Plavix

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Plavix - Future Not Looking Too Rosy

Plavix (clopidogrel), is a heart drug that manufacturers said was superior to aspirin when applying for FDA approval in 1997. The drug is co-produced and marketed worldwide by Bristol-Myers and Sanofi-Aventis, and was designed to prevent heart attacks and strokes in patients with cardiovascular disease.

Cardiovascular disease accounts for more than 900,000 deaths each year in the US alone and includes previous heart attack, ischemic stroke, angina, coronary artery bypass graft surgery, angioplasty, or transient ischemic attack, according to UpToDate, Patient information: Aspirin and cardiovascular disease, by Dr Charles Hennekens, MD, DrPH, FACC, on April 13, 2006.

Plavix is used to prevent the buildup of platelets. Platelets are tiny cell fragments in the blood that have a role in blood clotting. "Under normal circumstances," Dr Hennekens notes, "platelets clump together and help form blood clots that stop bleeding."

"However," he continues, "in cardiovascular disease, platelets clump together in narrowed arteries, which leads to the development of a clot within the artery; the platelet "plug" itself or the clot that forms can block blood flow."

When the arteries that supply blood to the brain are blocked, the supply of oxygen to the brain is impaired. The result is a transient ischemic attack (TIA), when the blockage is brief, or an ischemic stroke, when the blockage is of a longer duration.

When the arteries that supply blood and oxygen to the heart are blocked briefly, the result is often chest pain, referred to as angina. A blockage of longer duration can result in a heart attack. Clots cause more than 90% of all heart attacks, according to the November 7, 2005, Advocate.com.

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For years, aspirin has been touted as the best medication to reduce the risk of heart attack and stroke. Aspirin affects platelet function by blocking the production of thromboxane A-2, the chemical that causes platelets to clump together, theoretically decreasing the likelihood of development of a thrombotic event, according to the March 13, 2006, paper Plavix & Aspirin - Fusion or Fission.

However, aspirin comes with a risk of the development of bleeding ulcers, the paper notes, which may require endoscopic treatment and even surgery. So, with the anti-platelet effect of aspirin seen as a good thing, but its GI side effects a bad thing, researchers looked for other ways to inhibit platelet function and thienopyridines, like Plavix, were developed to block ADP receptors on platelets.

The study submitted to the FDA to support the approval of Plavix, indicated the drug could reduce the number of heart attacks and strokes more effectively than aspirin, and claimed that aspirin prevented about 25% of such complications, and while Plavix prevented about 33%.

An FDA advisory panel voted for the approval of Plavix in late October 1997, and said Plavix could be used for all types of patients studied in the trial, according to the October 25, 1997, New York Times.

However, the Times wrote, "panel members agreed with Dr. Dan Rodin, a panel member and a professor at Vanderbilt University, who said that while the drug might be approved, ''I'm not all that convinced that clopidogrel would beat aspirin,'' a widely used -- and cheaper -- alternative."

Dr Rodin specifically said, Plavix should not replace the general use of aspirin. Aspirin costs only pennies a pill, while Plavix sells for about $4 a pill in the US.

At the time of the drug's approval, analysts said its success would depend on what benefits the FDA allowed to be listed on the product label and how extensively the drug was promoted.

"It's a tough go convincing doctors not to use aspirin," Alex Zisson, an analyst at Hambrecht & Quist, told the New York Times. "Aspirin has been studied in so many trials. It clearly works."

Since its approval on November 17, 1997, Plavix has been used to treat tens of millions of patients in the US. According to a February 27, 2006, article in Forbes.com, based on figures obtained from the healthcare information firm, IMS Health, Plavix ranks 6th in sales on the list of the top 20 best-selling prescription drugs in the US for 2005.

In Bristol-Myers's First Quarter 2006 Earnings Report, filed on April 27, 2006, the company lists Plavix with net sales of $3.8 billion in 2005, and says the drug is currently the top product in net sales.

In addition, the report says, primarily due to increased demand, sales of Plavix have increased 21%, to $986 million in the first quarter of 2006, compared to $814 million during the same period in 2005.

Contrary to the company's predictions, the future of Plavix in reality might not be all that rosy. One of the benefits of Plavix was that it supposedly did not cause bleeding ulcers.

However, back on January 20, 2005, the New England Journal of Medicine reported a study that showed Plavix to be more dangerous to heart patients with a history of bleeding ulcers than an aspirin based treatment.

The study found that patients taking Plavix, experienced more than 12 times as many bleeding ulcers as patients who received aspirin plus Nexium, a medication to reduce stomach acid.

The year-long study was conducted by Hong Kong researchers, on 320 patients who had previous ulcers that had healed. Half of the subjects were given Plavix, and the other half received aspirin plus Nexium.

The results of the study showed that 13 patients, or 8.6%, of those taking Plavix, experienced renewed ulcer bleeding during the year, while only one of the patients taking aspirin along with Nexium had a renewed ulcer bleed.

Up to half of the patients taking Plavix, do so because their doctors believe that Plavix is safer on the stomach than aspirin, said Dr Francis Chan, the study's lead author. The study, he advised, suggests that the guidelines should be changed and that many of the patients who are taking Plavix should consider switching to aspirin plus a heartburn pill.

Another study this year found more serious problems in patients treated with Plavix.

For many years, people with no previous history of heart attacks, who conditions like high blood pressure or high cholesterol, were prescribed Plavix together with aspirin to prevent heart attacks.

Aspirin is known to prevent heart attacks in men but reportedly does little to lower the risk of stroke with men. On the other hand, aspirin fends off strokes in women but only reduces the risk of heart attack in women 65 or older. The combination of Plavix and aspirin had been used with people who had a previous heart attack to reduce the risk of a second attack.

For these reasons, doctors believed the combination would prevent heart attacks in people with risk factors like diabetes, heavy smoking, and high cholesterol.

However, the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance study (CHARISMA), published in the April 20, 2006, New England Journal of Medicine, and first reported on March 12, 2006, at a conference of the American College of Cardiology, found that combining the 2 drugs, not only did not help, it nearly doubled the risk of death, heart attack or stroke in people with no history of heart disease.

To determine the benefits of the 2 drug treatment, Dr Eric Topel, of Case Western Reserve University in Cleveland, and Dr Deepak Bhatt of the Cleveland Clinic led a 2 year study, on 15,603 people in 32 countries. One group in the study was given a low daily dose of both aspirin and Plavix, and the other group was given aspirin and a placebo. The patients were followed for a median of 28 months.

Overall, adding Plavix made little difference with any patients except for reducing hospitalizations slightly. But in the 20% of patients who had no previous signs of heart disease, heart-related deaths almost doubled to 3.9% in those who received aspirin and Plavix, compared to 2.2% in patients taking aspirin alone.

In addition, Plavix plus aspirin was found to be associated with increased risk for moderate and serious bleeding, investigators reported at the American College conference.

"The risk associated with dual antiplatelet therapy in the asymptomatic group was not anticipated," the investigators noted. "The excess fatalities in this subgroup and the heightened risk of bleeding complications," they said, "suggest that we should be cautious about too quickly dismissing this unexpected finding as the play of chance."

The analysis of adverse events showed that patients taking Plavix plus aspirin had a severe bleeding rate of 1.7 %, compared with 1.3 % for the aspirin only group.

The only patients even slightly helped, were those with previous heart disease. With those individuals, the risk of heart attack, stroke or death was about 7%, compared to 8% with patients taking only aspirin. However, experts found this insignificant when considering the overall findings of no benefit.

"This was a trial to determine the boundaries of benefit, and it did," said Dr Topel. "You don't use this drug for patients without coronary artery disease."

In an editorial accompanying the study in the NEJM, Marc Pfeffer, MD, PhD, of Brigham and Women's Hospital and Harvard Medical School, and John Jarcho, MD, of the NEJM, said: "The data show no significant benefit associated with long-term clopidogrel therapy in addition to aspirin."

The cost and risks of Plavix do not justify expanding its use for prevention, said Dr Marc Pfeffer of Brigham and Women's Hospital in Boston, and Dr John Jarcho, of the New England Journal of Medicine, in an editorial published with the study in the April 20, 2006, NEJM.

In regard to another concern, experts say Plavix is a long-lasting drug with no readily available antidote, so once taken, platelets are pretty much out of commission anywhere from 5 to 10 days, the time it takes the body to rid itself of the old platelets and make new ones, during which time excessive bleeding can occur if surgery is performed.

For that reason, one surgeon said he really does not like the drug because an emergency operation on a patient taking Plavix can be either a "death-defying high wire act above Niagara Falls, or a death-producing disaster."

The organizers of the American College of Cardiology conference issued an "expression of concern," saying Sanofi-Aventis had informed stock analysts in advance about the study's results, in violation of the conference's embargo policies.

A Sanofi spokesperson denied the claim, saying the company provided no results in advance, according to the SFGate.com on March 12, 2006.

In addition to problem resulting from adverse studies, Plavix is also entangled in patent litigation that includes a major battle with the Federal Trade Commission. According to the July 10, 2006, Financial Times, "Bristol-Myers Squibb and Sanofi-Aventis' proposed settlement to end patent litigation over their biggest drug Plavix could be derailed by stringent sanctions agreed by Bristol with US regulators in 2003."

The two drug makers are negotiating with the FTC, and some state authorities over a deal with Apotex, a US subsidiary of Apotex Inc, the largest Canadian-owned prescription drug maker, with a sales and marketing headquarters in Florida and an operations center in Indianapolis.

Apotex won FDA approval for a generic version of Plavix earlier this year. The agreement reached with Sanofi and Bristol allowed the company to avoid a trial that was scheduled to begin in June 2006.

Unlike other drug companies that have had so-called "reverse payment" deals legally challenged after the fact, the Financial Times says, Bristol was forced to seek a "blessing its joint settlement with Apotex from the FTC before the deal was executed because of restrictions placed on the company by the regulator in 2003."

The FTC has said reverse payment transactions harm consumers by keeping drug prices high. Earlier this year the agency asked the Supreme Court to consider a case involving a reverse payment settlement, over objections from the Justice Department, indicating an unusual dispute between the antitrust authorities.

Under the terms of the 2003 agreement in a case where there was a delay in generic entry of three older drugs, Bristol is barred from entering into patent settlements that included a payment without seeking the FTC's approval.

If the FTC objects and Bristol moves ahead with the deal, the Times says, the company would likely face stiff penalties for violating the agreement. Furthermore, it notes, because the FTC's decision will be an advisory opinion within the discretion of the FTC, it will be difficult to find grounds to challenge the FTC opinion in court.

The terms of the consent decree state that any payments in a patent settlement deal could be "the lesser of expected future litigation costs to resolve the patent infringement claim or $2m." The current deal is expected to include at least a $40m payment, the Times said.

Late last month, in a move analysts call feeble at best, Bristol amended the terms of the Apotex deal to include allowing company to sell its generic in June 2011, instead of September.

In the company's April 20, 2006 SEC filings, Bristol does not sound too hopeful about the deal gaining approved by the FTC. "The proposed settlement is subject to certain conditions," the report notes, "including antitrust review and clearance by the Federal Trade Commission and state attorneys general."

"There is a significant risk," Bristol says, "that required antitrust clearance will not be obtained."

"In such event," the filing says, "the proposed settlement would be terminated, and the litigation would be reinstated." It also notes that similar proceedings are ongoing in Canada. In regard to other litigation matters, the company's filing states:

"The company and its subsidiaries are the subject of a number of significant pending lawsuits, claims, proceedings and investigations. It is not possible at this time reasonably to assess the final outcome of these investigations or litigations.

"Management continues to believe ... that during the next few years, the aggregate impact, beyond current reserves, of these and other legal matters affecting the company is reasonably likely to be material to the company's results of operations and cash flows, and may be material to its financial condition and liquidity. The company's expectations for 2006 described above do not reflect the potential impact of litigation on the company's results of operations."

"It is not possible at this time," the report concludes, "reasonably to assess the outcome of these litigations, or if there were an adverse determination in these litigations, the timing of potential generic competition."

by Evelyn Pringle

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Sources:

1. Heart attack risks, The Advocate.com, November 7, 2005
   
   
2. Plavix FDA approved, October 25, 1997 New York Times,
   
   
3. Bristol-Myers's First Quarter 2006 Financial Results, SEC Filing, Press release, April 27, 2006
   
   
4. Taking Plavix With Aspirin Proves Risky, SFGate.com, March 12, 2006,
   
   
5. ACC: Plavix-Aspirin Combo No Better than Aspirin Alone for CVD Event Reduction, Med Page Today, March 12, 2006
   
   
6. American College of Cardiology 2006 Annual Meeting; Bhatt DL et al. The Main Results of the CHARISMA Trial. Late-breaking clinical trial presented March 12.
   
   
7. Plavix & Aspirin -- Fusion or Fission?, March 13, 2006
   
   
8. Plavix deal is little relief for Bristol and Sanofi, July 10, 2006, Financial Times.com

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