COX-2 Inhibitors and NSAIDs increase the risk of atherothrombosis- a metanalysis

[Anil Tuladhar]

The authors aimed to assess the effects of selective cyclo-oxygenase-2 (COX 2) inhibitors and traditional non-steroidal anti-inflammatory drugs (NSAIDs) on the risk of vascular events.

This is a meta-analysis of published and unpublished tabular data from randomised trials, with indirect estimation of the effects of traditional NSAIDs.

Data sources: Medline and Embase (January 1966 to April 2005); Food and Drug Administration records; and data on file from Novartis, Pfizer, and Merck.

Eligible studies were randomised trials that included a comparison of a selective COX 2 inhibitor versus placebo or a selective COX 2 inhibitor versus a traditional NSAID, of at least four weeks' duration, with information on serious vascular events (defined as myocardial infarction, stroke, or vascular death). Individual investigators and manufacturers provided information on the number of patients randomised, numbers of vascular events, and the person time of follow-up for each randomised group.

Results: In placebo comparisons, allocation to a selective COX 2 inhibitor was associated with a 42% relative increase in the incidence of serious vascular events (1.2%/year v 0.9%/year; rate ratio 1.42, 95% confidence interval 1.13 to 1.78; P = 0.003), with no significant heterogeneity among the different selective COX 2 inhibitors. This was chiefly attributable to an increased risk of myocardial infarction (0.6%/year v 0.3%/year; 1.86, 1.33 to 2.59; P = 0.0003), with little apparent difference in other vascular outcomes. Among trials of at least one year's duration (mean 2.7 years), the rate ratio for vascular events was 1.45 (1.12 to 1.89; P = 0.005). Overall, the incidence of serious vascular events was similar between a selective COX 2 inhibitor and any traditional NSAID (1.0%/year v 0.9%/year; 1.16, 0.97 to 1.38; P = 0.1). However, statistical heterogeneity (P = 0.001) was found between trials of a selective COX 2 inhibitor versus naproxen (1.57, 1.21 to 2.03) and of a selective COX 2 inhibitor versus non-naproxen NSAIDs (0.88, 0.69 to 1.12). The summary rate ratio for vascular events, compared with placebo, was 0.92 (0.67 to 1.26) for naproxen, 1.51 (0.96 to 2.37) for ibuprofen, and 1.63 (1.12 to 2.37) for diclofenac.

The authors concluded that selective COX 2 inhibitors are associated with a moderate increase in the risk of vascular events, as are high dose regimens of ibuprofen and diclofenac, but high dose naproxen is not associated with such an excess.

[Soul]

Dear Dr A Tuladhar
Similar article has been posted in this site this morning. And my reply to that article (similar to this one) was:"In this study COX-2 inhibitor has been shown to be associated with cardiovascular mobidity. But what is the exact mechanism by which that do so? Ya we are aware of the fact that COX-2 stimulates NO pruduction.And studies have also shown that COX-2 plays important protective roles in the regulation of myocardial damage. COX-2 also produces PGI2, which is reported to have protective effects in myocardial cell damage. So, is this vasodilation which is responsible for the beneficial effect of COX-2?"
What do you say? Looking for ur response. Thanks in advance for solving my query.

[Anil Tuladhar]

Thanks for your swift response and my apology for duplicating the same article as I was unaware that this has been posted earlier.The COX enzyme is crucial to the formation of prostaglandins and exists in two isoforms, a constitutive isoform (COX1) and an inducible isoform that is expressed at sites of inflammation (COX2). The idea that anti-inflammatory effects are mediated through inhibition of COX2, whereas adverse gastrointestinal effects are attributable to inhibition of COX1, whose prostaglandins protect the gastric mucosa, led to the development of selective COX2 inhibitors.

We can never be sure that we know all there is to know about mechanisms. COX-2 inhibitors have been known to reduce production of prostacyclin, a vasodilator and inhibitor of platelet aggregation, which may lead to increased prothrombotic activity. You are absolutely right in saying that vasodilator effect of COX-2 have cardioprotective effect. But the jury is still out why COX-2 inhibitors has so much of negative effect on cardiovascular events.

[Soul]

Thanks for ur response.

[Aneeta]

uPPPs---I am blank on this

[Anil Tuladhar]

This is add-on to my above comments:

It has been proposed that coxibs may adversely influence the prostacyclin (antithrombotic): thromboxane (prothrombotic) ratio in the vascular wall. Coxibs may inhibit the production of prostacyclin (antithrombotic) and leave thromboxane (prothrombotic) generation unaffected (as there are no COX-2 receptors in platelets), thus promoting platelet aggregation and atherosclerosis.

Furthermore, inhibition of prostacyclin in the kidney could lead to sodium and water retention, causing hypertension. These biological actions might increase the risk of cardiovascular events, including myocardial infarction and stroke.

The mechanism postulated for naproxen’s possible cardioprotective effect is its inhibition of thromboxane with consequent platelet aggregation.

Readers may find following attached review article helpful.

[Status Epilepticus]

My point here is that in a country like Nepal where people can't afford to eat nutritious food what is the point prescribing a selective COX-2 inhibitor instead of prescribing some nutritious food. After all these new drugs are very expensive and they are out of reach of the General Public.

A similar thing happened when i was discussing about the laboratory diagnosis of tuberculosis. One of my teachers asked me the question "What is the relevance of demonstrating M tuberculosis using a PCR machine instead of going on a therapeutic trial on the basis of the signs and symptoms?"

As all of us know here in Nepal we spend almost 90% we earn on food. The remaining 10% for everything else. So is it better to send our children to private schools instead of using drugs like selective COX-2 inhibitors?

[Anil Tuladhar]

Thanks for Status epilepticus' reply. I do not deny for a second about whatever has been tried to explain and I believe everyone is aware of this. But this is a section for journal club where we brainstorm and critically analyse the interesting and controversial topical articles.

I don't know but there must be some section in this xenoMED where articles can be posted and discussed about whatever has been mentioned in above comments.