Study Tallies Heart Risk from Pain Relievers

Taking high doses of common pain relievers for a long time may increase the risk of heart attack or stroke up to one-third, a review of research finds. The study focused on nonsteroidal anti-inflammatory drugs (NSAIDs). These drugs include ibuprofen (Advil, Motrin and generics) and naproxen (Naprosyn, Anaprox, Aleve and generics). Diclofenac, another NSAID, is popular in Europe. Rofecoxib (Vioxx) was taken off the market in 2004 because of an increased heart attack risk. Other coxibs, including celecoxib (Celebrex), are still sold. Experts still debate whether other NSAIDs carry the same risk as Vioxx. The new research review combined results of 639 studies. People in these studies were randomly assigned to take an NSAID or a placebo (fake pill). Taking high-dose diclofenac or a coxib increased the risk of heart attacks, strokes and related death by about one-third. That's equal to about 3 extra events for each 1,000 people at average risk who took a high dose of the drug for a year. On average, one event would be fatal. Taking high-dose ibuprofen increased the risk of heart attack but not stroke. Naproxen did not show an increased risk. The journal Lancet published the study online May 29. Reuters and MedPage Today wrote about it.

By Howard LeWine, M.D.
Harvard Medical School

What Is the Doctor's Reaction?

Most people don't think twice about taking over-the-counter Motrin, Advil or Aleve. These drugs belong to a class called nonsteroidal anti-inflammatory drugs (NSAIDs).

NSAIDs are very popular. But how about safety?

People take NSAIDs most often to relieve pain. They also reduce inflammation for many people with arthritis. NSAIDs can calm a throbbing, gouty joint within hours.

With some exceptions, they are considered pretty safe when used from time to time in low to moderate doses. The exceptions include people with kidney disease and those with a history of peptic ulcer or bleeding in the stomach or upper intestine. They should avoid using NSAIDs.

NSAIDs can cause fluid build-up in the body. So people with heart failure or high blood pressure need to check with their doctors before taking NSAIDs.

That's not all. Right from the time NSAIDs were first introduced, there was concern about potential increased risk of heart attacks and strokes. This concern was amplified in 2004, when rofecoxib (Vioxx), a prescription NSAID, was found to increase the risk of both. Since then, Vioxx and several related NSAIDs have been taken off the market.

Experts still debate whether the other NSAIDs increase heart attack and stroke risk. The evidence is far from clear. Some studies suggest all of them except aspirin are guilty. Other studies have shown varying degrees of risk for different NSAIDs.

This week we get a little more clarity on the issue. Researchers in England performed an extensive review of studies that addressed the connection between NSAIDs and heart and stroke risk. They analyzed 639 clinical trials that included a total of nearly 354,000 patients.

Here are some of their key findings:

• The dose matters, a lot. High doses of most NSAIDs used on a regular basis increase the risk of heart attack. For some NSAIDs, stroke risk may increase as well.
• Naproxen (Naprosyn, Anaprox, Aleve, generic versions) appears to be an exception. Full-dose naproxen, at 1,000 milligrams per day, was not linked with any higher risk.
• High-dose ibuprofen (Motrin, Advil, generic versions) at 2,400 milligrams per day increased heart attack risk, but not stroke risk.
• High-dose diclofenac (Voltaren, generics) and coxibs (Celebrex and others) primarily increase heart attack risk. But they also increase stroke risk. Diclofenac is a popular NSAID in Europe. It's prescribed much less often in the United States.
• All NSAIDs were linked with higher rates of heart failure and internal bleeding.

What Changes Can I Make Now?

Don't worry if you occasionally take an over-the-counter NSAID as long as you follow the directions on the bottle. The dose of each pill is lower than prescription doses. For some NSAIDs, it's a lot lower.

What if you need a higher dose of an NSAID for chronic pain, arthritis or some other type of inflammation? You and your doctor will need to examine your personal risks from the NSAID. You will balance that against how much the NSAID is helping you.

You want to consider three major side effects:

• Kidney damage -- This applies equally to all NSAIDs other than aspirin. People with impaired kidney function should not take high-dose NSAIDs. If there is only a minimal decrease in function, then an occasional NSAID in low dose may be OK. But always check with your doctor first.
• Stomach and upper intestinal bleeding -- Again, the dose matters. The higher the dose and the longer you take an NSAID, the greater the bleeding risk. People with a history of peptic ulcer disease, upper intestinal bleeding and seniors have a higher risk. If you need an NSAID, a coxib such as Celebrex is less risky. Or you can take an acid blocker with the NSAID to lower your chance of internal bleeding.
• Increased heart attack and stroke risk -- Naproxen may have the lowest risk of these adverse events. However, it's important to note that the actual risk from other high-dose NSAIDs is extremely low for a person with no history of heart disease. On the other hand, people with known heart disease, or with multiple factors that increase their risk of heart disease, need to consider the risk of heart attack and stroke before taking an NSAID. I would choose naproxen for these patients.

If you take an NSAID and also take aspirin for heart attack or stroke prevention, don't take them at the same time of the day. This is especially true for ibuprofen. Take the baby aspirin in the morning with breakfast. Then wait at least an hour before taking any ibuprofen. The reason is that ibuprofen and aspirin both latch on to platelets in the blood at the same spots. If you take the ibuprofen first, the aspirin won't have its usual effect of reducing blood clotting.

What Can I Expect Looking to the Future?

This well-done study has provided guidance about use of NSAIDs in people who have a higher than average risk of heart attack and stroke. You and your doctor can use this information to make more informed decisions if and when you need a high-dose NSAID.