There has been significant activity at the Food
& Drug Administration (FDA) over the safety profile of Vioxx,
specifically concerning serious cardiovascular injury.
Interestingly, this class of drugs which is being discussed and
debated by many counsel is one of the hottest selling groups of
drugs that the pharmaceutical industry has seen in recent years.
Equally interesting is the fact that the drugs at issue are the
progeny of the drug that spawned the birth of the modem
pharmaceutical industry over 100 years ago-aspirin.
Coxibs are members of a broader class of drugs known as
nonsteroidal anti-inflammatory drugs; other members of this
class of drugs include ibuprofen, naproxen, Naprosyn, and, as
stated previously, aspirin. Throughout the developmentand use of nonsteroidal anti-inflammatory agents (NSAIDs) it has
been widely recognized that this class of drugs is extremely
effective at reducing pain through the inhibition of the
cyclo-oxygenase enzyme, causing the inhibition of the production
of prostaglandin and prostacylin, thus inhibiting inflammation
in joints, and thereby eliminating pain. However, what has
also been widely recognized about NSAID therapy is that in
addition to mediating joint pain due to inflammation, it has
also been responsible for significant gastrointestinal side
effects, including perforations, ulcerations, and bleeds.
Chronology of Vioxx
November 23, 1998--Merck, the manufacturer and marketer of Vioxx,
submits its New Drug Application (NDA) to the FDA on this date.
April 20, 1999-- The Advisory Committee on Arthritis Drugs (FDA)
meets to review the medical profile of Vioxx.
May 21, 1999--FDA approves Vioxx (Rofecoxib), a new drug for the
treatment of osteoarthritis, menstrual pain, and for the
management of acute pain in adults.
June 22, 1999--Merck enters into a speaker's contract with Peter
Holt, M.D., who subsequently conducts several live and audio
conferences to educate [sic] health care professionals on the
claimed benefits of Vioxx.
October 8, 1999-- less than five months into the market history
of Vioxx, Merck updates the package insert.
June 8, 13, and 16, 2000--promotional audio conferences are held
by Peter Holt, M.D., the substance of which was, at a minimum,
directed by Merck for use by Dr. Holt. Portions of these
presentations are the subject of a subsequent warning letter to
Merck for violations of the Food, Drug & Cosmetic Act.
June of 2000--there was information presented before the
European United League Against Rheumatism, an organization in
which Merck is a member and a corporate sponsor that
demonstrated a statistically significant increase in
hypertension and myocardial infarction.
February 8, 2001-- the FDA Arthritis Advisory Committee meets to
discuss concerns over cardiovascular risks associated with the
use of Vioxx. In order to understand the context of this
Advisory Committee meeting, it is important to understand the
purpose of the study reviewed and out of which the cardiac
concerns were spawned. Merck, in an attempt to rid Vioxx
of the standard NSAID gastrointestinal warnings, initiated the
Vioxx Gastrointestinal Outcomes Research Study (VIGOR) to assess
the gut-sparing benefits of this medication. There were no
cardiac endpoints assessed in the VIGOR study. Despite its
initial claim that Vioxx would not disrupt the GI tract and
complicate the care regimen with the same GI problems as general
NSAIDS, the Food & Drug Administration, when faced with a lack
aspects of the drug, required Merck to carry the
same GI warnings as general NSAIDS; that is, Merck
was compelled to include on its label precautions
that 2-4 percent of individuals taking Vioxx would
suffer GI complications. It
has been, and continues to be a major selling point
for Merck, both from a theoretical, scientific
standpoint as well as a strong marketing standpoint,
that as a Cox-2 inhibitor Vioxx does not cause
the same problems in the GI tract as do other general
VIGOR study was undertaken.
There two important aspects of the February 8, 2001 Advisory
The first is that it underscores the fact that Merck, in
was focused on the GI aspects of Vioxx and not cardiac issues.
Secondly, is the memo of Shari L. Targum, M.D., the Project
Manager for the Division of Anti-inflammatory Drug Products
concerning cardiac issues. In Dr. Targum's memorandum it
is clearly stated that as early as November 18, 1999, the Data
and Safety Monitoring Board of the
VIGOR study, a committee independent from the
sponsor, was concerned over the
cardiovascular events experienced in the Vioxx group,
compared to the group taking Naproxen. This memo
establishes a date of recognition within the FDA of when serious
cardiovascular events were brought to the attention of Merck,
and a starting point for determining what actions were
undertaken once a red flag is raised.
May 22, 2001-- in the wake of studies that clearly demonstrate
concerns over the
cardiovascular safety profile of Vioxx, in particular
the increased incidents of cerebrovascular accidents, myocardial
infarction, deep vein thrombosis, and pulmonary embolism, among
other cardiovascular injuries, Merck made two significant press
releases. The first coming on May 22, 2001, titled Merck,
Sharp & Dohme Reconfirms Favorable Cardiovascular Safety of
Vioxx, Emphasizes Powerful Pain Relief and a second, which was
released on June 16, 2001 in Europe, which claims Vioxx Similar
to Placebo and Three (3) Widely Prescribed NSAIDs Regarding
July 11, 2001--the Vioxx package insert is updated for the
August 2001: Cleveland Clinic study published in the Journal of
the American Medical Association associates Vioxx with
September 17, 2001--Merck receives its strongest FDA warning
letter to date relative to its drugs.
April 11, 2002-FDA instructed Merck to include certain label
October 2003: Merck-funded study finds patients taking Vioxx are
at a 39% increased risk of heart attack within the first 90
days, compared with Celebrex.
August 2004: HMO Kaiser
Permanente reconsiders Vioxx for its member patients after an
FDA study finds that patients who had taken more than 5 mg a
day were 3.15 times as likely to have a heart problem.
September 2004: FDA approves Vioxx to treat juvenile rheumatoid
Sept. 30, 2004: Merck announces a voluntary
world-wide withdrawal of Vioxx.
Source: David Miceli, Esq.
& Physician’s Desk Reference (PDR), 53rd-55th
Vioxx and its Side Effects
On September 30, 2004,
Merck pulled its best selling arthritis drug, Vioxx, from the
market, due to mounting medical concerns regarding increased
risks of heart attack and stroke associated with taking the
drug. Despite the fact that Merck knew that Vioxx caused
cardiovascular problems years before beginning production, they
launched an extensive mass marketing campaign to convince
consumers that Vioxx was a safer and more effective product than
non-prescription, less expensive arthritis drugs. Unfortunately
for the public,
Vioxx was neither safer nor more effective. In
the face of increasing scrutiny, Merck finally removed their
drug from the market, but not before clearing 3 billion dollars
What is Vioxx?
is a nonsteroidal anti-inflammatory (NSAID) prescription drug
that was approved by the United States Food and Drug
Administration for the treatment of rheumatoid arthritis,
osteoarthritis, menstrual cramps and acute pain in adults. Vioxx®
belongs to a class of drugs known as Cox-2 inhibitors and is a
brand name used by Merck & Co., Inc. Cox-2 inhibitors were
initially thought to be safer than other NSAID drugs, such as
aspirin and ibuprofen, because they were believed to be less
irritating to the gastrointestinal tract.
distributing Vioxx® throughout the United States in 1999,
despite information in its clinical trials and post-marketing
reports that associated Vioxx® with hypertension-related adverse
health effects. Merck marketed Vioxx® as safe and effective for
people suffering from hypertension and people at risk for stroke
or other cardiac problems. In May 2002, the United States Food
and Drug Administration (FDA) published a Talk Paper about new
label warnings for Vioxx® (Rofecoxib). FDA Talk Papers are
prepared to guide FDA personnel in responding with consistency
and accuracy to questions from the public on subjects of current
interest. According to the FDA, recent studies demonstrate that
Vioxx® is associated with a higher rate of serious
cardiovascular thromboembolic adverse events, including heart
attacks, angina pectoris, and peripheral vascular events. Other
side effects associated with Vioxx® include seizures, strokes,
or liver and kidney problems. The new label warnings were based
on the results of the Vioxx Gastrointestinal Outcomes Research
What Are Cox-2
scientific terms, Cox-2 inhibitors inhibit the enzyme involved
in the inflammation of body tissue. Traditional nonsteroidal
anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen,
inhibit both the Cox-1 and Cox-2 enzymes. This creates another
problem because they stop the "good" Cox-1 enzyme that helps
protect the lining of the stomach. Cox-2 inhibitors, in theory,
do not impair the good Cox-1 enzyme, but only inhibit the Cox-2
enzyme that is responsible for inflammation. Cox-2 inhibitors
therefore should cause fewer gastrointestinal problems. However,
Cox-2 inhibitors, like traditional NSAIDs, can cause gastric
Cox-2 inhibitors increase the risk of heart
attack. The Cox-1 enzyme may play a role in preventing clot
formation that leads to heart problems. Thus, aspirin and other
NSAIDs that inhibit the Cox-1 enzyme probably protect people
from developing heart attacks, whereas Cox-2 inhibitors may
actually increase the risk of developing cardiovascular
What Are The Risks Associated With Using Vioxx?
Recent studies suggest that Vioxx increases the risk of heart
attack substantially more than do traditional NSAIDs. For
example, there is an increase in the development of heart
attacks in people treated with Vioxx, when compared with those
treated with naproxen, a traditional NSAID. The risk of heart
attack is especially a concern for those users who may have had
cardiac problems in the past.
The Risk for Myocardial Infarction with Cyclooxygenase-2
Inhibitors: A Population Study of Elderly Adults --
Lévesque et al. 142 (7): 481 -- Annals of Internal Medicine
What is the problem and what is known about it
People commonly use nonsteroidal
anti-inflammatory drugs (NSAIDs) to relieve pain. Examples of
NSAIDs include aspirin, etodolac (Lodine), ibuprofen (Advil or
Motrin), and naproxen (Aleve). NSAIDs can irritate the lining of
the stomach and cause ulcers and bleeding. Drugs called
cyclooxygenase-2 (COX-2) inhibitors are a particular "selective"
type of NSAID that may not injure the stomach lining as much as
other NSAIDs. Examples of COX-2 inhibitors are celecoxib (Celebrex),
meloxicam (Mobicox), rofecoxib (Vioxx), and valdecoxib (Bextra).
Some COX-2 inhibitors may increase the risk for heart disease.
For example, rofecoxib was withdrawn from the market in
September 2004 because a large trial found that it increased the
risk for heart attacks and strokes. We do not know whether other
COX-2 inhibitors and nonselective NSAIDs have similar or
Are COX-2 drugs safe for you? An interview with a Mayo Clinic
specialist - MayoClinic.com
First it was Vioxx — pulled from the market in
September 2004 with no advance notice. Then came warnings
about Celebrex, Aleve and Bextra. Eric Matteson, M.D., a
rheumatologist at Mayo Clinic, Rochester, Minn., discusses
the safety implications of these commonly prescribed arthritis pain
relievers, known as COX-2 inhibitors, as well as the safety of
traditional nonsteroidal anti-inflammatory drugs (NSAIDs).
Merck Says SEC Has Started Formal Probe of Vioxx
Jan. 28 (Bloomberg) -- Merck & Co. said the U.S.
Securities and Exchange Commission has started a formal
probe into its handling of Vioxx, the painkiller pulled
from the market Sept. 30 because of its link to heart
attacks and strokes. |
The SEC's decision wasn't
unexpected, the Whitehouse Station, New Jersey-based
company said in a statement today. A formal probe gives
the SEC staff the power to issue subpoenas for documents
Merck wouldn't comment on the SEC
matter beyond the press release, company spokesman Tony
Plohoros said. SEC spokesman John Heine declined to
comment on the investigation. Merck shares fell as much
as 9.2 percent.
Vioxx may have caused as many as
140,000 heart attacks in the U.S. between its 1999
introduction and the recall, Food and Drug
Administration safety reviewer David Graham said in a
study published this week by the U.K. medical journal
Lancet. As of Dec. 31, Merck said 55 lawsuits had been
filed by 1,400 plaintiffs' groups alleging injuries
linked to Vioxx, including heart attacks and kidney
The Department of Justice and certain
Congressional committees also are conducting probes.
Judges Decide Where to Hear Vioxx Cases
A panel of seven judges met here to consider where the
federal cases against Merck & Co. over its now defunct
arthritis drug Vioxx should be consolidated. |
Merck asked that all federal cases be placed under one
jurisdiction because it streamlines the process of
company said it has counted at least 1,400 plaintiff
groups and at least 55 lawsuits alleging the drug for
arthritis and acute pain caused medical problems such as
heart attacks, strokes, kidney damage and
gastrointestinal bleeding. Research by The Associated
Press, however, identified at least 700 lawsuits.
Assessing the risks
It's time to take stock of what we know and don't know
about the side effects of pain relievers|
The Wall Street Journal
issues have been more confusing than the barrage of news
reports over the past three months linking popular pain
relievers with heart attacks.
about the popular arthritis drugs Vioxx, Celebrex,
Bextra and naproxen, the drug in Aleve, health
authorities are reviewing dozens of studies of at least
18 anti-inflammatory medications, including household
names such as aspirin and Advil...
What is the
evidence against these popular pain drugs?
first real evidence against Vioxx came in March 2000
from a study of 8,000 rheumatoid arthritis patients. It
showed that Vioxx users had five times the risk of heart
attack as naproxen users, with 0.5 percent of the Vioxx
group suffering heart attacks compared with 0.1 percent
of the naproxen group. Last September, a three-year
study of patients with a genetic polyp disease showed
that the patients who took Merck's Vioxx for more than
18 months were twice as likely to have heart attacks or
strokes. Then, in December, the National Cancer
Institute stopped another polyp study using Pfizer's
Celebrex after finding that Celebrex users had twice the
risk of heart attack. Days later, the National
Institutes of Health stopped a study of 2,400
Alzheimer's patients, citing higher risks from naproxen.
Questions have also emerged about Pfizer's Bextra.
More Debate, More Data
It also contains Topol's response, in which he publishes a new analysis
data that he says shows a "significant"
increase in heart attack and stroke in patients taking
Vioxx after as little as six weeks. The data was
previously available only in briefing documents prepared
by staff at the Food and Drug Administration. |
The fight is more than just academic. The dueling
letters are one of the few times that Merck's scientists
have publicly defended their approach to the drug since
the company pulled it off the market. And Topol's
analysis seems to show that even if Merck wasn't aware
of the possible risks to the heart posed by Vioxx,
perhaps it should have been.
Face Of The Year: David Graham
NEW YORK - On Nov. 18, an unassuming safety researcher from the
U.S. Food and Drug Administration sat down before a Senate
committee and tore his bosses to shreds. |
The FDA, he
said, had ignored warnings that the pain pill Vioxx was killing
people by causing heart attacks and strokes--and he said the
agency was incapable of defending the public against another
drug disaster. "I could have given a very mealy-mouthed
statement," says David Graham, the scientist. "But then I would
have been part of the problem."
Quiet scientist no more
study that has thrown Graham into the limelight involved
analyzing a database of 1.4 million Kaiser Permanente
members. Graham and his collaborators compared the rate
of heart attacks and sudden cardiac deaths in patients
who took Vioxx or Celebrex, its main competitor, or
other non-steroidal anti-inflammatory drugs (NSAIDs),
such as ibuprofen.|
"We did this study because I
recognized Vioxx was a potential disaster," Graham says.
It had all the ingredients: a blockbuster drug used by
millions that carried a significantly increased risk of
heart attacks, the leading killer in industrialized
countries. "I don't think that (FDA management)
appreciated what we might find."
Graham and his
collaborators found that Vioxx users had a higher rate
of heart attacks and sudden cardiac deaths than Celebrex
Drug-Safety Reviewer Says F.D.A. Delayed Vioxx Study
ABSTRACT - Dr David Graham, federal drug-safety reviewer, contends that
effort to publish his study demonstrating dangers of
Vioxx was delayed and demeaned by top officials at Food
and Drug Administration; Graham says one of his bosses
at FDA, Dr Anne Trontell, referred to his Vioxx study's
conclusions as mere 'scientific rumor'; Graham's charges
come in midst of Congressional inquiry into whether
agency has been slow to respond to findings that Vioxx
and other drugs may be harmful to heart in some cases;
Sen Charles E Grassley has criticized agency for
suppressing findings of its own drug safety reviewer
that concluded that drugs are risky; Graham is seeking
to launch study of safety of Bextra and Mobic, two
arthritis pills that are similar to Vioxx (M) |
Study Says Drug's Dangers Were Apparent Years Ago
Merck and federal officials should have withdrawn the
painkiller Vioxx from the market as early as 2000
because studies of the drug had clearly shown that it
doubled the risk of heart attacks among users, according
to a study released yesterday by The Lancet, a British
medical ... Authors of... |
The New York Times > Reuters > News >
Merck Knew Vioxx Was Unsafe by 2000 - Report
WASHINGTON (Reuters) - Pharmaceutical giant Merck & Co Inc. had
evidence by 2000 that its painkiller Vioxx, which was
pulled off the market on Sept. 30, was not safe, a heart
specialist told CBS News program ``60 Minutes'' on
Dr. Eric Topol, chief of cardiovascular
medicine at the Cleveland Clinic, examined all available
data about Vioxx and other similar pain relief
medications in 2001 for a study published in the Journal
of the American Medical Association.
the company conducted its biggest clinical trial of the
drug, widely known as the ``Vigor'' study, in 1999,
which found that Vioxx users had nearly a fivefold
increase in heart attacks.
Topol, a well-known cardiovascular researcher, also
reviewed an unpublished clinical trial of Vioxx by Merck
in 1998 that showed patients who took the drug were six
times more likely to have serious cardiovascular events
-- including heart attacks and strokes -- than patients
who took another arthritis drug or placebo
MayoClinic.com - Are COX-2 drugs safe for you?
An interview with a Mayo Clinic specialist
The arthritis drug rofecoxib (Vioxx) was withdrawn from
the market after a study demonstrated that it increases
the risk of heart attack and stroke. Vioxx, a COX-2
inhibitor, is a nonsteroidal anti-inflammatory drug (NSAID)
used to manage pain and inflammation. The drug is sold
in some countries under the name Ceoxx.|
about the safety of the other COX-2 inhibitors, Celebrex
and Bextra, soon followed. And now an old standby — the
nonprescription naproxen (Aleve, others) — is up for
scrutiny. Millions of people around the world have
relied on these medications for pain relief. So if
you're confused about what to do next, you're not alone.
Eric Matteson, M.D., a rheumatologist at Mayo Clinic,
Rochester, Minn., discusses common concerns about Vioxx
and related drugs.
Why was Vioxx pulled off the
The immediate withdrawal of the drug was
based on data from a three-year trial designed to
evaluate the possible effectiveness of Vioxx in
preventing the recurrence of colon polyps. In comparing
people taking Vioxx versus those taking a placebo, the
study reported an increased relative risk of
cardiovascular problems, such as heart attack and
stroke, after 18 months of Vioxx. According to the Food
and Drug Administration, although your risk of having a
heart attack or stroke related to Vioxx is very small
compared to people not taking Vioxx, the degree of risk
depends on how much Vioxx they have taken, and for how
What is the risk associated with Vioxx?
Your risk overall is low. Studies show your risk of
heart attack and stroke can be as low as a couple of
percentage points higher to as much as three times
higher than the risk faced by those who haven't taken
Vioxx. The risk appears to be greater for those who take
very high doses of Vioxx — 5 milligrams (mg). Most
people take 12.5-mg or 5-mg doses.
The Vioxx Safety
Study Merck Didn't Do
On Sunday, 60 Minutes will run a story
asking if Merck (nyse:
MRK - news - people ) knew about the dangers of Vioxx, the
arthritis drug that was pulled from the market because
it doubled the risk of heart attack and stroke. On Thursday,
congressional hearings will begin in an attempt to answer
much the same question. But there's another question worth asking:
Did Merck do enough to study Vioxx's effect on the heart?
At a December 2001 meeting with financial analysts, Merck
promised to study the safety of Vioxx and a follow-up drug,
Arcoxia. To help prove the heart safety of Arcoxia, Merck
announced a 23,542-patient trial called MEDAL in September 2002.
Yet no similar study was conducted for Vioxx
(see: ("Merck's Missing Study").
60 Minutes' Ed Bradley explores potential warnings ignored by
drug maker Merck of its recently pulled arthiritis drug, Vioxx.
(CBS) When the pharmaceutical giant Merck pulled its
blockbuster pain medication Vioxx off the market in late
September, it became the largest prescription drug recall in
The company says it took immediate action after
a new study showed that Vioxx doubled the risk of heart attacks
and strokes in some patients.
However, according to
internal Merck documents 60 Minutes has seen, and
interviews with outside scientists, Merck had concerns that
Vioxx could possibly cause cardiovascular risks long before it
was pulled off the market.
CBS News | Prescription For Trouble | November 14, 2004 21:55:57
How did Vioxx
|But the new Vioxx study was not the first to raise concerns about
heart attack and stroke risk. "We have been concerned
and aware of the potential for cardiovascular effects
for the last few years," Steven Galson, acting director
of the FDA's Center for Drug Evaluation and Research,
said the day Merck announced the withdrawal. "This is
not a total surprise."|
In fact, in April 2000 the
FDA required Merck to add labeling information about a
possible link to such problems. Yet 2 million Americans
were taking Vioxx when it was pulled.
describe the rise and fall of Vioxx as a cautionary tale
of masterful public relations, aggressive marketing and
ineffective regulation. "The FDA didn't do anything,"
says Eric Topol, chief of cardiovascular medicine at the
Cleveland Clinic. "They were passive here."
Chuck Grassley, R-Iowa, says the FDA was worse than
passive. Investigators for the Senate Finance Committee,
which Grassley chairs, met Thursday with FDA researcher
David Graham, lead scientist on a study presented in
August at a medical meeting in France.
Justice Dept. And S.E.C. Investigating Merck Drug
|ABSTRACT - Justice Department
and Securities and Exchange Commission are investigating
Merck & Co in connection with Vioxx, painkiller that was
withdrawn from market in late September because it
increased risk of heart attacks in long-term users;
Justice Department issues subpoena requesting
information related to company's research, marketing and
selling activities with respect to Vioxx; SEC has begun
informal inquiry (M) || |
PRESS RELEASE: Vioxx® pulled from market
As a physician who has been cautioning patients about
the ills of both medications, I did not feel the urge to
dance like the stars of so many commercials for
arthritis remedies. Both Celebrex® and Vioxx® are known
as COX-2 inhibitors, a sub-class of non-steroidal
anti-inflammatory drugs, or NSAIDS. Older NSAIDS include
ibuprofen, naproxen, indomethacin, and many others,
including the prototype aspirin. |
-In 1998, fatalities due to NSAIDS among arthritis
sufferers rivaled deaths from AIDS.
-CHF from NSAIDS
may have exceeded GI toxicity, which already accounted
for 107,000 admissions per year.
-NSAIDS were called
a silent epidemic by a prestigious medical journal, and
then, incomplete and misleading data published in
another leading journal turned newer, but still
unimproved, substitutes into a multi-billion-dollar
-NSAIDS inhibit enzymes in the body called
cyclooxygenase, of which there are two sub-types: COX-1
and Cox-2. The older NSAIDS block both, while the newer
ones target only COX-2. Why is this important?
-According to the New England Journal of Medicine, in
1998 NSAIDS accounted for 16,50 deaths in the U.S.
among arthritis sufferers alone, and 107,000 people were
hospitalized due to NSAID-related bleeding from the
stomach or bowels. The journal editors called this a
-The deaths among arthritis
sufferers due to NSAIDS approached all deaths in this
country from AIDS that year—and far exceeded deaths from
breast cancer, leukemia, lymphoma, or several other
feared killers combined. Worse, the numbers did not
include over-the-counter preparations or uses such as
headache, backache, dental pain, menstrual or
postoperative pain, or many others.
athletes pitched Advil® on television, and physicians
wrote thousands upon thousands of new NSAID
prescriptions, where were the lapel ribbons,
fundraisers, or public awareness campaigns concerning
-Physicians have been aware of at least
one dangerous NSAID complication: GI bleeding. But this
was felt to be due to inhibition of the COX-1 enzyme.
Hence, the search for selective COX-2 blockers. And in
1999—the year after the New England Journal editorial—Vioxx®
and Celebrex® hit the streets running. Hailed as safer,
both were said to lower the incidence of stomach ulcer
and bleeding. Physician offices and professional
journals were bombarded with this news. Billions of
dollars of prescriptions were written. But the whole
story had not been told.
-Bleeding is not the only
side effect associated with NSAIDS. In March 2000, the
Archives of Internal Medicine speculated: “The burden of
illness from NSAID-related CHF (congestive heart
failure) may exceed that resulting from gastrointestinal
damage.” Other studies indicate half of all hospital
admissions for CHF may be due to NSAIDS. And yet this
and other potential side effects were ignored by the
researchers and marketers hailing Vioxx® and Celebrex®
Merck and federal officials should have withdrawn the painkiller
Study Says Drug's Dangers Were Apparent Years Ago|
Merck and federal officials should have withdrawn the
painkiller Vioxx from the market as early as 2000
because studies of the drug had clearly shown that it
doubled the risk of heart attacks among users, according
to a study released yesterday by The Lancet, a British
Authors of the study pooled data
from 5,273 patients who participated in 18 clinical
trials conducted before 2001. They found that patients
given Vioxx had 2.3 times the risk of heart attacks as
those given placebos or other pain medications. Merck
withdrew Vioxx on Sept. 30 of this year after a
company-sponsored trial found a doubling of the risks
for heart attack or stroke among those who took the
medicine for 18 months or more.
Merck Faces Huge Fallout Over Vioxx Suits
wounded by the withdrawal of its Vioxx pain reliever
from the market, Merck & Co. must now contend with
hundreds of lawsuits over the drug's side effects -
lawsuits that threaten to further damage the company's
finances and reputation. |
Wall Street analysts
are concerned about Merck's potential legal liability.
This week, Standard & Poor's Corp. warned that it might
downgrade its ratings on Merck's debt because of the
huge payouts the company might be forced to make.
Merck withdrew Vioxx from the market Sept. 30 because
the drug doubled the risk of heart attacks and strokes
in patients taking it longer than 18 months. Merck's
stock plunged nearly 27 percent and the company lost $28
billion in shareholder value after the announcement -
partly in response to the loss of revenue from Merck's
second best-selling drug, but also because of the
lawsuits, said Richard Evans, an analyst at Sanford C.
Bernstein Research. He estimates Merck's legal costs
could reach $12 billion
Pfizer Says Bextra, Heart Problems Linked
Oct. 15, 2004
coronary bypass trials are ones that Dr. Eric Topol, of
the Cleveland Clinic Foundation and an early and
outspoken critic of
Vioxx, said he found concerning as they show
a cluster of heart attacks and strokes. He said the
danger signal does not appear to be as strong as it was
"Celebrex and Bextra do appear safer than
Vioxx but whether they are really safe, especially in
patients with heart risk, that's an open question,"
Pfizer has updated the label on
several occasions since Bextra was approved to reflect
the risk of
Stevens-Johnson syndrome, a form of allergic
reaction caused usually by certain types of drug.
Symptoms usually begin as a blistering of the mouth and
lips, spreading to the throat, tongue and other parts of
the body. The blisters sometimes become so extensive as
to be fatal.
TIME.com: A Painful
Mistake -- Oct. 11, 2004
causing the heart attacks, or was naproxen protecting the heart?
Few experts fault Merck for continuing to market Vioxx on the
basis of that study alone.
But the evidence didn't stop there. Subsequent studies based on
reviews of large numbers of clinical records continued to
show troubling indications. The final straw was a piece of research that Merck conducted.
It was a particularly careful study — a randomized, double-blind
trial of 2,600 patients, comparing Vioxx with a placebo —
designed to determine whether Vioxx might prevent the formation
of polyps in the colon. The study was scheduled to last three
years, but two weeks ago, the panel of doctors and statisticians
that was monitoring the trial's safety data informed Merck that
the evidence of cardiovascular
problems in the subjects taking Vioxx was clear — so clear that the trial
should be halted immediately.
Promise and Peril of
Cast Harsher Light on
Although the reason Vioxx caused heart problems is
not certain, researchers believe its selective action on
the COX-2 enzyme, but not the COX-1, throws the prostanoids involved
in clotting out of balance.
The result is a tendency for
blood to clot -- and clots are the first step of heart attacks
and most strokes. If that theory is correct, it means that
Vioxx's cleverness was also its Achilles' heel
Vioxx® pulled from market:
But is this reason to celebrate?
-In 1998, fatalities due to NSAIDS among
arthritis sufferers rivaled deaths from AIDS.
NSAIDS may have exceeded GI toxicity, which already accounted
for 107,000 admissions per year.
-NSAIDS were called a
silent epidemic by a prestigious medical journal, and then,
incomplete and misleading data published in another leading
journal turned newer, but still unimproved, substitutes into a
-NSAIDS inhibit enzymes in
the body called cyclooxygenase, of which there are two
sub-types: COX-1 and Cox-2. The older NSAIDS block both, while
the newer ones target only COX-2. Why is this important?
-According to the New England Journal of Medicine, in 1998
NSAIDS accounted for 16,50 deaths in the U.S. among arthritis
sufferers alone, and 107,000 people were hospitalized due to
NSAID-related bleeding from the stomach or bowels. The journal
editors called this a “silent epidemic.”
-The deaths among
arthritis sufferers due to NSAIDS approached all deaths in this
country from AIDS that year—and far exceeded deaths from breast
cancer, leukemia, lymphoma, or several other feared killers
combined. Worse, the numbers did not include over-the-counter
preparations or uses such as headache, backache, dental pain,
menstrual or postoperative pain, or many others.
retired athletes pitched Advil® on television, and physicians
wrote thousands upon thousands of new NSAID prescriptions, where
were the lapel ribbons, fundraisers, or public awareness
campaigns concerning this killer?
-Physicians have been
aware of at least one dangerous NSAID complication: GI bleeding.
But this was felt to be due to inhibition of the COX-1 enzyme.
Hence, the search for selective COX-2 blockers. And in 1999—the
year after the New England Journal editorial—Vioxx® and Celebrex®
hit the streets running. Hailed as safer, both were said to
lower the incidence of stomach ulcer and bleeding. Physician
offices and professional journals were bombarded with this news.
Billions of dollars of prescriptions were written.
But the whole story had not been told.
is not the only side effect associated with NSAIDS. In March
2000, the Archives of Internal Medicine speculated: “The burden
of illness from NSAID-related
CHF (congestive heart failure) may exceed that
resulting from gastrointestinal damage.” Other studies indicate
half of all hospital admissions for CHF may be due to NSAIDS.
And yet this and other potential side effects were ignored by
the researchers and marketers hailing Vioxx® and Celebrex®