Good Riddance to a Bad Drug (Vioxx)

NY Times ^ | October 2, 2004 | ERIC J. TOPOL

[neverdem]

CAD is coronary artery disease.

[Vision]

Does this mean I don't have to sit through that clam commercial anymore?

[NJ_Tom]

Concerning Comment #34, I doubt the duration of the effect would be truly "permanent" - otherwise, a few aspirin would lead to irreversible bleeding problems. If the duration of aspirin's inhibitory effect on Platelet Aggregating Factor is particularly long lasting, it shouldn't matter when one takes a second drug - unless the second drug directly interferes with the mechanism by which aspirin inhibits PAF. Regardless of the duration of the inhibition, this "thinning" effect of aspirin would reduce the incidence of thrombosis-related stroke & heart attack.

Has the mechanism by which Vioxx increases the cited risks clearly been identified as an increased tendency to clot formation? -- or is its linkage to stroke & heart attack purely statistical?

To return to my original question, does anyone know how closely the clinical study subjects were supervised to ensure they didn't take OTC (over-the-counter) medications?

As I read the article, it implied a higher incidence of stroke & heart attack regardless of whether there was pre-existing CAD.

[neverdem]

Concerning Comment #34, I doubt the duration of the effect would be truly "permanent" - otherwise, a few aspirin would lead to irreversible bleeding problems. If the duration of aspirin's inhibitory effect on Platelet Aggregating Factor is particularly long lasting, it shouldn't matter when one takes a second drug - unless the second drug directly interferes with the mechanism by which aspirin inhibits PAF. Regardless of the duration of the inhibition, this "thinning" effect of aspirin would reduce the incidence of thrombosis-related stroke & heart attack. Has the mechanism by which Vioxx increases the cited risks clearly been identified as an increased tendency to clot formation? -- or is its linkage to stroke & heart attack purely statistical?

AFAIK, it's just statistical in a proprietary study that was looking for data that taking Vioxx decreased the incidence of colon cancer.

It took a long time to find an article. The second sentence states: "This prevents the access of the substrate (arachidonic aid) to the catalytic site of the enzyme at tyrosine385 and results in an irreversible inhibition of platelet-dependent thromboxane formation." IIRC, the lifespan of platelets is about 9 days.

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1: Semin Thromb Hemost. 1997;23(4):349-56.

Related Articles,

Aspirin and platelets: the antiplatelet action of aspirin and its role in thrombosis treatment and prophylaxis.

Schror K.

Institut fur Pharmakologie, Heinrich-Heine-Universitat Dusseldorf, Germany.

The antithrombotic action of aspirin (acetylsalicylic acid) is due to inhibition of platelet function by acetylation of the platelet cyclooxygenase (COX) at the functionally important amino acid serine529. This prevents the access of the substrate (arachidonic aid) to the catalytic site of the enzyme at tyrosine385 and results in an irreversible inhibition of platelet-dependent thromboxane formation. Aspirin is an approximately 150- to 200-fold more potent inhibitor of the (constitutive) isoform of the platelet enzyme (COX-1) than the (inducible) isoform (COX-2) which is expressed by cytokines, inflammatory stimuli, and some growth factors. This explains the different dosage requirements of aspirin as an antithrombotic (COX-1) and an anti-inflammatory drug (COX-2), respectively. Aspirin is the "gold standard" antiplatelet agent for prevention of arterial thromboses. The optimum dose of aspirin as an antithrombotic drug can differ in different organ circulations. While 100 mg/day is sufficient for prevention of thrombus formation in the coronary circulation, higher doses may be required for the prevention of vascular events in the cerebral and peripheral circulation. However, any effective antiplatelet dose of aspirin is associated with an increased risk of bleeding. Therefore, the individual benefit/risk ratio determines the administration of the compound. There are no known prostaglandin-independent mechanisms for the antithrombotic action of aspirin in clinical use. Thus, platelet activation caused by other factors remains unchanged and might result in a resistance against inhibition of platelet function by aspirin. This involves platelet activation by shear stress and ADP. Additionally, there is no "sparing" of endothelial prostacyclin synthesis in clinical conditions of atherosclerotic endothelial injury. In this case, inhibition of COX-1 by aspirin will also reduce the amount of precursors for vascular prostacyclin synthesis, provided, for example, from adhering platelets.

Publication Types:

• Review
• Review, Tutorial

PMID: 9263351 [PubMed - indexed for MEDLINE]

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Oct 4 2004 14:25:05To return to my original question, does anyone know how closely the clinical study subjects were supervised to ensure they didn't take OTC (over-the-counter) medications?

It's methods haven't been disclosed. It hasn't been published AFAIK.

As I read the article, it implied a higher incidence of stroke & heart attack regardless of whether there was pre-existing CAD.

I believe the prevalance of all diseases mentioned increase with age. I don't believe hardly anyone knows that they have CAD until they're symptomatic.

[clamper1797]

Celebrex and Bextra are also Cox-2 inhibitors and may have similar side effects ...

[neverdem]

Does this mean I don't have to sit through that clam commercial anymore?

If that's the guy clamming on the beach, I guess so. Why, you didn't like it? I wrote it and got rich! /sarcasm>

[neverdem]

Celebrex and Bextra will probably get the same scrutiny. Cox-2 inhibitors may become orphaned drugs that only get prescribed after patients sign informed consent.

[Vision]

It was a good commerical, but there was something about it I didn't like. Not sure why.

[MarkL]

Personally, I never got much relief from either Vioxx or Celebrex. I have crohns disease, and one of the symptoms is artritus. Remacaid helped somewhat, but not enough to get me completely off of prednisone.

I just take prednisone for the crohns, and lots of ibuprofin for my joints.

Mark

[neverdem]

Have you seen this, Crohn's disease, sick cows and contaminated milk?

Good luck and watch out for the adverse effects of those meds.

[MarkL]

No, I missed that one! Thanks!

Mark

[Judith Anne]

I have a progressive arthritis, possibly connected to lupus, and when I took Vioxx, my blood pressure went up and I swelled up as well...went back to the old aspirin standby, and occasional use (one or two a week) of Ultram when it hurts all over.

[wardaddy]

100s of millions I think..

[chas1776]

Vioxx was my wife's salvation.
She is now on Celbrex, I am listening to lawyers say it is just a substitute for asprin or ibprofen. This is far from the truth. She started with asprin but when you start spitting blood you need another drug. Vioxx worked better than any drug that she has ever taken. Vioxx is prescribed by doctors for athritis. Obviously there are problems associated with the (Vioxx) drug but there are problems that it controls. She would rather die without pain than what she is suffering now.,

[paleocon patriarch]

I took both Vioxx and later, Bextra before I had an unexplained heart attack while working out. Never smoked. Cholesterol 165, no genetic heart trouble in my family, not diabetic, run 4-6 miles a day.

I'm fine now, but very suspicious of all prescription drugs.

[neverdem]

I can see these Cox-2 inhibitors becoming orphaned drugs, but being prescribed along with aspirin and/or other drugs that inhibit platelet aggregation, i.e. drugs that inhibit the formation of blood clots. The risk of GI bleeding will be higher. Patients will have to sign informed consent.

Studies need to be done. IIRC, about 20% of the population are unaffected by aspirin with respect to platelet inhibition and the clinical benefit of preventing myocardial infarction("heart attacks") and the most common type of stroke.

[Pharmboy]

Topol had a long rant about this published in the New England Journal of Medicine just prior to the drug being pulled. Topol has been taking money from drug companies hand over fist for YEARS (even to the point of chairing TWO symposia at the same time at the heart meeting last spring).

I think he is assuaging his guilt with this holier-than-thou attitude and multi-rants on this issue. Just my opinion, I could be wrong.

[neverdem]

I'm fine now, but very suspicious of all prescription drugs.

I'm sorry to hear about your MI. Healthy skepticism doesn't hurt. There are benefits and risks with drugs, weapons, etc. Take care.