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Ibuprofen May Interfere with Aspirin's Heart Benefits

Study warns of right timing when taking both

WEDNESDAY, Dec. 19, 2001 (HealthDayNews) -- Heart patients who take painkillers in addition to their daily aspirin may be sapping the cardiovascular protection they think they're getting, new research says.

Pennsylvania scientists say some non-steroidal anti-inflammatory drugs (NSAIDs) can handcuff aspirin's ability to block clotting by beating it to its site of action in the bloodstream. Although there's no evidence yet in patients that the interaction is causing harm, the researchers say the effect is strong enough to warrant concern, and that doctors and patients should carefully consider not only what drugs they use but in what order.

"There's a huge difference whether you give one drug first or the other," says study co-author Dr. Garrett FitzGerald, a University of Pennsylvania pharmacologist. And since these medications are available over the counter, they're "a very seductive choice" for self-treatment, he says. The findings appear in the Dec. 20 issue of The New England Journal of Medicine.

FitzGerald says the findings show not only that it's dangerous to combine drugs, but that doctors shouldn't recommend doing so without first knowing how the compounds interact. And so far, the latest work is the first to shed light on even a few of these potential conflicts. "You really have to address this with each particular drug before you make a statement about it," FitzGerald says.

Medicine has come a long way since the days of two aspirin and a follow-up phone call. But the drug remains a widely used therapy.

Millions of Americans take low doses of aspirin each day to ward off first and second heart attacks and reduce their risks of stroke. Meanwhile, millions more take NSAIDs such as ibuprofen (like Advil and Motrin) and acetaminophen (like Tylenol) for arthritis and other aches and pains. And an unknown but likely impressive number take the two classes of pills together, FitzGerald says.

In the latest study, he and his colleagues sought to learn whether the two families of compounds might interfere with each other.

They had a reasonable motive for doing so. Aspirin and NSAIDs target an enzyme called cyclooxygenase (cox), inactivating it by plugging up a channel in its structure. The enzyme comes in two forms: cox-1, which helps blood cells known as platelets clot, and cox-2, which triggers a cascade of chemicals involved in pain and swelling.

Aspirin and NSAIDs latch onto cox-1 at different sites on the molecule. But whereas aspirin permanently gums up cox-1 -- and must do so to protect the heart and vessels -- NSAIDs, which interact with both forms of cox, run only temporary interference.

FitzGerald's group studied various combinations of aspirin and NSAIDs in about 30 men and women, ages 18 to 65.

Taking aspirin at least two hours before ibuprofen preserved aspirin's anti-clotting powers, but reversing the order erased aspirin's ability to stop platelets from clumping after six days. It also muzzled aspirin's ability to reduce blood levels of a molecule called thromboxane, which promotes clots.

In a second experiment, the researchers gave the drugs in a more natural setting, with three daily doses of the anti-inflammatory -- at 10 a.m., 3 p.m., and 8 p.m. -- and low-dose aspirin at 8 a.m. "We were worried about chronic users who take [ibuprofen] several times a day" for pain, FitzGerald says. "But we wanted to stack the odds against detecting an interaction."

Even so, he says there was enough ibuprofen left over from the previous night's dose to mute aspirin's blood-thinning benefits. Yet such a hangover did not appear when they combined aspirin with an older NSAID called diclofenac, or Voltaren, which binds to cox-1 differently from ibuprofen. Nor did acetaminophen seem to interrupt aspirin's cardiovascular protection, regardless of when it was taken.

FitzGerald's group also looked for an interaction between aspirin and rofecoxib, or Vioxx, a so-called cox-2 inhibitor which only knocks out that form of the cox enzyme. "Sure enough, there was no reaction," he says, indicating that the real problem lies with drugs that target the same molecule.

In an unrelated study also published this week in the same journal, Swedish scientists say people who take aspirin and acetaminophen together for prolonged periods are at about twice the risk of chronic kidney failure as those who take aspirin alone.

The link between these drugs and kidney damage has long been known, says Dr. Leslie Crofford, a University of Michigan rheumatologist and author of an editorial accompanying the two articles. But the Swedish work is the first to suggest that the combination may accelerate the organ failure.

Crofford says people who use low-dose aspirin to prevent heart problems are unlikely to be taking ibuprofen and other NSAIDs for very long, so the interference is probably minimal.

On the other hand, she says the two studies are a clear signal to doctors that they need to use caution when recommending anti-inflammatory drugs and analgesics. "You may be getting synergistic toxicity even if you're using them for different things," she says.

What To Do

So what should you do if you take preventive aspirin but need an anti-inflammatory or want pain medication? FitzGerald says the newer cox-2 drugs might be helpful, but they're more expensive than conventional NSAIDs.

Another option might be simply to boost the dose of aspirin. Although marketing dogma says this strategy poses a bleeding risk, FitzGerald says the issue has never been adequately studied. "It remains a formal possibility that taking a high dose of aspirin might take care of both problems," he says.

To learn more about NSAIDs and their link to ulcers, try the National Institute of Diabetes and Digestive and Kidney Diseases.

For an explanation of how NSAIDs and analgesics work, try Pharmacology Central.

SOURCES: Interviews with Garret A. FitzGerald, M.D., chair, department of pharmacology, and director, Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia; Leslie Crofford, M.D., associate professor of internal medicine, University of Michigan Medical School, Ann Arbor; Dec. 20, 2001, The New England Journal of Medicine
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