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Owing to summer vacation, today’s post updates a 2011 post and a 2013 post with some new information.

Anti-inflammatory drugs are among the most well-loved products in the modern medicine cabinet. They can provide good pain control, reduce inflammation, and eliminate fever. We give non-steroidal anti-inflammatory drugs (NSAIDs) in infancy, continuing through childhood and then adulthood for the aches and pains of modern living. It’s the later stages of life where NSAIDs are used most frequently, usually in the treatment of joint disease like osteoarthritis, which eventually affects pretty much everyone. Over 17 million Americans use NSAIDs on a daily basis, and this number will grow as the population ages. While they’re widely used, they also have a long list of side effects. Not only can they cause stomach ulcers and bleeding by damaging the lining of the gastrointestinal tract, cardiovascular risks are also significant.

It was the arrival (and withdrawal) of the drugs Bextra (valdecoxib) and Vioxx (rofecoxib) that led to a much better understanding of the potential for these drugs to increase the risks of heart attacks and strokes. And it’s now well-documented that these effects are not limited to the “COX-2″ drugs – almost all NSAIDs, including the old standbys we have used for years, raise the risk of heart attacks and strokes.

Natural origins

ASA (acetylsalicylic acid, better known as aspirin) is the prototypical NSAID. ASA traces its origins back to willow bark, a natural source of the chemical salicylate. All NSAIDs work the same way, interrupting the production of inflammatory and pain-related hormones called prostaglandins. Since ASA’s introduction in 1897, more than two dozen chemically-related drugs have been developed. They’re now among the most commonly used drugs used worldwide. If you believe the marketing, you may think there are vast differences between the NSAIDs in terms of efficacy and safety. But the evidence show that NSAIDs are similarly effective at the population level, though individual response, and toxicities, can vary between drugs. Currently available NSAIDs differ in their side effect profile based on the way they work at a molecular level. The discovery of different forms of what are called “cyclooxygenase” enzymes led to interest in developing drugs that targeted COX-2 (at sites of inflammation) rather than COX-1 enzymes. COX-1 enzymes regulate normal cellular processes including protecting the lining of the stomach and blood clotting. Inhibit COX-2 rather than COX-1, the thinking went, and you could get the anti-inflammatory action of traditional NSAIDs without serious gastrointestinal side effects. Traditional NSAIDs (e.g., Advil) are considered “unselective” NSAIDS. To minimize GI side effects, manufacturer’s developed more “selective” NSAIDs that preferentially inhibited COX-2. “COX-2” drugs like Celebrex (celecoxib) provide comparable pain relief to a traditional NSAID, like Naprosyn (naproxen) but with a lesser risk of causing stomach ulcers and bleeds. However, as the Vioxx debacle demonstrated, COX-2 inhibitors had a significant prothrombic (i.e., blood clotting) effect – with devastating cardiac consequences (e.g., heart attack and stroke).

The risks of NSAIDs

Prescription drugs can cause harm. They can even hospitalize. While we may think nothing of popping a few Advil now and then, NSAIDs have been linked to about 30% of drug-related hospital admissions, and it’s estimated that 12,000-16,000 Americans die annually as a result of gastrointestinal bleeding caused by NSAIDs.

Stomach bleeding and ulcers are an expected side effect of the way NSAIDs work – their effect on prostaglandins. The lining of the gut is weakened, and stomach and duodenal ulcers result. Even very low doses of ASA have been documented to have measurable effects on the mucosal lining of the gastrointestinal tract. The risks of gastrointestinal toxicity are significantly increased in the elderly, in those on high doses of NSAIDs, and when combined with other drugs (e.g., steroids) that suppress normal stomach protection.

The cardiovascular risks of NSAIDs became well documented following the worldwide withdrawal of Vioxx and international examinations of the cardiovascular risks of the entire category of drugs. Data have now emerged to convincingly establish that most NSAIDs (except ASA in low doses) are associated with an increased risk of cardiovascular events. Vioxx alone is estimated to have caused as many as 140,000 heart attacks over the five years it was sold in the US. Chronic (routine) consumption of NSAID drugs is linked to small but real increases in heart attacks and stroke. These effects may be a consequence of interference with the beneficial effects of concurrent low dose ASA, direct negative cardiovascular effects, and worsening of fluid balance, leading to heart failure.

When it comes to cardiovascular risks, not all NSAIDs are the same, and the US Food and Drug Administration (FDA) has met regularly to review emerging data since the Vioxx/Bextra withdrawal. The FDA also asked Pfizer to examine celecoxib’s safety compared with ibuprofen and naproxen in what became known as the PRECISION trial (Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen Or Naproxen) that launched in 2005. As of 2015 there are over 24,000 participants enrolled, however the rate of cardiovascular events has been lower than expected, limiting any conclusions about the differences in cardiovascular harms. The trial wasn’t expected to conclude until the end of 2015 [PDF], and that date has since been revised to 2016.

The most recent FDA meeting was in 2014. It resulted in an FDA announcement earlier this month that strengthened their warning on the use on non-aspirin NSAIDs and the risk of heart attack and stroke. If you’re interested in the details of the FDA’s review, there is a nice open-access summary in Drug Safety, but here are a few highlights of some of the data examined:

A 2011 network meta-analysis examined traditional NSAIDs, like naproxen, ibuprofen, and diclofenac, as well as the COX-2 selective NSAIDs, like celecoxib and rofecoxib. It concluded “Although uncertainty remains little evidence exists to suggest that any of the investigated drugs are safe in cardiovascular terms. Naproxen seemed least harmful. Cardiovascular risk needs to be taken into account when prescribing any non-steroidal anti-inflammatory drug.”

A 2011 Danish observational study examined NSAID use in those with cardiovascular disease and concluded that even short-term use of NSAIDS raises the risk of heart attack and death. It recommended against short- and long-term use of NSAIDs in this group.

A 2013 network meta-analysis of trials concluded that the cardiovascular risks of diclofenac and high-dose ibuprofen are comparable to the COX-2 drugs, and noted that naproxen is associated with less risk than other NSAIDs.

Given the latest data, the FDA has now announced the following for over-the-counter and prescription NSAIDs (excluding ASA):

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

The risk appears greater at higher doses.

It was previously thought that all NSAIDs may have a similar risk. Newer information makes it less clear that the risk for heart attack or stroke is similar for all NSAIDs; however, this newer information is not sufficient for us to determine that the risk of any particular NSAID is definitely higher or lower than that of any other particular NSAID.

NSAIDs can increase the risk of heart attack or stroke in patients with or without heart disease or risk factors for heart disease. A large number of studies support this finding, with varying estimates of how much the risk is increased, depending on the drugs and the doses studied.

In general, patients with heart disease or risk factors for it have a greater likelihood of heart attack or stroke following NSAID use than patients without these risk factors because they have a higher risk at baseline.

Patients treated with NSAIDs following a first heart attack were more likely to die in the first year after the heart attack compared to patients who were not treated with NSAIDs after their first heart attack.

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

So for the individual consumer, when do the risks outweigh the benefits of NSAIDs? Ultimately this comes down to an individual consideration of reasons for use, risk factors, and expected benefits. When used for treating short-term conditions, the increase in risk for those without cardiovascular disease appears to be very low. While the data seems pretty convincing that naproxen is associated with less cardiovascular risk, the FDA did not make a definitive statement to this effect. In those with a low risk of cardiovascular disease, there doesn’t appear to be much difference between ibuprofen and naproxen when taken occasionally. In those that need to take an NSAID for a longer period, naproxen (versus the other NSAIDs) looks like a safer choice from a cardiovascular perspective.

Topical NSAIDs: The evidence

Over the past two decades, evidence has emerged to demonstrate that topical versions (e.g., over-the counter gels) of NSAIDs are well absorbed through the skin and reach therapeutic levels in synovial fluid, muscle, and fascia. Given the cardiovascular harms of NSAIDs seem to be dose-related, do topical versions provide comparable benefits with less harm? A 2012 Cochrane Review provides the most recent summary of the evidence for chronic pain, concluding that there is good evidence that topical NSAIDs (like diclofenac) provide similar pain relief to oral NSAIDs (for knee and hand osteoarthritis) with reduced gastrointestinal side effects. The reviewers note that there is a lack of long-term safety data for topical NSAIDs, and consequently there is a lack of evidence on the associated cardiovascular risks. (This is owing to their relative rarity compared with gastrointestinal side effects.) A 2010 Cochrane review also reports positive findings about the use of these products in the treatment of acute pain conditions. Forty-seven trials were included in their analysis that considered topical NSAIDs for strains, sprains, and overuse-type injuries. Compared to placebo, topical NSAIDs were evaluated to be more effective, with fewer side effects. Given the systemic absorption of NSAIDS like diclofenac is lower with topical versions, the toxicity we associate with oral NSAIDs should be lessened, too. There’s little evidence to demonstrate that topical NSAIDs are effective for some types of pain, like back pain, headache, or neuropathic pain. But based on what’s now known about the cardiovascular toxicity of NSAIDs, it’s likely that topical products provide a superior risk/benefit perspective over the oral NSAIDs (at least for some pain/joint conditions).

What about Tylenol?

As Harriet Hall noted last year, while acetaminophen (paracetamol) is widely used for the treatment of pain, the evidence for its efficacy is modest. As long as it is given in appropriate doses, however, there’s no evidence that suggests that Tylenol is associated with the cardiovascular risks of NSAIDs. However, it seems reasonable to continue to use acetaminophen before trying NSAIDs for conditions that require pain relief but not anti-inflammatory effects.

Conclusion: NSAIDs are convenient, effective, and safe, but not harmless

While NSAIDS may be conveniently purchased in large quantities from your neighbourhood drug store, don’t let the ease of access imply these products are harmless, especially if used inappropriately. Everyone that takes an NSAID raises their risk of cardiovascular and gastrointestinal harm to some extent. Consequently, the safest strategy is to take the lowest effective dose for the shortest duration of time. Those with pre-existing cardiac conditions or risk factors should check with their primary care provider before taking NSAIDs, to determine if non-NSAID alternatives may offer a better balance of benefit vs. risk.

While the evidence comparing NSAIDs is still somewhat murky, naproxen seems safest amongst the non-prescription oral NSAIDs. Topical NSAIDs also appear to be useful alternatives to regular oral NSAID use. Among the prescription NSAIDs, it’s somewhat of a mystery that oral diclofenac remains licensed and in use as a prescription drug despite the evidence that it causes heart attacks and strokes in rates similar to that of Vioxx.

The lesson in the NSAID–cardiovascular story is the impact and need for good evidence. All drugs, even those with life-changing benefits, may have serious albeit rare unintended consequences. The evolving safety evidence on NSAIDs is a constant reminder of the challenge of balancing risks and benefits in the absence of good evidence.

Photo via flickr user An Nguyen used under a CC licence.