Ibuprofen blocks aspirin's ability to protect against heart attacks

December 19, 2001

Common arthritis drugs can stop aspirin from thinning the blood

(Philadelphia, PA) - The ibuprofen that you take to ease arthritis pain can counteract the aspirin that you take to protect your heart, according to researchers at the University of Pennsylvania School of Medicine. The researchers studied how aspirin, taken to prevent second heart attacks, interacts with nonsteroidal anti-inflammatory drugs (NSAIDs), a group of drugs that includes ibuprofen, commonly taken to treat rheumatoid arthritis. Their findings are published in the December 20th issue of the New England Journal of Medicine.

"Our findings have shown that multiple daily doses of ibuprofen can undermine the cardioprotective effects of a daily aspirin regimen," said Garret A. FitzGerald, MD, Robinette Professor of Cardiovascular Medicine, chair of the Penn Department of Pharmacology, and director of the Penn Center for Experimental Therapeutics. "NSAIDs and aspirin are two of the most frequently consumed drugs in North America and, since people commonly take both drugs daily, it is important to see how they could interact." Much of their concern rests in the fact that aspirin and NSAIDs both inhibit two different versions of the same enzyme, a protein called cyclooxygenase (COX). One variant of the enzyme, COX-1, found in platelets, is essential in creating the molecules that allow platelets to clot blood. The other variant, COX-2, produces the molecules responsible for the pain and inflammation symptomatic of arthritis.

Aspirin will bind to the COX-1 enzyme irreversibly, thereby permanently putting the enzyme - and the platelet - out of commission. Such a sustained effect on platelets is key to the ability of aspirin to prevent heart attack and stroke. NSAIDs, however, bind less strongly to a different part of the enzyme, and only impair platelets for a short time. There is no evidence that NSAIDs prevent heart attack or stroke, but their effects on COX-2 help relieve pain and swelling.

"Since both NSAIDs and aspirin both bind near the reactive site deep within the COX-1 enzyme, we thought that NSAIDs might physically block aspirin from reaching its target," explained Muredach Reilly, MD, a Penn cardiologist and co-author of the study. "It would not do you a lot of good to take one medication only to have another wipe out its effects."

In particular, the researchers studied the over the counter NSAIDs ibuprofen (e.g. Advil®), diclofenac (Voltaren®) and acetaminophen (e.g. Tylenol®), as well as the prescription NSAID refocoxib (e.g. Vioxx®), which is part of a class of newer, COX-2 specific, NSAIDs. To determine how the drugs might interact, the researchers first studied how the order of dosing might influence the effects of combinations of aspirin with the various NSAIDs on the number of working platelets in volunteers. As they had guessed, taking ibuprofen before aspirin prevented aspirin's effects on platelet COX-1. If they took aspirin 2 hours before the ibuprofen, however, there was no problem.

They then repeated the study, giving ibuprofen three times a day - the way people would generally take the drug for persistent pain or inflammation. This time they loaded the die against the interaction by giving the aspirin two hours before the morning dose of ibuprofen each day. To their surprise, there was still enough ibuprofen around from the prior evening's dose to cause the aspirin-blocking interaction. "We know that aspirin works to protect the heart by acting as a blood thinner, that is, it prevents clotting by inactivating the enzyme that makes platelets stick together," said FitzGerald. "This study tells us that ibuprofen can prevent this from happening by denying aspirin access to the enzyme's active site." As expected, the researchers failed to see an interaction with rofecoxib, an important point of distinction for patients on aspirin who are making a choice amongst NSAIDs. As a member of the newer COX-2 specific drugs, rofecoxib does not bind to COX-1 in platelets. Perhaps more surprisingly, the interaction was also absent from combinations of aspirin with diclofenac, an older NSAID. The interaction occurs in a narrow channel deep within the COX-1 molecule. "There is some evidence that diclofenac binds within the enzyme somewhat differently than does ibuprofen, but the failure to interact may also reflect its preference for COX-2, its turnover, or some other factor as yet to be identified," said FitzGerald. The researchers also failed to see an interaction with 1000mg of acetaminophen. However, they did find out that at this dose acetaminophen is a weak NSAID. It remains to be seen if higher doses of acetaminophen can exert a full NSAID effect and whether they might effect aspirin like ibuprofen does.

"This study tells us that patients who take ibuprofen, the most common NSAID consumed in North America, are susceptible to an interaction that would undermine the cardioprotective action of low dose aspirin," said FitzGerald. "Patients taking aspirin to protect against heart attack should seek the advice of their doctors before commencing additional treatments for pain or inflammation."
-end-
This study was funded, in part, by the National Institutes of Health and the Bayer Corporation.

Editor's Note: Neither Dr. FitzGerald nor Dr. Reilly have any financial stake in Bayer Pharmaceuticals.

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University of Pennsylvania School of Medicine

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