NEWS - More criticism for Merck and FDA over cardiac effects of Vioxx

[Guest guest]

More criticism for Merck and FDA over cardiac effects of rofecoxib

Rheumawire

Oct 7, 2004

Sue

Boston, MA - Both Merck and the FDA come in for fresh criticism in the

latest round of discussions on the withdrawal of rofecoxib (Vioxx,

Merck) because of cardiac side effects. Two perspectives published

online October 6, 2004 in the New England Journal of Medicine and an

editorial in the Lancet all say that the company and the regulatory

authorities should have done more to address cardiovascular concerns

earlier.[1,2,3] And a new analysis suggesting that the drug could have

caused more than 27 000 serious cardiac events will add to Merck's

troubles.

One of the NEJM perspectives also puts forward a mechanism to explain

the adverse cardiovascular profile of rofecoxib, which suggests that the

other COX-2 inhibitors may also increase cardiovascular events.

The estimate of 27 000 MIs and sudden cardiac deaths attributed to

rofecoxib comes from a nested case-control study, which has previously

been reported by rheumawire. The authors, led by Dr J Graham (US

Food and Drug Administration Office of Drug Safety), analyzed the

medical records of 1.4 million people insured by the Kaiser Permanente

HMO and treated with a COX-2 inhibitor or regular nonsteroidal

anti-inflammatory drug (NSAID) between 1999 and 2001. The primary

results of the study, which were reported in August 2004, showed that

patients taking high doses of rofecoxib had three times the risk of MI

and sudden cardiac death compared with patients not taking coxibs or

other NSAIDs.

The latest information from this study, which has been reported in the

Wall Street Journal, examines the difference in cardiac events between

patients taking rofecoxib and those taking celecoxib (Celebrex,

Pfizer).[4] It estimated that of 58 MIs or sudden cardiac deaths among

patients taking the low dose of rofecoxib (less than 25 mg), 21 would

not have occurred had they all been taking celecoxib, and for the high

dose (over 25 mg) 9.7 events out of 10 would not have occurred. When

these figures are projected to the 20 million Americans who are believed

to have taken rofecoxib, that gives a figure of 27 785 cardiac events.

The FDA is not commenting on the validity of these estimates. An FDA

spokesperson commented to the Wall Street Journal that " it would be

irresponsible of us to react that quickly, " that the projections relied

on " a lot of assumptions, " and that such conclusions are " speculative, "

but that the report appeared " carefully done. "

The study has not been released to the public, but a copy has been

requested by Senate Finance Committee Chairman Grassley (R-IA),

who is investigating how the FDA handles safety concerns. Another

Republican who is challenging the FDA on the way it handled rofecoxib is

House Government Reform Committee Chairman Tom . In letter to the

FDA commissioner, he says he is concerned whether the FDA had been

sufficiently aggressive in monitoring drug safety. The estimate of 27

000 events is another blow for Merck, which is facing a flood of

lawsuits, which will focus on whether the company could have acted

sooner on the cardiovascular concerns. One cardiologist who believes it

could have done, Dr Topol (Cleveland Clinic, OH), has called for a

Congressional hearing into the way the issue was handled by both Merck

and the FDA.

Writing in a perspective in the October 21, 2004 issue of the New

England Journal of Medicine (which has been released online early),

Topol says: " The senior executives at Merck and the leadership at the

FDA share responsibility for not having taken appropriate action and not

recognizing that they are accountable for the public health. " He notes

that rofecoxib was " the largest prescription-drug withdrawal in history,

but had the many warning signs along the way been heeded, such a debacle

could have been prevented. "

Topol asks why the FDA's Arthritis Advisory Committee waited two years

after the approval of rofecoxib to discuss concern about cardiovascular

risks and points out that he and his colleagues reviewed the data from

that meeting and concluded, based on the clear-cut excess number of MIs

associated with rofecoxib, that it was " mandatory to conduct a trial

specifically assessing cardiovascular risk and benefit of these agents. "

He states that such a trial needed to be conducted in patients with

established coronary artery disease, who frequently have coexisting

osteoarthritis and have the highest risk of further cardiovascular

events. But he points out that such a trial was never carried out. " The

FDA has the authority to mandate that a trial be conducted, but it never

took the initiative, " he comments, adding that Merck responded by

issuing a relentless series of publications and symposiums " to debunk

the concern about adverse cardiovascular effects. "

Topol claims that it was only by " happenstance " that the colon-polyps

trial discovered the excess cardiovascular events with rofecoxib. He

says that over the five-and-a-half-year saga many epidemiologic studies

confirmed the concern about serious cardiovascular events with

rofecoxib, but each time Merck claimed the study was flawed, and

meanwhile the company was spending more than $100 million per year in

direct-to-consumer advertisinganother activity regulated by the FDA and

a critical mechanism in building the " blockbuster status of a drug. "

Topol argues: " Considering the tens of millions of patients who were

taking rofecoxib, we are dealing with an enormous public-health issue. .

. Given the finding in the colon-polyp trial in low-risk patients

without known cardiovascular diseasean excess of 16 myocardial

infarctions or strokes per 1000 patientsit is possible that there are

tens of thousands of patients who have had major adverse events

attributable to rofecoxib. "

He says, " It is clear to me that Merck's commercial interest in

rofecoxib sales exceeded its concern about the drug's potential

cardiovascular toxicity, " adding: " The FDA's passive position of waiting

for data to accrue is not acceptable, given strong signals that there

was a problem and the vast number of patients who were being exposed. "

Topol concedes that there are many facts that have not been made public,

such as the direct communication between the FDA and Merck, but he adds,

" All the facts can and should be scrutinized closely in a Congressional

review in order to avert such a catastrophe in the future. "

In a second perspective in the New England Journal of Medicine, Dr

Garret Fitzgerald (University of Pennsylvania, Philadelphia) puts

forward a mechanism that would explain the adverse cardiovascular

profile of rofecoxib but that suggests that the other COX-2 inhibitors

would also increase cardiovascular events.

He explains that selective COX-2 inhibitors suppress the formation of

prostaglandin PGI2, which is the predominant cyclooxygenase product in

endothelium, inhibiting platelet aggregation, causing vasodilatation,

and preventing the proliferation of vascular smooth-muscle cells in

vitro.

The individual cardiovascular effects of PGI2 contrast with those of

thromboxane A2, the major COX-1 product of platelets, which causes

platelet aggregation, vasoconstriction, and vascular proliferation.

Whereas aspirin and traditional NSAIDs inhibit both thromboxane A2 and

PGI2, the coxibs leave thromboxane A2 generation unaffected, and thus

the balance is tipped toward the prothrombotic thromboxane effects.

" Thus, a single mechanism, depression of PGI2 formation, might be

expected to elevate blood pressure, accelerate atherogenesis, and

predispose patients receiving coxibs to an exaggerated thrombotic

response to the rupture of an atherosclerotic plaque, " Fitzgerald

comments.

As this mechanism would implicate all selective COX-2 inhibitors, he

reviews the evidence on whether other drugs in this class may also cause

cardiovascular side effects and reports that there are hints of an

increased cardiovascular risk in studies of other COX-2 inhibitors but

that this is not clear-cut.

However, Fitzgerald says that the APPROVE study of rofecoxib has given

" clear evidence of an increase in cardiovascular risk that revealed

itself in a manner consistent with a mechanistic explanation that

extends to all the coxibs. "

It seems to be time for the FDA urgently to adjust its guidance to

patients and doctors to reflect this new reality, " he states, adding

that the FDA " has a role to play beyond watchful waiting. " In the

absence of such guidance, Fitzgerald advises that the selective COX-2

inhibitors remain a rational choice for patients at low cardiovascular

risk who have had serious gastrointestinal events, especially while

taking traditional NSAIDs, but that it would seem prudent to avoid

coxibs in patients who have cardiovascular disease or who are at risk

for it.

Fitzgerald agrees with Topol that more should have been done to

investigate the cardiovascular effects of coxibs sooner. " The rational

basis for addressing the cardiovascular effects of these drugs has been

clear for the past five years, yet even the most fundamental questions

have not been addressed directly. Much information could have been

derived from careful mechanistic studies in small numbers of patients

and volunteers. However, drug companies are driven by the current

requirements for drug approval to design studies such as TARGET. This

most expensive and largest of the outcome studies involved exposing more

than 18 000 patients to lumiracoxib for a year. It laid the foundation

for the approval of another coxib, but it failed to address important

questions about cardiovascular risk. "

He concludes that it is essential to determine whether the

cardiovascular risk is or is not a class effect. " The burden of proof

now rests with those who claim that this is a problem for rofecoxib

alone and does not extend to other coxibs. We must remember that the

absence of evidence is not the evidence of absence. "

An editorial in the October 9, 2004 issue of the Lancet raises similar

concerns. " Merck's vigorous defense of this drug in the past was clearly

an error. If the dangers associated with rofecoxib were not proven, they

were certainly possible, even probable, given the available data, and it

should not have been left to a small trial in a novel application to

reveal them, " it charges. " The Vioxx story is one of blindly aggressive

marketing by Merck mixed with repeated episodes of complacency by drug

regulators. Without more vigilant drug regulation in the future, doctors

will continue to be misled and patients' lives will continue to be

endangered, " it adds.

Sources

Topol EJ. Failing the public health--rofecoxib, Merck,

and the FDA. N Engl J Med 2004; 351:1707-1709.

FitzGerald GA. ibs and cardiovascular disease. N

Engl J Med 2004; 351:1709-1711.

[Editorial] Vioxx: an unequal partnership between

safety and efficacy. Lancet 2004; 364:1287-1288.

Mathews AW. New Vioxx study projects cases of heart

attacks. Wall Street Journal October 6, 2004; A2 Available at:

http://www.wsj.com.

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org