Vioxx, Other “Super Aspirins” Are Super Disasters – Other Cox-2 Alternatives Have Safety Problems Too

Article by Public Citizen’s Health Research Group at worstpill.org

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 Cox-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 Cox-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, Peter 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 Raymond 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 Cox-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. Douglas 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 Cox-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[s] 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” Cox-2 inhibitors and, instead, to rely on the older drugs in the NSAID family such as ibuprofen and naproxen.

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Public Citizen is a national, nonprofit consumer advocacy organization based in Washington, D.C.For more information, please visit www.worstpills.org.

FDA Estimates Vioxx Caused 27,785 Deaths

from Consumer Affairs Magazine
Nov 04 '04


The Food and Drug Administration (FDA) estimates that Vioxx may have contributed to 27,785 heart attacks and sudden cardiac deaths between 1999 and 2003. The estimate is based on the number of prescriptions issued for Vioxx between 1999 and 2003.

David Graham, the associate director for science in FDA's office of drug safety, made the estimate based on 92.8 million U.S. prescriptions for Vioxx between 1999 and 2003. It's part of a study Graham conducted in cooperation with Kaiser Permanente.

Merck pulled Vioxx, a popular pain reliever widely used by arthritis patients, off the market in September, saying it was "putting patient safety first" but the Wall Street Journal reported earlier that company officials had fought for years to protect the highly profitable drug and to keep news of the health risks quiet.

Vioxx was a big moneymaker for Merck, generating about $2.5 billion in yearly sales.

In his study, Graham's team examined records for 1.39 million members of Kaiser Permanente, including 26,748 who took Vioxx and 40,405 who were on Pfizer's Celebrex, another COX-2 inhibitor.

The study found that high doses of Vioxx, or rofecoxib, tripled risks of heart attacks and sudden cardiac death. Graham planned to present the findings at an epidemiology conference Aug. 25, but his supervisors said the results were "too preliminary" and recommended that the study be submitted first to a medical journal so it could undergo peer review or be presented at the conference with an alternative FDA opinion.

When the study was presented Aug. 25, the abstract said, "[T]his and other studies cast serious doubt on the safety of rofecoxib ... and its use by physicians and patients" at doses exceeding 25 milligrams. "When Graham submitted a revised, final version to FDA on Sept. 30, FDA's announcement of the study's release did not mention specific data on cardiovascular risks.

About 20 million Americans had taken Vioxx by the time Merck withdrew it.

The company responded to the latest report by saying there is "no reliable way to estimate the actual events."

"Because heart attacks and strokes occur in the general population, one cannot say that if someone had an event while taking Vioxx, that Vioxx caused it," a Merck spokesman said.

Drug Safety at the FDA Under Fire: What to Do?

Criticism of FDA's Drug Safety Efforts Triggers Debate

Aside from criticizing the FDA for not acting sooner to protect Americans from the potential risks associated with Vioxx, Graham also warned that five additional popular prescription drugs should be closely monitored due to safety concerns. Graham fingered Crestor, Bextra, Meridia, Serevent, and Accutane in his statement…. During his testimony, Graham, who is an associate science director at the FDA's Office of Drug Safety, said that the recommendations of drug safety reviewers are often overruled by officials in the FDA's Office of New Drugs. He asked lawmakers to create an independent drug safety monitoring office free of the influence from regulators who approve new drugs.

But Galson says the FDA's Office of New Drugs is already an independent office and is separate from the office that reviews drug safety. Both offices report to Galson, as the acting director of the Center for Drug Evaluation and Research.

To address post-approval drug safety concerns, Galson says he recently asked the Institute of Medicine (IOM) to look at the structure of the FDA's post-marketing surveillance program and to give their advice on whether additional changes are needed to the agency's approach to drug safety.

This is a bureaucratic response, one which before all else defends the agency.  That leaves us with two concerns:  (1) is the IOM an independent, credible agency, and (2) is it likely that their recommendations if critical of the existing structure will be implemented?  The answer to the first is a qualified yes, for it is funded by Congress, and as for (2).  There are too many political loops to jump including a President who is in bed with the pharmaceutical industry, as is Congress, and Galson will surely oppose a review system outside the FDA, for bureaucrats always defend their turf.   Finally studies are the do-something, do-nothing dodge.  In a couple of years a report will be generated by the IOM and reviewed, and by that time Congress, the President, and the public will have forgotten the cause for the study.  Skepticism is further reinforced by the track record of the FDA, which has consistently been pro-pharmaceutical industry.  The chances for significant in the public’s interest action is slim, while the pretend concern and pretend we are doing something has already started.  History is repeating itself.--jk 

FDA whistleblower claims he'll be forced from post


by Rita Rubin | Nov 26 '04  USA TODAY

Food and Drug Administration whistleblower David Graham said Wednesday that he expects as soon as next week to be forced from his job in the Office of Drug Safety.

''I'm going to be transferred, and I don't want to go,'' said Graham, who told a Senate committee on Nov. 18 that the FDA is ''virtually defenseless'' against another ''terrible tragedy and a profound regulatory failure'' like Vioxx, an arthritis drug pulled off the market over concerns that it increased the risk of heart attack, stroke or sudden cardiac death.

Graham, associate director for science and medicine in the FDA office, went on to name five other drugs -- Meridia, Crestor, Accutane, Serevent and Bextra -- that he says threaten the public's safety.

Graham's attorney, Tom Devine, legal director of the Government Accountability Project, said his client ''got a very credible warning'' about the job change from a staff member in the office of acting FDA Commissioner Lester Crawford.

''He's going to be exiled from work reviewing drugs and put to work in the office of the commissioner,'' said Devine, adding that Graham has no legal recourse against such a move. ''He'll be paid to fill space under the watchful eye of a babysitter.'' Devine's non-profit group is a public-interest organization and law firm that defends whistleblowers.

Graham says he met with Crawford on Nov. 9 to discuss the agency's plans to strengthen the safety program for marketed drugs.

The Food and Drug Administration would neither confirm nor deny that Graham is to be transferred. In a statement to USA TODAY on Wednesday, the agency said, ''For privacy reasons, the FDA does not comment on personnel issues.''

The Food and Drug Administration would neither confirm nor deny that Graham is to be transferred. In a statement to USA TODAY on Wednesday, the agency said, ''For privacy reasons, the FDA does not comment on personnel issues.''

BMJ , a British medical journal, reported this week that a caller to Devine's group, who claimed to be another FDA whistleblower, described Graham as a bully whose research might reflect scientific misconduct. The call was found to have come from an FDA manager trying to discredit Graham.

Vioxx Unsafe: So What About Similar Drugs?

Editorial: Other Drugs in Vioxx Class Must Prove Heart Safety

Oct. 7, 2004 -- Now that we know Vioxx wasn't safe, can we trust its sister drugs, Bextra and Celebrex? No, argues a New England Journal of Medicine (NEJM) editorial.

Vioxx, like Bextra and Celebrex (and two more drugs not approved in the U.S.) are members of a family called Cox-2 selective inhibitors. All fight pain and inflammation by blocking a molecule called Cox-2.

Blocking Cox-2 also predisposes people to heart attacks, according to a five-year-old theory by Garret FitzGerald, MD, director of the Institute for Translational Medicine and Therapeutics at the University of Pennsylvania in Philadelphia.

"Now, with Vioxx, we see the manifestation of a risk entirely consistent with precisely the mechanism we proposed," FitzGerald tells WebMD. "That puts the burden of proving safety on the manufacturers of these [other] drugs."

Vioxx: 160,000 Heart Attacks and Strokes

This call for safety studies has a familiar ring to it. In August 2001, Eric J. Topol, MD, chairman of the Cleveland Clinic cardiology department, was troubled by heart-safety data in Vioxx clinical trials. He called on the FDA to demand specially designed heart-safety studies. That never happened. Instead, three years later, a study looking at whether Vioxx could prevent colon polyps found the drug posed an unacceptably high heart risk.

Ten million people have taken Vioxx, partly due to an aggressive direct-to-consumer advertising campaign. Topol calculates that 160,000 of these patients had a Vioxx-caused heart attack or stroke.

"I believe that there should be a full Congressional review of this case," Topol writes in an NEJM editorial. "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."

SOURCES: FitzGerald, G.A. The New England Journal of Medicine, Oct. 21, 2004; vol 351: pp 1709-1711. Topol, E.J. The New England Journal of Medicine, Oct. 21, 2004; vol 351: pp 1707-1709. The Lancet, Oct. 9, 2004; vol 364: pp 1287-1288. Topol, E.J. The Lancet, Aug. 21, 2004; vol 364: pp 639-640. Garret FitzGerald, MD, director, institute for translational medicine and therapeutics, University of Pennsylvania, Philadelphia. News release, Merck. News release, Pfizer. FDA. Mitch Gandelman, MD, vice president for worldwide medical, oncology, and pain information, Pfizer. Stephen M. Lindsey, MD, head of the rheumatology department, Ochsner Clinic Foundation, Baton Rouge.

Bextra Ups Heart Attack, Stroke Risk

But Maker of Painkiller Says Findings are "Unsubstantiated"

Nov. 10, 2004 (New Orleans) -- A leading heart researcher says the painkiller Bextra increases the risk of heart attacks and strokes and may pose a greater risk than Vioxx. But Bextra's manufacturer calls the new findings "unsubstantiated."

In October, the painkiller Vioxx was voluntarily pulled from the market because it was found to increase heart attack and stroke risk.

In a new study, Garret FitzGerald, MD, PharmD, of the University of Pennsylvania, says he looked at data of Bextra use in more than 2,000 heart bypass surgery patients and nearly 5,700 arthritis patients.

Among all the patients -- heart bypass surgery patients and arthritis patients -- FitzGerald says the risk for heart attacks and strokes was more than twice as high in those taking Bextra.

FitzGerald says the finding should not be overstated, yet he was quoted in a news article in the New York Times as saying "The magnitude of the signal with Bextra is even higher than what we saw in Vioxx ...This is a time bomb waiting to go off." When WebMD asked if that quote was not itself an example of overstatement, FitzGerald said that it wasn't and offered this example of overstatement: "I could have said the bomb went off."

FitzGerald notes that his findings do not come from a placebo-controlled trial, which is the gold standard of medical evidence in which a drug is compared to a placebo. {That is misleading for following an operation, a placebo for pain would be cruel.  It is totally accepted to compare two drugs in a clinical situation—jk}  But FitzGerald says that in light of the Vioxx withdrawal "the landscape has changed, which adds weight to these findings."

Moreover, he says that his study suggests the problem is not with a single molecule found in a single drug like Vioxx, but rather a problem for the entire class of drugs that Vioxx and Bextra belong to, called Cox-2 inhibitors. One other Cox-2 inhibitor is available in the U.S. -- Celebrex. Bextra and Celebrex are made by Pfizer, a WebMD sponsor.

FitzGerald says he is not recommending that Cox-2 inhibitors be taken off the market but that he thinks patients with heart disease should be advised of the risk associated with the drugs.

Bextra's Manufacturer Responds

Pfizer issued a statement in response to a New York Times article in which the company states that the news article "draws unsubstantiated conclusions about the cardiovascular safety of its Cox-2 medicine Bextra and is based on information that has not been published in a medical journal or subject to independent scientific review."

The company notes that an analysis of studies of arthritis patients published earlier this year in the American Journal of Therapeutics found no such risk with Bextra. Pfizer says those findings showed that short- and intermediate-term treatment with Bextra was not associated with an increased risk of heart attack or stroke compared with more traditional anti-inflammatory drugs, like ibuprofen or naproxen, or with placebo. That conclusion was based on an evaluation of clinical trials of nearly 8,000 patients treated with Bextra for up to 52 weeks.  {Without knowing the details, this can be a totally misleading defense by Pfizer.  If the group of 8,000 was divided into 4, and if the average time on these drugs were 26 weeks, and if the age group was under 40, there would not be enough coronaries or strokes to have a statistically significant finding,  In a Merck study it was found that  “For the first 18 months of the trial, patients taking Vioxx every day had no more heart attacks or strokes than those taking placebo pills. But after 18 months on Vioxx, patients' heart attack and stroke risks doubled.”  Thus we can see the Pfizer statement is deliberately misleading, because the study was not long enough to produce deadly results—jk)

But after 18 months on Vioxx, patients' heart attack and stroke risks doubled, —jk} 

An FDA advisory committee is set to meet in February 2005 to review the safety of all Cox-2 inhibitors.  {Given the magnitude of the problem, 3 months later to have a review is irresponsible—jk}

SOURCES: Garret FitzGerald, MD, PharmD, University of Pennsylvania. Pfizer, Inc. The New York Times: "New Study Links Pfizer's Bextra, Similar to Vioxx, to Heart Attacks," Nov. 10, 2004.

Study May ID Source of Vioxx Problem

Argues Against Harmful Effect From Entire Class of Cox-2 Drugs

Nov. 11, 2004 -- A private research team claims to have identified a unique action of the painkiller Vioxx, which is independent of its anti-inflammatory action, that might explain why it's linked to heart attack and stroke and why other similar drugs might not be.

The researchers say the findings should reassure patients about the cardiovascular safety of other Cox-2 drugs, but two cardiologists contacted by WebMD remain unconvinced.

Vioxx was withdrawn from the market by manufacturer Merck & Co. a month and a half ago after research showed that long-term use doubled the risk of heart attack and stroke.

While some clinical trials have shown that another widely prescribed Cox-2, Pfizer's Celebrex, is more heart friendly than Vioxx, The Cleveland Clinic cardiologist Steven E. Nissen, MD, says the jury is still out. Pfizer is a WebMD sponsor.

"The clinical evidence to date has not implicated [Celebrex]," he tells WebMD. "But this drug has also has not been studied as carefully in patients with a high risk of cardiovascular disease."

Molecular Evidence

The newly reported study was conducted by researchers with Elucida Research of Beverly, Mass., and published in the latest issue of the journal Atherosclerosis. Elucida founder R. Preston Mason, PhD, says the two-year study uncovered important differences in the action of the Cox-2 drugs. These important differences may be key to linking Vioxx to cardiovascular disease risk.

In addition to Vioxx and Celebrex the researchers examined two other Cox-2s, Pfizer's Bextra and Merck's Arcoxia, which has not yet been approved for use in the U.S.

They found that Vioxx and Arcoxia changed LDL or "bad" cholesterol in a way that could facilitate atherosclerosis and contribute to an increased risk of heart disease. Specifically, the researchers say the drug alters low-density lipoprotein or "bad" cholesterol, in a way that makes these cholesterol molecules more susceptible to free radical damage. The effects were found to be independent of the drugs' Cox-2 function, and were not seen with the Pfizer drugs Celebrex and Bextra.  {However, the first article, the red portion, shows that there is an acute risk with Bextra--jk}

"This is the first evidence that there might be important differences in the molecules of these drugs that could account for differences in their cardiovascular safety," says Mason, who is also on the faculty of Harvard Medical School in Boston.

Mason tells WebMD that the research team received no drug company funding for the study. But he acknowledges that his company has received funding from Pfizer, but not from Merck.

A spokesperson for Merck declined to comment on the study, saying that the company is aware of a number of potential mechanisms that have been proposed to explain the cardiovascular findings with Vioxx.

"At Merck we are currently reviewing and further analyzing the existing data and working with outside consultants to determine the best path forward for obtaining additional information and data necessary to further clarify the mechanism of action involved in the cardiovascular events seen with Vioxx," he said.

"Based on this information we will assess the possibility that a potential mechanism-based risk could extend to other Cox-2 inhibitors and nonselective NSAIDs." Examples of nonselective NSAIDs are ibuprofen and naproxen.

Bextra Safety Questioned

The findings of this study argue against an effect from an entire class of drugs, i.e. Cox-2 drugs, but another widely publicized study appears to support a class effect. Preliminary research reported Wednesday at the annual meeting of the American Heart Association in New Orleans, concluded that Bextra (another drug of the Cox-2 class of anti-inflammatory drugs) may pose an even greater cardiovascular risk than Vioxx. The findings were based on data involving more than 2,000 heart bypass patients and nearly 5,700 arthritis patients, but a spokesperson for Pfizer says the researchers' choice of studies was suspect.

"What they did was pool studies [combine data from several studies] that were not appropriate to pool and leave out other studies that should have been included," the spokesperson told WebMD.

Gail Cawkwell, MD, PhD, who serves as Cox-2 medical director for Pfizer added that the study was presented without appropriate scientific review.

"This study gives such a misleading picture for prescribers and patients that we are anxious to make sure that it is not interpreted inappropriately," she says.

What's a Patient to Do?

The Cleveland Clinic cardiologist Nissen says until the adverse risk of heart disease for Cox-2 drugs is clear, arthritis patients and others with chronic pain might be better off using other nonsteroidal anti-inflammatory pain relievers if they don't experience gastrointestinal problems with these drugs.

"I would certainly want patients to take a drug like naproxen (Aleve) first," he says. "For those that experience GI intolerance it looks like [Celebrex] is a reasonable alternative, but we would like to see more studies of cardiovascular risk with this drug."

Former American Heart Association president Robert Bonow, MD, agrees that more study is needed to prove the cardiovascular safety of Celebrex.

"I think the safety of this entire class of drugs has been called into question," he tells WebMD. "Until we have more prospective trials -- and I would hope that the FDA will mandate this -- it would be prudent to recommend that these drugs be prescribed very carefully and to use alternatives in patients with proven heart disease."

In late May, Canadian researchers reported in The Lancet an increased risk for heart failure among elderly people using Vioxx that wasn't noted in those taking its rival, Celebrex. Compared to Celebrex users, those taking Vioxx were 80% more likely to be admitted to the hospital with heart failure. {Isn’t 80% more heart failures enough reason for prompt response to protect the public?--jk}