Friday, February 22, 2013

Study Raises Red Flag on Diclofenac

NSAID Cardiac RiskInformation on cardiovascular risks associated with different nonsteroidal anti-inflammatory drugs, or NSAIDs, has been available for several years, but practitioners in many countries have not changed their prescribing of these agents based on that information. After a thorough data analysis, researchers recently concluded that diclofenac is among the most widely recommended and used NSAIDs, but due to its considerable cardiovascular risks it should be removed from lists of essential medicines worldwide.

Writing in the online journal PLoS Medicine, Patricia McGettigan, from The London School of Medicine and Dentistry in the UK, and David Henry, from the University of Toronto in Ontario, Canada, report on the extent to which evidence on cardiovascular risks associated with different NSAIDs has translated into guidance and sales in a broad selection of countries globally [McGettigan and Henry 2013]. They gathered data from several sources:

  1. The researchers amalgamated extensive data on the relative risks of cardiovascular events associated with individual NSAIDs compared with placebo or non-use of NSAIDs from published meta-analyses of randomized trials and observational studies.

  2. They obtained information on NSAIDs recommended in 100 countries from national Essential Medicines Lists, or EMLs. (Essential medicines are drugs that have been judged as satisfying the priority health care needs of a population.)

  3. Finally, information on NSAID prescriptions or sales for 15 low-, middle-, and high-income countries — including England, Canada, and 13 countries across South Asian, Southeast Asian, and Asian Pacific regions — was obtained from Intercontinental Medical Statistics Health (IMS Health) or national prescription pricing audits (in the case of England and Canada).

In their analysis, diclofenac, etoricoxib, and rofecoxib consistently ranked highest in terms of cardiovascular risks compared with placebo or no NSAID use. And, all 3 had a higher relative risks of cardiovascular events than naproxen, which was associated with the lowest risk of all NSAIDs. Yet, while 74 national EMLs listed diclofenac, only 27 EMLs listed naproxen.

According to the EMLs available for 100 countries, the most commonly recommended NSAIDs were ibuprofen (90 countries), aspirin (88 countries), diclofenac (74 countries), indomethacin (aka indometacin, 56 countries), and naproxen (27 countries). None of the national EMLs recommended rofecoxib, which had been withdrawn from world markets 8 years ago because of its cardiovascular risks. In 51 of the countries that listed diclofenac, naproxen was not included on their EMLs at all.

In terms of estimated usage, diclofenac and etoricoxib accounted for roughly one-third of total NSAID prescriptions across the 15 countries assessed, and this proportion did not differ 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 3 most popular drugs — ibuprofen, mefenamic acid, and naproxen — combined. However, naproxen alone had an average market share of less than 10%.

Overall, the researchers conclude that evidence regarding cardiovascular risks associated with diclofenac has not been translated into appropriate selection in EMLs or for usage of this drug. They stress that NSAID recommendations should be based on the optimum balance of benefit and harm, with lower risk drugs — such as ibuprofen and naproxen — given greatest preference. Diclofenac has a clear disadvantage in terms of cardiovascular risk, and it has no advantage in terms of gastrointestinal safety; so, they recommend the removal of diclofenac from EMLs and further suggest, “There are strong arguments to revoke its marketing authorizations globally.”

COMMENTARY: It is important to note that this study appears to address only oral formulations of the NSAIDs in question, and may not be equally applicable to injectable versions, NSAID/opioid combination products, or topical formulations. In particular, there are topical formulations of diclofenac that with recommended usage and localized application may not incur risks to the same extent as their systemic counterparts.

Cardiovascular risk assessments by McGettigan and Henry of the various NSAIDs in the present study were limited by insufficient data in several areas: 1) cardiac risk profiles of individual patients taking NSAIDs, 2) prevalence of use among high-risk patients, 3) dosages taken, and 4) duration of therapy. As with all analyses of this nature, data were analyzed on a macroscopic level; whereas, risks in individual patients, especially during short-term or only episodic analgesic use, may be different from overall population averages.

Previous discussions in Pain-Topics UPDATES have highlighted the fact that all NSAIDs incur gastrointestinal and cardiovascular risks to some extent, with naproxen almost always having the most favorable cardiac safety profile. Risks may vary depending on the cardiovascular adverse event being investigated. For example, an examination by Trelle et al. of 31 RCTs comparing NSAIDs with placebo, encompassing 115,000 patient years of followup, found that large-dose ibuprofen had a relatively high risk of stroke followed closely by diclofenac; rofecoxib had the greatest risk of myocardial infarction; and, diclofenac and etoricoxib exhibited the highest risk of cardiovascular death [see UPDATE here].

In an earlier paper by McGettigan and Henry (2011, see UPDATE here), these researchers conducted a systematic review and meta-analysis of 51 observational studies covering nearly 3-million patients. They concluded that diclofenac and rofecoxib have the overall highest cardiac risks, and naproxen and ibuprofen the least risks. However, in a sub-set of studies risk increases were seen with ibuprofen at higher daily doses.

ANSAID risk figure (at right) from that review depicts pooled Relative Risks for cardiovascular adverse events, demonstrating considerable overlap of Confidence Intervals for many of the NSAIDs; so, the safety profiles can become somewhat muddled. Absolute risk differences between the various agents are not provided in the data; however, diclofenac is clearly among the least favorable in terms of cardiac safety, comparable to the discontinued rofecoxib, and naproxen has a highly favorable safety profile in this regard.

In this analysis, ibuprofen also was considered to have a favorable cardiac risk profile, provided maximum recommended doses are not exceeded. However, this advantage needs to be weighed against ibuprofen’s moderate gastrointestinal risks and its potential to antagonize beneficial cardiac effects of low-dose aspirin if the two therapies are used concurrently.

The latest study by McGettigan and Henry [2013] took a global perspective and they came out quite strongly against diclofenac. A major issue seems to be diclofenac’s very extensive use, despite its cardiac concerns, and the relatively sparse use of naproxen as a much safer alternative worldwide. Overall, the findings of this study, and the breadth and depth of good evidence questioning NSAID safety in general, have important public health implications that merit greater attention by practitioners and patients everywhere.

REFERENCE: McGettigan P, Henry D (2013) 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 Med 10(2): e1001388 [available here].

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Eric Widera said...

As always an excellent analysis of the study. It is interesting that there seems to be a lot of teaching about the differences between opioids in medical training, but little education on the differences between NSAIDs.

SB. Leavitt, MA, PhD said...

Thank you, Dr. Widera, for your comment -- and also for the terrific and important work you do at the blog. Unfortunately, NSAIDs are being touted in some circles these days as the “safe” alternative to opioids; yet, at the high doses required for analgesia comparable to opioids, many of the NSAIDs may be lethal. They may not be addictive or sold on the streets and abused, but NSAIDs can be very harmful to health when wrongly used, as you know.

Robert Baxter said...

Relative risk is a useful measure, but, when it comes to counselling patients, what is more useful to know is absolute risk - how many adverse events of what type per 1000 patient-years. That information is lacking in this study.

Unknown said...

I am concerned when a drug is withdrawn from the Essential Medicine List and no substitute is added. Diclofenac is often used in African hospitals and clinics where opioids are not available

SB. Leavitt, MA, PhD said...

I agree with Mr. Baxter (above) that knowing absolute risks would be helpful. From that NNH (numbers needed to harm) can be calculated, which can be interpreted in a meaningful way for patients. I’m not certain that discussing # adverse events per 1,000 pt. years would be helpful for counseling purposes.