INFO - Vioxx, Other Super Aspirins Are Super Disasters - Other -2 Alternatives Have Safety Problems Too

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Public Citizen

September 30, 2004

Vioxx, Other " Super Aspirins " Are Super Disasters - Other -2

Alternatives Have Safety Problems Too

Statement by Sidney M. Wolfe, MD, Director of Public Citizen's Health

Research Group, Concerning Withdrawal of Vioxx From the Market

Today's announcement by Merck is the latest evidence that this family of

drugs, the -2 inhibitors, once referred to as " super aspirins, " are

turning out to be more like super disasters. As discussed below, there

are safety problems with Celebrex as well as Bextra, the two other

big-selling -2 inhibitors that are the most-prescribed alternatives

to Vioxx.

In trying to appear " a good citizen, " Merck ignores its checkered

history with Vioxx. In today's statement announcing the withdrawal of

Vioxx from the market, S. Kim, Ph.D., president of Merck Research

Laboratories asserted that " Merck has always believed that prospective,

randomized, controlled clinical trials are the best way to evaluate the

safety of medicines. " Yet after an earlier randomized trial, the VIGOR

study, published almost four years ago (November 2000), that found Vioxx

caused a four- to five-fold increase in heart attacks, Merck received,

on Sept. 17, 2001, a warning letter from the U.S. Food and Drug

Administration (FDA) because the company's ads for the drug failed to

mention this increased risk of heart attacks. In the eight-page warning

letter addressed to Merck President and CEO V. Gilmartin, the

FDA stated:

You have engaged in a promotional campaign for Vioxx that minimizes the

potentially serious cardiovascular findings that were observed in the

Vioxx Gastrointestinal Outcomes Research (VIGOR) study, and thus,

misrepresents the safety profile for Vioxx. Specifically, your

promotional campaign discounts the fact that in the VIGOR study,

patients on Vioxx were observed to have a four to five fold increase in

myocardial infarctions (MIs) compared to patients on the comparator

nonsteroidal anti-inflammatory drug (NSAID), Naprosyn (naproxen).

In Merck's VIGOR study, comparing rofecoxib to naproxen, there was a

highly statistically significant five-fold increase in heart attacks in

the overall rofecoxib group (0.5 percent) compared to the naproxen group

(0.1 percent). This amounted to 20 heart attacks with rofecoxib (out of

4,047 patients) compared with four with naproxen (out of 4,029

patients). This increased number of heart attacks was also accompanied

by an increase in other thrombotic (blood clotting) adverse effects such

as strokes and blood clots in the legs as well as problems with

hypertension in the rofecoxib group compared with the naproxen group.

In an article published three and a half years ago in our monthly

newsletter, Worst Pills, Best Pills News (now online at WorstPills.org),

we warned readers that both Vioxx and Celebrex were DO NOT USE drugs -

our designation for drugs that are not safe and effective enough to use.

Although Merck's withdrawal of Vioxx " solves " the serious safety

problems with this drug, the most-prescribed alternatives, Celebrex and

Bextra, also have some concerns about their cardiac toxicity.

Cardiovascular Toxicity and -2 Inhibitors

In a study published in the Aug. 29, 2000, Proceedings of the National

Academy of Sciences, the ability of rabbits to withstand temporary

experimental coronary artery occlusion (experimental heart attack) was

significantly impaired by treatment with celecoxib (Celebrex), which

completely blocked the cardioprotective effects of the COX-2 enzyme. The

authors of that study concluded that COX-2 enzyme is a " cardioprotective

protein. " Therefore, it is implied, drugs that block this

cardioprotective enzyme, such as COX-2 inhibitors, may neutralize its

protective effects.

Problems with Celebrex

Although a CLASS study involving Celebrex did not find a significantly

elevated number of heart attacks in those using celecoxib compared to

those using the older NSAIDs (ibuprofen or diclofenac), there was also

cause for concern about heart toxicity with celecoxib. An expert from

the FDA's Division of Cardio-Renal Drug Products, Dr.

Throckmorton, found that " the incidence of adverse events related to

cardiac ischemia (decreased blood flow to the heart) was higher in the

celecoxib [Celebrex] group ... and was most pronounced in the group of

patients not taking ASA (aspirin) " as a cardiovascular protective drug.

In these patients, the rate of heart attack was also highest in the

celecoxib group (0.2 percent) compared with users of the other two drugs

(0.1 percent). For all patients, on and off aspirin, there was a higher

incidence of atrial fibrillation, a type of heart rhythm disturbance, in

the celecoxib group compared to those taking ibuprofen or diclofenac.

Again this was more pronounced in the group not taking aspirin. Dr.

Throckmorton concluded by stating that " the data do not exclude a less

apparent pro-thrombotic [blood clot-forming] effect of celecoxib,

reflected in the relative rates of cardiac adverse events related to

ischemia. "

Safety Problems with the New -2 inhibitor, Valdecoxib (Bextra)

We have also warned readers of Worst Pills, Best Pills News not to use

Bextra. Because the FDA and Bextra's manufacturer, Pfizer, refused to

give us unpublished data concerning the drug, we filed suit against the

agency. The FDA had originally redacted all information in its reviews

concerning valdecoxib and acute pain. In the course of our litigation,

we received most of what we had requested in the lawsuit, including the

unredacted FDA Medical Officer's conclusions and recommendations about

the use of the drug for acute pain.

In the unredacted review the Medical Officer recommended:

Nonapproval [for the treatment] of the acute pain, including

opioid-sparing and prevention of operative pain. The only substantial

multidose safety database is found in the Coronary Artery Bypass Graft

(CABG) Surgery study 035. This study demonstrated an excess of serious

adverse events including death in association with the use of paracoxib

and valdecoxib 40 mg bid [twice daily] when added to ad lib [as needed]

parenteral [injectable] narcotic analgesia. ... These finding

warrants further investigation before valdecoxib can be considered safe

and effective for the treatment of pain, particularly multidose therapy

in the perioperative setting.

In summarizing the safety of valdecoxib the FDA Medical Officer stated:

With two notable exceptions - edema [swelling] and hypertension -

valdecoxib (Bextra) was comparable to the standard non-steroidal

agents [ibuprofen, naproxen, diclofenac] used as active controls in the

trials. ... The finding of a greater incidence of edema and hypertension

at doses above 20 mg/day, almost uniformly in the databases and clearly

when prospectively addressed in formal safety Trials 47 and 62, is of

concern. ... The excess of serious cardiovascular thromboembolic [blood

clots] in the valdecoxib arm of the CABG [Coronary Artery Bypass Graft]

trial is of note as the entire study population received prophylactic

low dose aspirin as part of the standard of care in this setting to

minimize just such events. Given the emerging concern over a possible

pro-thrombotic action of certain agents in the COX2 class, these data

are of concern. (Emphasis added.)

In summary, we advise patients not to use any of these " super aspirin "

-2 inhibitors and, instead, to rely on the older drugs in the NSAID

family such as ibuprofen and naproxen.

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based in Washington, D.C.For more information, please visit

www.worstpills.org.

http://www.citizen.org/publications/release.cfm?ID=7333

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org