A Study Related to Non-Steroidal Anti-Inflammatory Drug Use — Reveals How Little Critically Important Medical Research Information Makes It Out to Physicians and Patients

22 February 2013

Citation — to the study this essay is refers to

Patricia McGettigan and David Henry, Use of Non-Steroidal Anti-Inflammatory Drugs That Elevate Cardiovascular Risk: An Examination of Sales and Essential Medicines Lists in Low-, Middle-, and High-Income Countries, PLoS Medicine 10(2): e1001388, doi:10.1371/journal.pmed.1001388 (12 February 2013)

The study’s findings and implications fall into the category — “Are we really this stupid?”

The take-away lesson is that patients need to question medical information sources, including their own physicians.

Read on. What follows might save your life.

Background — NSAIDs are not harmless — and they differ from each other in the mix of risks for heart disease, bleeding, and gastro-intestinal upset that they potentially cause

Pertinent to this essay, you may recall that virtually all NSAIDs raise the risk of heart attacks or heart disease. The apparent exceptions are naproxen and aspirin.

Consequently, one might assume that physicians and the medical establishment would attempt to make themselves and their patients aware of the risk distinctions between members of the NSAID group.

Note

This isn’t a trivial issue. You may remember the September 2004 uproar, when Merck withdrew Vioxx (rofecoxib, an NSAID) from the market — after the drug had killed and sickened enough people to subject the manufacturer to a deluge of lawsuits.

The legal proceedings claimed (apparently legitimately) that Merck had known about rofecoxib’s worrisome cardiac effects and had concealed those from the FDA and the medical community.

Only after the Vioxx fiasco did the cardiac implications of virtually every other NSAID come into public light.

The authors of the above study therefore wondered whether the world’s medical establishments had awakened to elevated cardiac risks posed by some NSAIDs as compared to others.

NSAIDs’ relative risks for cardiovascular disease

Table 1 of the above cited paper is the single most important bit of information for readers to glance at.

It quantifies the relative risk (to the heart) of using one as opposed to another of a short list of 10 NSAIDs.

The study authors concluded from Table 1 that:

Three drugs (rofecoxib, diclofenac, etoricoxib) ranked consistently highest in terms of cardiovascular risk compared with nonuse.

Naproxen was associated with a low risk.

© 2013 Patricia McGettigan and David Henry, Use of Non-Steroidal Anti-Inflammatory Drugs That Elevate Cardiovascular Risk: An Examination of Sales and Essential Medicines Lists in Low-, Middle-, and High-Income Countries, PLoS Medicine 10(2): e1001388, doi:10.1371/journal.pmed.1001388 (12 February 2013) (at Methods and Findings) (paragraph split)

How to interpret Table 1 — relative risk

When we compare one drug to another, the concept of relative safety risk is commonly used. This quantifies the odds of something “bad” (or good) happening to you as compared with using an alternative drug.

For example — as the cited study uses the relative risk concept:

If your risk in using Drug A equals that in using Drug B — as compared to using no drug at all — then the relative risk is 1.0.

If A is 50 percent more dangerous than B — as compared to using no drug at all — then your risk in using A is 1.5.

If A is 30 percent less dangerous than B — as compared to using no drug at all — then your risk in using A is 0.70.

Now a bit science — the art of discriminating between the quality of studies

If you are scientifically literate, you already know that studies differ from each other in terms of their methodological quality and the questions they were designed to answer.

If you look at Table 1, you will immediately see that the paper’s authors categorized them into two groups: “observational” and “randomized.”

Very generally speaking and all things equal, randomized studies are more scientifically rigorous than observational studies.

However, observational studies have the advantage of usually dealing in larger numbers of subjects and, therefore, result in “higher” (meaning more persuasive) statistical power — all at the risk of containing concealed variables (confounders) that would (if spotted) destroy their ostensible persuasiveness.

You will also notice that the relative risks that Table 1 assigns to each drug varies from one study to another. You will also see that the two randomized studies were looking at different outcomes — composite versus cardiovascular. But that’s par for the scientific course.

The numerical take-away from Table 1

Here’s the kicker — Using the two randomized studies in Table 1 (which are admittedly not precisely equivalent because one was looking a composite outcomes and the other at cardiovascular events):

Vioxx (rofecoxib) was pulled from the market with a relative risk of 1.42 to 1.44.

But the following drugs remain in use worldwide —

Diclofenac — 1.60 to 1.63

Etoricoxib — 1.53

Ibuprofen — 1.51 to 2.26

As compared to the cardiovascularly safest —

Naproxen — 0.92 to 1.22

The paper’s authors wondered whether this information had made its way out into the global prescribing world.

The study looked at various nations’ lists of recommended medicines

These lists are called “Essential Medicines Lists.”

They are based on the World Health Organization’s recommendation that each country have a list of indispensable, widely available, and affordable medications:

Essential medicines are intended to be available within the context of functioning health systems at all times in adequate amounts, in the appropriate dosage forms, with assured quality and adequate information, and at a price the individual and the community can afford.

Oops — what are these medical establishments thinking?

One would think that such an essential medicines list would discriminate in favor of the significantly safer of two alternatives.

Apparently not so:

Three drugs (rofecoxib, diclofenac, etoricoxib) ranked consistently highest in terms of cardiovascular risk compared with nonuse.

Naproxen was associated with a low risk.

Diclofenac was listed on 74 national EMLs [essential medicine lists], naproxen on just 27.

Rofecoxib use was not documented in any country.

Diclofenac and etoricoxib accounted for one-third of total NSAID usage across the 15 countries . . . . This proportion did not vary between low- and high-income countries.

Diclofenac was by far the most commonly used NSAID, with a market share close to that of the next three most popular drugs combined.

Naproxen had an average market share of less than 10%.

The meaning of all this — for “you”

Know the relative cardiovascular risks of the NSAIDs you are on or are considering for use. Discuss those with your physician.

My personal experience, for example, bears out the cited study. The medical community is usually rather cavalier about the cardiovascular risk differences among currently marketed NSAIDs. The average physician (in my experience) pays more attention to the risks associated with induced gastro-intestinal distress, than he or she does to potentially subtle cardiovascular risks that they pose.

This does not indicate sloppy medical practice. I’ve been appalled at how difficult it is to track down a decent list of the cardiac-related, relative risks among the various NSAIDs. It is as if the medical establishment itself is not cognizant of what information is out there. Which, of course, is the study’s main point.

The moral? — (a) What you don’t know, your doctor may not tell you — and (b) the medical establishment does a poor job of communicating research findings in ways that people remember and prioritize

Research your meds.

For an illustrative vignette of what can happen, when an NSAID has concerning (but non-fatal) cardiac effects, read about my not so subtle experience with ibuprofen — after decades of using it.

Not everyone walks away.

PeteFree.com

A Study Related to Non-Steroidal Anti-Inflammatory Drug Use — Reveals How Little Critically Important Medical Research Information Makes It Out to Physicians and Patients