The Wall Street Journal, April 24, 2006

Bristol-Myers Squibb, Bayer, Schering-Plough: Aspirin dispute is fueled by funds of industry rivals

Over the past four years, medical publications have become full of talk about "aspirin resistance" -- suggesting that millions who take an aspirin a day to prevent heart attacks are wasting their effort. If that is true, widespread testing might be needed to detect the condition and doctors might have to turn to aspirin substitutes costing $4 a day.

But reports and commentary on the subject often fail to point out that many of those raising alarms about aspirin resistance have financial ties with drug and test makers who stand to profit from the idea's acceptance.

Last July, Harvard Medical School associate professor Daniel Simon warned that aspirin resistance may afflict as many as 30 percent of the 25 million Americans taking aspirin for their hearts. He wrote in Physician's Weekly, a trade publication, that these people are at higher risk for heart attacks and strokes and may need other anticlotting drugs.

The article didn't mention that Dr. Simon receives research funding from Accumetrics Inc., a privately held San Diego company that makes a test to measure aspirin resistance, and from pharmaceuticals maker Schering-Plough Corp., which sells a drug being tested as a potential benefit for patients deemed aspirin-resistant. He is also a consultant and paid speaker for Schering-Plough. Physician's Weekly Managing Editor Keith D'Oria says he knew of the ties, but didn't disclose them. He said the publication never discloses possible conflicts and instead uses the information for other purposes, such as contacting drug companies listed by doctors to see if they might place an ad near the doctor's commentary.

The issue of aspirin resistance is a powerful example of how key academic researchers with a financial interest can influence the care Americans receive. Fears of aspirin resistance have boosted sales of the anticlotting pill Plavix, the world's second best-selling drug after cholesterol fighter Lipitor. Even some doctors who are trying to debunk aspirin resistance have financial ties -- to aspirin maker Bayer AG.

"There is a real issue of who you can get unbiased opinion from in medicine," says John Eikelboom, a hematologist at McMaster University in Hamilton, Ontario, who has consulted for both an aspirin manufacturer and the maker of an alternative blood-thinner. "It is a terrible problem ... I try to be honest with myself, but I can't pretend I will always be as honest as necessary."

Mark Feldman, chairman of internal medicine at Presbyterian Hospital of Dallas, says much of the talk about aspirin resistance is generated by "companies pushing these tests." He recommends against testing and worries that some doctors are upping the dosage of aspirin for patients deemed resistant, which he says increases the risk of gastrointestinal problems for those patients.

Harvard's Dr. Simon, who will take up a new position in July as chief of cardiology at Case Western Reserve University in Cleveland, says it's a mistake to tune out the views of those with some conflicts of interest because industry is driving medical advances. Most unconflicted researchers "are not truly expert," he says.

Aspirin, which costs pennies a pill, inhibits sticky fragments in the blood called platelets. They pool together to form clots that can block arteries, causing heart attacks and strokes. The American Heart Association recommends that those who have suffered a heart attack or stroke take one aspirin a day, based on studies showing this regimen can reduce heart attacks and strokes by around 25 percent. Many doctors also prescribe aspirin for others at risk, such as overweight men over 40, and recommend a baby dose (81 milligrams) to limit potential damage to the stomach.

Aspirin resistance was little studied until 2002, when more than a dozen research reports on it were published. Each successive year has seen an increase in research work and publications on the topic.

Today, it's widely agreed that aspirin fails to have an anticlotting effect in at least a small number of patients. But critical questions remain unresolved, including how many such patients there are and how high their cardiovascular risk is. Perhaps most importantly, research has yet to show whether any drug or treatment can help aspirin-resistant people.

A 2002 study by Dr. Eikelboom and colleagues found that a high level of aspirin resistance -- as measured by a certain urine test -- could more than triple the risk of cardiovascular death. However, Dr. Eikelboom now says the urine test is "the wrong marker" and shouldn't be used to test for aspirin resistance.

Amid the uncertainty, doctors are increasingly testing patients for resistance and prescribing aspirin alternatives. Medicare, the federal health insurer for the elderly, says it paid for 43,000 laboratory tests used to measure aspirin resistance in 2004, which was double the number of tests it paid for just two years earlier. Dade Behring Inc. of Deerfield, Ill., reported last year that sales of its machine for measuring aspirin resistance "continued to grow in double digits."

Cardiologist Roger Acheatel of Escondido, Calif., began testing all of his patients who take aspirin for resistance after reading about the topic in the medical literature. He uses the Accumetrics test, which is covered by Medicare and most insurers. The test costs doctors and hospitals about $20 to $22. Medicare reimburses $30 for the test.

Dr. Acheatel often prescribes Plavix, which is sold by Bristol-Myers Squibb Co. and Sanofi-Aventis SA, for patients found to be aspirin-resistant. "Why deny people treatment?" he asks, adding that patients who are not tested for aspirin resistance are "behind the curve."

World-wide sales of Plavix reached $5.9 billion last year, according to IMS Health Inc., up 59 percent from two years earlier. Plavix, also known by the generic name clopidogrel, stops clotting via a mechanism that is different from aspirin's. Doctors often prescribe both aspirin and Plavix for patients receiving cardiac stents, which increase clotting risk. Online pharmacies quote a price of $4 to $4.50 for a daily dose of Plavix.

"Before Plavix we rarely heard a mention of aspirin resistance," says Sanjay Kaul, director of cardiology training at Cedars-Sinai Medical Center in Los Angeles. "One has to wonder if the commercial implications of this phenomenon trump scientific reality." Dr. Kaul says he doesn't test patients for aspirin resistance and accepts no industry funding or consulting work.

A Bristol-Myers spokesman denied that the company is seeking to undermine aspirin, saying there would be "no advantage" to doing so because Plavix is often taken together with aspirin.

Adding Plavix to aspirin as a preventative measure, however, appears to do little good and may also be harmful in some cases, according to a recent study. Published in the New England Journal of Medicine, the study said Plavix plus aspirin wasn't any more effective than aspirin alone in preventing heart attacks, strokes or deaths from cardiovascular disease. In one group of patients -- those who hadn't already had a heart attack or stroke -- the addition of Plavix increased the risk of death and bleeding complications. The study of more than 15,000 patients was funded by Plavix's makers.

The study does not mean Plavix is not effective in other situations. Days after the study results were announced, the country's two top cardiology organizations advised heart patients not to stop their Plavix treatment, especially if they had a drug-eluting stent implanted. Plavix is approved for patients with a recent heart attack or unstable chest pain, and for people treated with drug-eluting stents.

Among those lending credence to aspirin resistance has been Eric Topol, who recently left his position as head of cardiology at the Cleveland Clinic after clashing with Chief Executive Delos "Toby" Cosgrove. Dr. Topol is one of the world's most-cited authorities on the heart.

Dr. Topol co-authored an influential 2003 Cleveland Clinic study published in the Journal of the American College of Cardiology. It reported that among those taking aspirin, resistant people were three times as likely to die or suffer a heart attack or stroke as those who responded normally to aspirin.

The authors speculated that "future treatment of aspirin resistance with additional antiplatelet agents such as clopidogrel (Plavix) may significantly improve the poor prognosis." Several hospitals have cited the Cleveland Clinic study as backing for their decision to adopt the Accumetrics test.

The study looked at 326 patients, 17 of whom were determined to be aspirin resistant. Of those 17, four suffered either a death, a heart attack or a stroke. If just one fewer patient had died or suffered a stroke or heart attack, the result would have lacked statistical significance, according to Steven Steinhubl, a University of Kentucky cardiologist who conducts aspirin-resistance research and consults for several companies making anticlotting drugs.

The Cleveland team also used another method for determining aspirin resistance. Under that method, there was no statistically significant difference between the aspirin-resistant group and the normal group. But that result wasn't published. Dr. Steinhubl says the decision to publish only one result skewed the conclusion to a more alarmist one. "If you see what you want to see, you publish it," he says.

Dr. Topol says the test used in the published study is the "gold standard." He notes that even with the other test there was an indication of risk from aspirin resistance although the data weren't statistically significant.

In June 2004, Dr. Topol was quoted in an Accumetrics press release as saying that its aspirin test was "prototypic of the future of individualized medicine" and would allow doctors to "improve outcomes for a large number of patients." Dr. Topol says he never authorized the quote in the press release and it is inaccurate. Robert Hillman, chief executive of Accumetrics, said in an email that "it's impossible for me to recall the exact circumstances" of the release.

Although the press release didn't mention it, Dr. Topol at the time was a consultant to Accumetrics and also advised another aspirin resistance-testing firm, AspirinWorks, a division of Creative Clinical Concepts Inc. of Denver. He also served as a consultant to companies making or developing aspirin alternatives, including Bristol-Myers, Sanofi-Aventis, Eli Lilly & Co., and Medicines Co. All were paid positions, Dr. Topol says.

Dr. Topol says he has always been careful to avoid recommending that patients be tested for aspirin resistance. He says he has called for more thorough studies of the subject. In the case of Accumetrics and AspirinWorks, Dr. Topol says he was given shares in the companies in exchange for his consulting work. He says he forfeited those stakes in 2004 as part of a broader decision to sever financial ties with industry to avoid the perception of conflicts. "I never profited in any way from my work with Accumetrics or the company that developed the AspirinWorks assay," he says.

In addition to consulting with Accumetrics, Dr. Topol helped the company get venture-capital funding. In April 2003, Essex Woodlands Health Ventures of Chicago listed Dr. Topol as an "adjunct partner" who provided advice on "all aspects of the venture capital process." Essex Woodlands led a $13.5 million round of investment in Accumetrics in March 2004 and has since invested more in the company.

Dr. Topol "was certainly one of the individuals who played a factor in connecting us" with Accumetrics, says Immanuel Thangaraj, a managing director of Essex Woodlands. Mr. Thangaraj declined to say how much his firm paid Dr. Topol for the part-time position. Dr. Topol says he doesn't remember what he was paid.

Besides their research work, Dr. Topol and his Cleveland Clinic colleagues hit the lecture circuit to build awareness of aspirin resistance. At the annual meeting of the American Heart Association in November 2004, a packed room of doctors attended a symposium co-led by Dr. Topol: "The Cleveland Clinic Presents the Diagnosis and Management of Antiplatelet Resistance." Accumetrics and two drug companies making anticlotting drugs were among the event sponsors.

Dr. Eikelboom of McMaster University said he disagreed with the tenor of the symposium. "I was upset because I don't think we ought to be promoting testing for aspirin," he says, citing the lack of evidence that changing treatment for aspirin-resistant patients does any good. Dr. Topol's own comments at the symposium didn't promote testing, according to a transcript.

Harvard's Dr. Simon is about to enroll the first patient in a more than $2 million, 600-patient study that will use the Accumetrics test to determine if patients about to undergo angioplasty -- or unblocking of arteries -- are resistant to aspirin or Plavix. (Accumetrics now also makes a test to measure Plavix resistance.)

Patients classified as resistant will be placed into two groups -- one receiving Integrilin, an injectable anticlotting medication sold by Schering-Plough, and one receiving a placebo. The researchers will compare the two groups for differences in heart-attack rates. The study, initiated by Dr. Simon, is funded by Accumetrics and Schering-Plough.

Cardiologist Sidney Smith, a former American Heart Association president, says the federal government should fund an independent study to answer questions about aspirin resistance.

Some of the strongest criticisms of aspirin resistance have come from researchers with ties to Bayer. In December, the New England Journal of Medicine published a review article that concluded that none of the aspirin tests "is currently recommended" and that there was "no scientific basis for changing antiplatelet therapy." The four authors of the article all had financial ties to Bayer, which were disclosed.

In September 2004, the journal Circulation published a "special report" on aspirin resistance that warned the "current usage of the term aspirin resistance implies a linkage between a laboratory test and a clinical outcome that is presently unsubstantiated."

The lead author of that report, epidemiologist Charles Hennekens of the University of Miami School of Medicine, reported that he was a consultant for Bayer. The report didn't have disclosures regarding two other authors with Bayer connections: Steven Weisman, a former Bayer executive who remains a consultant to the company, and University of Pennsylvania researcher Garret FitzGerald, a Bayer consultant at the time the article was published.

A spokeswoman for the American Heart Association, which publishes Circulation, said the other authors reported their connections to Bayer but the information was omitted because of a production error. Dr. FitzGerald confirmed that he disclosed the relationship at the time the article was submitted.

Dr. Hennekens, who conducted a landmark study in the 1980s demonstrating the benefits of taking an aspirin a day, has been particularly critical of aspirin resistance. In a December 2004 commentary in Physician's Weekly, Dr. Hennekens cautioned that "exaggerated concern about this undocumented phenomenon may have the negative consequence of reduced aspirin use." His connection to Bayer was not disclosed in that article. He did not respond to telephone and email messages seeking comment. (by David Armstrong)