Comments on: Study Confirms Vioxx Causes Heart Risks

By: Justice in MI

Justice in MI — Wed, 15 Oct 2008 16:24:37 +0000

Thanks, guys. I have learned from the exchange. Agree that having the right comparators is key and that there is, indeed, much to learn about “class effect” and what is, and isn’t, in “class,” however defined.

I’ll leave the dead horse beyond saying, when spokesperson suggests “class effect” in general way, average person would interpret that to mean that the two or three Advil they are taking per day (600 mg) might have the same risks/benefits as the 400 mg. of Celebrex. That may turn out to be the case, but I’m not sure there is a “preponderance of evidence,” as spokesperson said, that points in that direction.

By: atlex

atlex — Wed, 15 Oct 2008 12:27:47 +0000

JiM and Nathan,

I want to remind both of you that this may not be a black and white issue that a drug is cardio toxic or not. It could well be that in high doses, most or all of these might be cardio toxic. The key is whether they are safe at therapeutic doses. JiM, you correctly indicated that in one study, 800mg TID of ibuprofen, has demonstrated some cardio toxicity. This is not an uncommon dose; thus, there should be concern. It could well be that at therapeutic doses, refecoxib is toxic, while celecoxib is not.

Atlex

By: Justice in MI

Justice in MI — Wed, 15 Oct 2008 05:01:27 +0000

Thanks for taking the time to post these, Nathan. They are useful and informative.

I do think there is a certain amount of spin going on in the way the implications data we have are being conveyed, but perhaps in the eye of the beholder.

By: Nathan

Nathan — Tue, 14 Oct 2008 23:56:20 +0000

JiM,
Actually, there appears to be quite a bit of meta-analysis to show that NSAIDS increase cardiac risk. You are asserting that the Merck spokesman was just “spinning” decent PR out of a bad result. From what I could read, NSAIDS aren’t as bad as COX-2 inhibitors, but there is pretty clearly an increased risk. Moreover, remember that the selective COX-2 inhibitors are under patent - and therefore there are ongoing clinical studies. I don’t think that there is a lot of money being sunk into clinical trials of generic NSAIDS. Therefore, most analyses are retrospective in nature and therefore a little less credible. Here’s just a few links I found: (I’m at home, so I don’t have full-text for the journals — so news releases will have to suffice)
http://www.theheart.org/viewArticle.do?primaryKey=501247

http://www.arthritis.org/cvd-nsaid.php

http://www.theheart.org/viewArticle.do?primaryKey=671815

By: Justice in MI

Justice in MI — Tue, 14 Oct 2008 23:51:40 +0000

Interesting study, Nathan. CHF is a somewhat different issue, but certainly relevant. Perhaps ironically, this 1999 piece ends with this:

“It is possible that drugs that are selective inhibitors of the inducible cyclo-oxygenase 2 will have a lower rate of adverse effects on the kidney and cardiovascular system, but this remains to be established in well-designed pharmacoepidemiological studies.”

Re: the overall logic, my lay understanding is that the relevant balance of thromboxane, prostacyclin, etc. and their relationship with amount of cox 2 is complex. Thus, the study that Atlex cites suggests that naproxen, even at high doses, has a significantly lower rate of CV AEs than either other high dose NSAIDS or coxibs. Since naproxen is non-selective - and thus I assume inhibiting of both cox’s - there would seem to be more going on than the amount of cox2 alone.

By: Nathan

Nathan — Tue, 14 Oct 2008 23:37:48 +0000

Here’s a primary literature reference. I didn’t read the whole thing, but it seems to address your question.

http://archinte.ama-assn.org/cgi/content/full/160/6/777

By: Nathan

Nathan — Tue, 14 Oct 2008 23:23:20 +0000

JiM,
Now I understand your question. However, think about it a little. NSAIDS inhibit COX-1 and COX-2. Since the selective COX-2 inhibitors are showing cardiac tox, one would fully expect that nonselective inhibitors would do the same. The only caveat might be if you somehow believe that hitting COX-1 is cardioPROTECTIVE and counterbalances the ill-effects of COX-2 inhibition.

By: Justice in MI

Justice in MI — Tue, 14 Oct 2008 22:56:50 +0000

Nathan - yes, the lancet piece is a comparison among cox-2s. My question was a comparison between cox-2s and non-selective NSAIDS.

As Graham’s study suggests, there may, indeed, be a difference among the cox2s. As far as comparison with non-selective NSAIDS, I am ready to keep the book open. I would appreciate it if others did the same, which I think the Merck spokesperson clearly was steering us away from.

Re: the study Atlex cites, the comparison with ibu was 800 mg, tid, certainly an extremely high does in the scheme of things. So, in my view, this study contributes little to the discussion as it would impact the average person.

By: atlex

atlex — Tue, 14 Oct 2008 20:17:36 +0000

JiM,

Here’s one reference courteous of Ed.

http://www.pharmalot.com/wp-content/uploads/2008/02/hennekens-cox-2.pdf

This book is certainly not closed on this controversy, but it would be an overreach to attribute Vioxx’s troubles to the whole class.

Atlex

By: atlex

atlex — Tue, 14 Oct 2008 20:10:15 +0000

JiM,

Remember, not everyone can spend most of the day online. There is evidence that some of the NSAIDs carry risks equal to some of the COX-2s, depending on the dose. Most retrospective analyses show, for instance, that celecoxib used at normal doses (200mg or less/day) carries a risk no greater than ibuprofen, etc. Of course, if I remember correctly, celecoxib is less COX-2 specific than Vioxx; that might have something to do with it.

By the way, I’ll look for the sources of this information and pass them along when I have a chance.

Atlex