Are ALL Arthritis Drugs Including Celebrex Risky for the Heart?

The big news out of the American Heart Association meetings in New Orleans is that Celebrex (celecoxib) is no more dangerous for the heart and cardiovascular system than pain relievers like ibuprofen or naproxen (New England Journal of Medicine, Nov. 13, 2016). Does that mean we can all breathe a sigh of relief? Not so fast. It may be no worse, but it is also no safer for the heart.

The Great Noninferiority Game:

Researchers have come up with a fascinating way of describing the concept of “no worse than.” They call it “noninferiority.” In other words, if drug X causes diarrhea in 30 percent of the people who take it and drug Y also causes diarrhea in 30 percent of patients, then drug Y is “noninferior” to drug X. Depending upon your perspective, that is either a glass-half-full or a glass-half-empty kind of situation. Drug companies love to spin noninferiority as a great thing.

The Good News About Celebrex:

One could argue that many researchers expected Celebrex to fare worse than ibuprofen and naproxen. That’s because it belongs to the same family of “coxib” medications as Vioxx (rofecoxib) and Bextra (valdecoxib). These COX-2 inhibitors selectively block an enzyme called cyclooxygenase-2. This targeted treatment was supposed to spare the digestive tract from damage caused by classic NSAIDs like ibuprofen and naproxen.

The Big Ooops!

There was an unexpected glitch, however. Researchers discovered that blocking the COX-2 enzyme seemed to have unexpected cardiovascular complications. The FDA requested that both Vioxx and Bextra be withdrawn from the market more than a decade ago because of an increased risk of heart attacks, strokes and death. The fear was that Celebrex might be just as bad.

That’s why the FDA asked Pfizer to conduct a large follow-up study (“PRECISION”). The results of this 24,000-patient trial comparing ibuprofen to naproxen to Celebrex produced interesting but confusing results. Celecoxib did not appear to cause more heart attacks or strokes than ibuprofen or naproxen. That’s what is meant by the conclusion in the New England Journal of Medicine that:

“At moderate doses, celecoxib was found to be noninferior to ibuprofen or naproxen with regard to cardiovascular safety.”

The Bad News About Celebrex:

There is another way to describe the results of the Celebrex vs. ibuprofen vs. naproxen study. It was no worse for the heart than other popular NSAIDs…but it was no better either!

The controversy over Vioxx back in 2004 forced the FDA to start looking at all NSAIDs to see whether they too might pose a risk for heart attacks, strokes and death. Prior to the COX-2 drug debacle, there was little awareness among health professionals and patients that NSAIDs like diclofenac, ibuprofen, meloxicam or naproxen could cause cardiovascular complications.

When we asked a high-level FDA official why it took the FDA so long to discover the problem, he confessed that the agency is not very good at picking up common complications. In other words, lots of people take NSAIDs every day. Lots of people have heart attacks every day. Since the FDA was not looking for such an association, it did not connect the dots. It turns out that it was far easier for the safety sleuths at the agency to link rare adverse drug reactions like kidney failure or bleeding ulcers to NSAIDs than it was to uncover a heart attack link.

NSAID Warnings:

Once researchers started looking they discovered that traditional NSAIDs were also capable of causing heart attacks, strokes and premature death. In 2005 the FDA alerted health professionals in a boxed warning that NSAIDs in general could increase the risk of heart attack and stroke, “either of which can lead to death.”

On July 9, 2015, the FDA strengthened the warning on prescription-strength NSAID labels:

“The risk of heart attack or stroke can occur as early as the first weeks of using an NSAID. The risk my increase with longer use of the NSAID.

“The risk appears greater at higher doses…

“NSAIDs can increase the risk of heart attack or stroke in patients with or without heart disease or risk factors for heart disease…

“There is an increased risk of heart failure with NSAID use.”

Are All NSAIDs Hard on the Heart?

A meta-analysis of 280 studies involving 124,513 patients concluded that traditional NSAIDs like diclofenac and ibuprofen were just as dangerous to the heart as coxibs like Vioxx and Celebrex (Lancet, Aug. 31, 2013). The investigators concluded that the risk of heart failure was doubled whether people were taking traditional NSAIDs or the newer coxibs like Celebrex.

A study in the European Heart Journal (Oct. 4, 2016) followed 7,297 patients who were taking either Celebrex or traditional NSAIDs for roughly 3 years. They found that cardiovascular events were…”similar on celecoxib and NSAIDs.”

High Risk Patients Especially Vulnerable:

People with high blood pressure or heart disease seem especially susceptible to NSAID nastiness. More than 22,000 volunteers from 14 different countries participated in a study that lasted over two years. Patients who used medications such as ibuprofen or naproxen were more likely to suffer heart attacks, strokes and death  (American Journal of Medicine, July, 2011).

The authors of the study concluded that, in patients with heart disease,

“chronic use of NSAIDs should be avoided where possible…Until further data are available, alternative modes of pain relief should be considered for these patients.”

People who have experienced a heart attack are in trouble if they need a pain reliever. A Danish study of 99,187 patients who had experienced a myocardial infarction (MI, also known as a heart attack) were substantially more likely to have another heart attack or suffer “coronary death” if they used an NSAID-type pain reliever (Circulation, Sept. 10, 2012).

Their Conclusions:

“The use of NSAIDs is associated with persistently increased coronary risk regardless of time elapsed after first-time MI. We advise long-term caution in using NSAIDs for patients after MI.”

People’s Pharmacy Take Home Message:

NSAIDs, including the newer generation coxibs, can be hard on the heart. Whether it is celecoxib (Celebrex), diclofenac, ibuprofen, meloxicam, naproxen or piroxicam, there is an increased risk for heart attacks and heart failure. High blood pressure and an irregular heart rhythm called atrial fibrillation (AFib) have also been linked to NSAIDs (BMJ Open, April 8, 2014).

As far as we can tell, there is no one NSAID that appears safer for the heart and cardiovascular system than any other NSAID. Some studies suggested that naproxen (Aleve, Naprosyn, etc) might be less likely to trigger a heart attack or other vascular event. There was even an effort to soften the warning on this NSAID. The new research published in the New England Journal of Medicine did not demonstrate an advantage of naproxen over other NSAIDs. Steve Nissen, MD, lead author of the study was quoted by NPR:

“What is so surprising about it is that most authorities have believed that if there was a drug that was the safest, it was naproxen,” Nissen says. “So we were pretty surprised that there was this borderline significant increase in all-cause mortality with naproxen.”

A Final Word:

How good are NSAIDs at relieving pain? That remains a bit of a mystery. There are some people who absolutely love their favorite NSAID and maintain that they could not function without celecoxib, naproxen, or ibuprofen. But others report modest benefit at best.

One of the most intriguing outcomes of Dr. Nissen’s PRECISION trial that many people have overlooked was the dropout rate. By the end of the study 69 percent of the participants had bailed out. These were patients suffering from the pain of osteo- or rheumatoid arthritis. That means they were in chronic pain that was unlikely to go away. The idea that two-thirds of the subjects gave up on their free medicine suggests to us that these drugs are not all that terrific for easing inflammation and pain.

The high drop-out rate has also led some scientists to question the validity of the data. And some skeptics have suggested that the deck was stacked in favor of celecoxib. The dose of Celebrex was pegged at 200 mg regardless of pain level. Doctors could increase the dose of ibuprofen and naproxen to help patients dealing with persistent pain. Some physicians have suggested that this protocol might have increased the risk of cardiac complications for both ibuprofen and naproxen while holding them constant for celecoxib.

If you would like to learn more about nondrug alternatives to NSAIDs, you will find our chapter on “joint pain and arthritis “in The People’s Pharmacy Quick & Handy Home Remedy book of great practical value. Here is a link to our bookstore where you can find it and other publications for dealing with pain and inflammation.