How Vioxx kills--jk

NSAIDs inhibit both COX-1 & 2 action.  COX-1- & 2 are involved in platelet formation, and they also cause a relaxation in the smooth muscles of the blood vassal—a reduction in inflammation.  A new class of NSAIDs were developed which worked only upon COX-2 and leave platelet production intact[1].  Recent studies have shown that the inhibition of the two forms of cyclooxygenase (COX) increase cerebral-vascular events principally by accelerating plaque formation—arteriosclerosis.  The only exception is ASPIRIN, which through an acelation process turns off the turns off the mechanism that accelerates the build up of plaque.     

Vioxx (a selective COX-2 inhibitor) works two ways to cause increased cardio-vascular events:  increases plaque formation and blood clotting.  Thus with plaque build the risk of myocardial infraction increases over time—this is a slow process.  The longest study, halted in 2004 (because of deaths) was but 16 months.  (The original studies for FDA approval were for but 6 weeks.)  Since its primary usage is for arthritis (long-term treatment) for which the higher 50 mg dosage is more commonly given and usage is commonly for more than 16 months, there is a very significant under-reporting of the damage done.  At the 50 mg dosage, in the 16-month study there was a 3-fold increase in cardiac events. Even off the drug, those in the 16-month study had a year later a 75% increased risk of an adverse event--(blood clotting has returned to normal, but the clogged arteries remain).  The effect of COX-2 inhibition is not limited to heart attacks and strokes, but also the full gambit of conditions associated with atherosclerosis.  Journal articles are to be found, for example associating Vioxx with retinal vein occlusion (Ophthalmologica, 2005 July-Aug;219(4):243-7).

The principal mechanism of plaque formation is initiated as an injury response by white blood cells which releases a chemical that promotes plaque formation (a soothing coating for arteries).  There are other mechanisms.  Carbon monoxide (a product of incomplete combustion while smoking) is one of initiator of this mechanism in white blood cells.[2]  COX-2 inhibitors enter into the LO pathways[i] by in a way that promotes the oxidation of LDL—oxidized LDS is the principal component of plaque.  COX-2 inhibitors turn off the chemical from the white cells that shuts of the inflammation response, thereby permitting the plaque formation to continue longer than normal.    

The second prong is the inhibition of thromboxanes.  All COX-1 inhibitor effect blood clotting by inhibiting thromboxanes, which inhibit palate formation.  Thus the positive side of the older NSAIDs (reduction of clotting) as to ceberal-vascular events does not occur with VIOXX.[3]  The selective COX-2 inhibitors thus are all worse than those which inhibit both. 

COX-1 inhibitors reduce one type of blood clots (the other principal one being the breaking off of plaque and it lodging in a coronary vessel or the brain for a stroke).  Only aspirin shuts off the injury-plaque formation mechanism. Aspirin is the only NSAID that doesn’t statically increase the risk of dying.

There is a lack of awareness of its benefits by care givers because of the infiltration extensive influence of big PHARMA upon medical education, and the fact that aspirin can be purchased for under 1¢ apiece.     

Blood Clots the second cause of increased heart attacks

Goodman & Gilman,[4] 11^th Ed.(684):  “Selective inhibition of COX-2 depress PGI­­-2 formation by endothelial cells without concomitant inhibition of platelet thromboxane.  Experiments in mice suggest that PGI-2 restrains the cardiovascular effects of TXA-2, affording a mechanism by which selective inhibitors might increase the risk of thrombosis (McAdam et al, 19999, Catella-Lawson et al., 1999).  This mechanism should pertain to individuals otherwise at risk of thrombosis, such as those with rheumatoid arthritis, as the relative risk of myocardial infraction is increased in these patients compared to patients with osteoarthritis or no arthritis.”  {Patients who would be taking long-term COX-2 inhibitors.  However, the study, which took theory into reality, was not of that group, but rather a test to see if it reduced the risk of Alzheimer’s disease.  At 16 months the study was stopped because of a 2.5 increase in myocardial infraction, and 3.4 at the higher dose.}

Goodman & Gilman, 11^th Ed.(690):  “Although aspirin is regarded as the standard against which other drugs should be compared for treatment of rheumatoid arthritis, many clinicians favor the use of other NSAIDs perceived to have better gastrointestinal tolerability, even though this perception remains unproven by convincing clinical trials.”  {As I pointed out, most test use a coated NSAID compared to an uncoated aspirin, and often at lower therapeutic dose.--jk}

The coxibs (COX-2-selective NSAIDs) do not inhibit production of platelet thromboxane (a potent platelet agonist and vasoconstrictor), but selectively suppress endothelial prostacyclin (an intrinsic vasodilator and platelet inhibitor).  It has been hypothesised that selective inhibition of prostacyclin production by coxibs without concomitant platelet inhibition leads to thrombosis in at-risk individuals

WRITTEN BEFORE VIOXX WAS BANNED

Medical Journal of Australia, MJA 2004; 181 (10): 524-525

Journal of the Australian Medial Association, Established 1914

What is the basis for the increased cardiovascular risk?

Traditional non-steroidal anti-inflammatory drugs (NSAIDs) suppress prostaglandin synthesis by inhibiting both constitutively expressed COX-1 (primarily responsible for “housekeeping” functions such as gastric protection and haemostasis) and the inducible COX-2 (which is upregulated in inflammatory conditions). The coxibs (COX-2-selective NSAIDs) do not inhibit production of platelet thromboxane (a potent platelet agonist and vasoconstrictor), but selectively suppress endothelial prostacyclin (an intrinsic vasodilator and platelet inhibitor).. It has been hypothesised that selective inhibition of prostacyclin production by coxibs without concomitant platelet inhibition leads to thrombosis in at-risk individuals 10,11 However, alternative hypotheses suggest that blockade of COX-2 in atheromatous plaques may reduce vascular inflammation and the progression of vascular disease, and perhaps even prevent events.9,12

Is the thrombotic risk a class effect?

The celecoxib studies have not demonstrated an increased risk of thrombosis,2,7,8 but there are no long-term safety studies. Several second-generation coxibs have recently been approved for use in the United States (Lumiracoxib, Valdecoxib) and Europe (Etoricoxib, a derivative of rofecoxib). While randomised trials involving these drugs have not shown a significant increase in thrombosis risk,13,14 they have not excluded it. Consequently, their potential risk for causing cardiovascular events has also been questioned.8,11 Given the clear demonstration of increased cardiovascular risk with rofecoxib, it is now incumbent on drug manufacturers and regulatory authorities to demonstrate cardiovascular safety for all existing and new coxibs.

Goodman & Gilman, 11^th Ed. P. 690:  “Although aspirin is regarded as the standard against which other drugs should be compared for treatment of rheumatoid arthritis, many clinicians favor the use of other NSAIDs perceived to have better gastrointestinal tolerability, even though this perception remains unproven by convincing clinical trials.”  {As I pointed out, most test use a a low does of a coated NSAID compared to an uncoated aspirin.--jk}

Disclaimer:  The information, facts, and opinions provided here is not a substitute for professional advice.  It only indicates what JK believes, does, or would do.  Always consult your primary care physician for any medical advice, diagnosis, and treatment.