time recording of both NSAID or aspirin use and the occurrence of clinically relevant bleeding.

During the course of the clinical trial, 23 percent of patients used an NSAID and 15 percent took aspirin for one or more days. The rate of clinically relevant bleeding was 1.8-fold higher when subjects treated with an anticoagulant used an NSAID than on days when they were not taking an NSAID. The rate of major bleeding increased more than twofold when subjects were on an NSAID.

Similarly, when subjects took aspirin during the trial, they had a 1.7-fold higher risk of clinically relevant bleeding than when they were not taking aspirin. There also was a trend toward more frequent major bleeding with aspirin use, but this result did not reach statistical significance. The increased risks for bleeding with NSAID or aspirin use were similar for both rivaroxaban-treated and enoxaparin-treated subjects.

The results also indicated that the risk of bleeding in patients taking anticoagulants increases soon after starting the NSAID or aspirin and does not increase further with ongoing use of the drug combination.

The study investigators concluded that physicians and patients need to be very cautious about combining anticoagulants with either NSAIDs or aspirin. NSAIDs and aspirin should be used in anticoagulant-treated patients only when there is a genuine need, no safer alternatives are available and the benefits outweigh the risks.

What You Can Do to Minimize Bleeding Risk When Taking an Anticoagulant

Avoid taking non-steroidal anti-inflammatory drugs (NSAIDs) or aspirin unless directed to do so by a physician.

Avoid casual, short-term use of over-the-counter NSAIDs, such as ibuprofen (ADVIL, MOTRIN IB) and naproxen (ALEVE). Before taking a cold or sinus remedy, scan the label to see if the list of active ingredients includes an NSAID.

If treatment with an NSAID or aspirin is absolutely necessary, always take the drug for the shortest amount of time and at the lowest dose needed to achieve the desired benefit.

Be aware that using acetaminophen (TYLENOL) as a substitute for an NSAID can also increase the risk of bleeding in patients taking warfarin (COUMADIN, JANTOVEN).

When taking warfarin, maintain a consistent diet to avoid major changes in vitamin K intake, which can significantly affect the action of the drug.

Follow your physician’s instructions regarding blood tests for monitoring warfarin levels.

Call your doctor right away if you get any of the following signs or symptoms of a bleeding problem:

  • Pain, swelling or discomfort
  • Headache, dizziness or weakness
  • Unusual bruising
  • Nosebleeds
  • Bleeding gums
  • Bleeding from cuts that takes a long time to stop
  • Menstrual bleeding or vaginal bleeding that is heavier than normal
  • Pink, red or brown urine
  • Red or black stools
  • Bloody sputum
  • Vomited blood or material resembling coffee


[1] Food and Drug Administration. Drugs@FDA. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails. 8246 Searched each generic drug name on October 28, 2014.

[2] Davidson BL, Verheijen S, Lensing AWA, et al. Bleeding risk of patients with acute venous thromboembolism taking nonsteroidal anti-inflammatory drugs or aspirin. JAMA Intern Med. 2014;174(6):947-953.

[3] Ibid.