Avoiding Toxic Anti-inflammatory Drugs

Summarized by Robert W. Griffith, MD
November 21, 2006

Summary

Reviews of published studies concerning COX-2 inhibitor heart and kidney side effects show that Vioxx^® is the main culprit. The still available COX-2 inhibitor, Celebrex^®, has a clean profile at doses of 200 mg daily or below.

Introduction

Nonsteroidal anti-inflammatory drugs (NSAIDs), which are taken by millions of arthritis sufferers, have been associated with multiple complications when used on a chronic basis. Cardiovascular problems (heart attack, irregular rhythm, high blood pressure) were reported with the COX-2 inhibitors, a subclass of NSAIDs; Vioxx^® (rofecoxib) was withdrawn, and Celebrex^® (celecoxib) carries a very severe FDA warning.

NSAIDs can reduce pain and inflammation from many medical conditions by inhibiting two different COX enzymes called COX-1 and COX-2. NSAIDs that inhibit only COX-2 enzymes were created to provide relief from pain and inflammation while avoiding side effects such as heartburn, stomach bleeding, or diarrhea, which can occur when NSAIDs are taken regularly for long periods.

It's become clear that the division into COX-1 and COX-2 inhibitors is not perfect, so that some 'regular' NSAIDs also have occasional cardiovascular side effects, and some COX-2 inhibitors may cause gastric problems. Two recent articles and an editorial in the Journal of the American Medical Association try to clarify the situation. Here's a summary of the two articles. A listing of the drugs discussed, with both their generic and brand names, is given at the end of this piece.

Cardiovascular effects of COX-2 inhibitors and non-selective NSAIDs

The Australian authors of the first article reviewed 23 published studies that compared the risk of cardiovascular events for both types of anti-inflammatory drugs. The vast majority of events were heart attacks (myocardial infarcts or MIs), but they included cases of sudden cardiac death and stroke (one study).

There was a dose-related risk for such events with rofecoxib, which was evident during the first month of treatment. There was no such effect with celecoxib at doses of 200 mg daily, but a possible effect at 400 mg daily cannot be excluded.

Two older drugs usually considered as 'regular' NSAIDs - diclofenac and meloxicam - are, in fact, fairly pronounced COX-2 inhibitors. They both showed an increased risk of provoking a cardiovascular event. Indomethacin, a drug not often used because of its gastric toxicity, also had an increased risk of cardiovascular effects.

The rank order for increased cardiovascular risk was given as (highest first): rofecoxib, diclofenac, indomethacin, meloxicam, ibuprofen, celecoxib, piroxicam, and naproxen. Naproxen, the last in this list, has been claimed to have a protective effect against heart toxicity; this, however, is false - there was no statistically significant evidence of any 'benefit' in these analyses, just a lack of any deleterious effect.

Kidney and cardiac irregularity effects of rofecoxib

The renal (kidney) and pro-arrhythmic (irregularity of heartbeat) effects of COX-2 inhibitors has received less attention than their increased MI risk. The second article published, coming from the Harvard School of Public Health, focused on this problem. The authors analyzed 114 clinical trials covering 116,000 patients. They found that rofecoxib treatment was associated with an increased risk of peripheral edema (tissue swelling), high blood pressure, and impaired kidney function; and it was seen at both low and high doses.

The risk of irregular heartbeats was also increased in patients given rofecoxib, along with an increase in sudden cardiac deaths. No such effects were seen with celecoxib, valdecoxib, or etoricoxib. In fact, there was a significantly lower risk of high blood pressure and kidney impairment with celecoxib.

What's the best choice for patients?

In an accompanying editorial,¹ Dr David Graham of the FDA advised that for most patients with arthritis or others who need chronic pain relief, naproxen (Aleve^®, Naprosyn^®) appears to be the safest choice of NSAID, from a cardiovascular perspective. For those at high risk for NSAID-related gastrointestinal side effects, naproxen plus a proton pump inhibitor (e.g. Prilosec^® or Nexium^®) is less expensive and just as effective as low-dose celecoxib, and probably safer.

Further studies will reveal just how risky celecoxib is, from a cardiac safety viewpoint, and whether it has any 'protective' effect on kidney function and high blood pressure. The clinical studies necessary to show the safety and effectiveness of the two COX-2 inhibitors in development (etoricoxib and lumiracoxib), coupled with FDA's new awareness of potential problems, should lead to ultra-safe and effective compounds. Until then, a little Aleve or Naprosyn, maybe with Prilosec, should do very well.

NSAIDs (COX-1 plus COX-2 Inhibitors)
Ibuprophen Advil^®, Motrin^®
Indomethacin Indocin^®
Naproxen Aleve^®, Naprosyn^®
Piroxicam Feldene^®

COX-2 Inhibitors
Celocoxib Celebrex^®
Diclofenac Voltaren^®
Etoricoxib* Arcoxia^®*
Lumiracoxib* Prexige^®*
Meloxicam Mobic^®
Rofecoxib+ Vioxx^®+
Valdecoxib+ Bextra^®+

+ = withdrawn
* = in development

Sources

• McGettigan P, Henry D. Cardiovascular risk ands inhibition of cyclooxygenase. JAMA 2006;296(doi:10.1001/jama.296.13.jrv60011)



• Zhang J, Ding EL, Song Y. Adverse effects of cyclooxygnease 2 inhibitors on renal and arrhythmia events. JAMA 2006;296(doi:10.1001/jama.296.13.jrv60015)

Footnotes
1. Graham DJ. COX-2 inhibitors, other NSAIDs, and cardiovascular risk. Editorial. JAMA 2006;296(doi:10.1001/jama.296.13.jed60058)

Related Links
About.com: NSAIDs Side Effects
FDA's 2005 Warning on COX-2 Drugs
Mayo Clinic: NSAIDs - How to Avoid Side Effects

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