The new study, as reported by Forbes.com, includes an examination of Trasylol use in 49 randomized clinical trials, and also includes new information from the Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART) study, published earlier this year. The findings of the new study, which was conducted by Canadian and Australian reserachers, will be published in the Jan. 20 issue of the Canadian Medical Association Journal.

Trasylol had been used extensively since 1987, and was only pulled from the U.S. market by manufacturer Bayer in November 2007. It seems incredible that a product that recent tests have proved significantly more dangerous than other similar drugs could have flown under the radar for 20 years.

The BART study revealed that patients treated with Trasylol were 53 percent more likely to die than patients treated with similar drugs. The study compared Trasylol (aprotinin) with two other drugs, Cyklokapron (tranexamic acid) and Amicar (aminocaproic acid).

The new Canadian-Australian study confirms the BART results, saying Trasylol carries a higher risk of death, and, to add insult to injury, a significantly higher price tag than its alternatives.

According to the Forbes report, some of the blame for Trasylol’s longevity in the marketplace is being placed on the U.S. Food and Drug Administration.

Bloomberg recently ran an article about pharmaceutical companies enjoying their “get out of jail free cards” — revisions to regulations that favor the rights of pharmaceutical companies over consumers who use their drugs. The revised regulations, written just after George W. Bush’s second inauguration in 2005, allow federal law to trump state law, thereby clearing the path for drug manufacturers to develop, test, market, and essentially do business with impunity from the law.

Think corporate Utopia. Think David vs. Goliath where Goliath enjoys a major handicap.

According to the U.S. Constitution, any decision to pre-empt state law must be authorized by Congress. However, several federal agencies have navigated around that obstacle (probably whining that it takes an act of Congress to trump state law) by inconspicuously writing language into the preamble of federal regulations and then using those preambles to change the law.

The issue, however, is not as clear cut as it would seem. Some trial courts have ruled the regulatory preambles to be permissible. The American Association for Justice on the other hand belies them to be unconstitutional. In any case, pre-emption effectively strips state government and courts – and the U.S. Congress – of its authority.

Not exactly the antithesis of “big government,” yet some politicians would whisk away any concerns as tort reform. To get a clearer picture of the dangers posed by corporate immunity, look at the individual cases – the examples of real people who are grappling with greatly diminished protection.

Look at Joe Randone and his family, who are suing Bayer. Randone was a 52-year-old heart patient when he was given Trasylol in an IV drip. Immediately after the surgery, Randone suffered from two heart attacks and kidney failure. His gall bladder had to be removed and he was so swollen he couldn’t close his eyes, which were eventually sewn shut to protect his corneas. Gangrene set in to his lower extremities and both of his legs had to be amputated. Randone held on like this for 8 months but ultimately passed away in his hospital bed. All of this happened while Bayer, the manufacturer of Trasylol, was aware of the drug’s dangers and took no measures to prove its safety one way or another, even after smaller tests indicated the drug was highly toxic.

Bayer is claiming immunity in the Randone  case because Trasylol was approved by the FDA. Also, language in the preamble to the FDA’s prescription drug labeling rule also may turn out to be an easy escape route for Bayer.

Who are the government and the FDA really protecting? Pharmaceutical companies and medical device manufacturers are businesses; they need to make profits and their pipeline must look promising to investors. Loosening regulations and excusing corporations from accountability, however, seems to be as shortsighted as it is callous.

As scores of people become injured or die from taking newer, barely tested medications, doesn’t it stand to reason that doctors and patients would want to stick with the tried and trusted generics? How long will it be before the regulations intended to help corporations cause them to implode?

Think corporate Utopia. Think David vs. Goliath where Goliath enjoys a major handicap.

According to the U.S. Constitution, any decision to pre-empt state law must be authorized by Congress. However, several federal agencies have navigated around that obstacle (probably whining that it takes an act of Congress to trump state law) by inconspicuously writing language into the preamble of federal regulations and then using those preambles to change the law.

The issue, however, is not as clear cut as it would seem. Some trial courts have ruled the regulatory preambles to be permissible. The American Association for Justice on the other hand belies them to be unconstitutional. In any case, pre-emption effectively strips state government and courts – and the U.S. Congress – of its authority.

Not exactly the antithesis of “big government,” yet some politicians would whisk away any concerns as tort reform. To get a clearer picture of the dangers posed by corporate immunity, look at the individual cases – the examples of real people who are grappling with greatly diminished protection.

Look at Joe Randone and his family, who are suing Bayer. Randone was a 52-year-old heart patient when he was given Trasylol in an IV drip. Immediately after the surgery, Randone suffered from two heart attacks and kidney failure. His gall bladder had to be removed and he was so swollen he couldn’t close his eyes, which were eventually sewn shut to protect his corneas. Gangrene set in to his lower extremities and both of his legs had to be amputated. Randone held on like this for 8 months but ultimately passed away in his hospital bed. All of this happened while Bayer, the manufacturer of Trasylol, was aware of the drug’s dangers and took no measures to prove its safety one way or another, even after smaller tests indicated the drug was extremely dangerous.

Bayer is claiming immunity in this case because Trasylol was approved by the Food and Drug Administration. However, language in the preamble to the FDA’s prescription drug labeling rule may provide the easiest escape route for Bayer.

Who are the government and the FDA protecting? If pharmaceutical companies and medical device manufacturers receive complete immunity from the law, then they can knowingly market and sell dangerous drugs that leave scores of people injured or dead.

It is through the courts, and litigation, that the voice of the consumer is heard, and his rights protected. A recent editorial by the editors of the New England Journal of Medicine supports this idea.

The two aspirin products, Bayer Women’s Low Dose Aspirin + Calcium and Bayer Aspirin with Heart Advantage, are misbranded, mislabelled, and confusing to consumers, according to the FDA.

According to Bayer, its Women’s Low Dose Aspirin fights heart disease and osteoporosis with a combination of 81 mg of aspirin and the equivalent of an 8-oz glass of milk in calcium for possible “lifesaving benefits.”

Bayer Heart Advantage combines the same low dose of aspirin with plant phytosterols, molecular entities found in fruits and vegetables that are valuable for their cholesterol lowering properties.

While Bayer’s web site instructs users to talk to their doctors before beginning any aspirin regimen, the message isn’t so clear on the medicine’s packaging. Both Bayer medicines are packaged to appeal directly to consumers, who might be lead to think that they can treat their heart conditions, cholesterol, and osteoporosis with these OTC medicines.

The FDA requires that medicines designed to treat heart disease and osteoporosis be reviewed by its researchers. Federal law also forbids such medications to be sold OTC.

Labeling on Bayer’s Heart Advantage claims that the drug lowers cholesterol. Labeling for Bayer Women’s says that it fights osteoporosis. Improper use of medicines containing aspirin often causes serious side effects such as gastrointestinal bleeding. Aspirin resistance can also have devastating effects on the heart.

Bayer believes that neither products violate FDA regulations, but promises to review the case and report back to the FDA within 15 business days. The FDA indicated in its letter to Bayer that the company would face legal action.

Bayer is already under fire by the FDA and general public for its marketing of Trasylol when ample studies found the drug to be highly toxic to many people.

Both complaints were filed in the St. Clair County Circuit Court.

Gary Harms received a Trasylol injection in 2005 while he was undergoing heart surgery at Des Peres Hospital in St. Louis, Missouri. He has since suffered from acute renal failure and requires regular dialysis to perform the functions of his failed kidneys.

Researchers first discovered a link between Trasylol and kidney failure in the early 1980s when lab animals that received the drug developed severe kidney failure. Subsequent tests confirmed Trasylol’s danger to humans, yet Bayer consistently denied the existence of a link between their drug and acute renal failure and death. The company also failed to fund and perform adequate clinical tests that would have conclusively demonstrated the drug’s risks.

Harms’ suit claims that he has suffered from emotional distress and anxiety, physical personal injury, medical expense, loss of consortium, services, love and affection, permanent loss of an important bodily function, permanent impairment of the ability to enjoy life and financial expenses. He seeks $550,000 in addition to attorney’s fees and other costs.

Richard Kopsie also received Trasylol during his coronary artery bypass graft surgery at Christian Hospital in St. Louis, Missouri in 1996. He experienced kidney failure shortly after surgery and required dialysis for years. Kopsie passed away in March 2003 at the age of 53, but his final years were marked by pain and suffering from Trasylol-induced injuries, medical costs, disability, and a diminished ability to enjoy life, according to the complaint filed by his wife Linda.

Linda Kopsie seeks a $1.1 million on 22 counts plus attorney’s feels and other costs against Bayer.

Both suits claim that Bayer acted negligently for continuing to market Trasylol when the drug’s dangers were known, for failing to alert the FDA to dangers of the drug, and failing to attach appropriate warnings and safety information to the drug. For years, Bayer also avoided performing large scale tests that would have effectively underscored the drug’s dangers.

Journal editor Dr. Jeffrey M. Drazen says the litigation process and the court system is a “key defense mechanism” to insure drug safety and to obtain justice if drug manufacturers have not made the risks involved with its product clear.

The doctors say the FDA is incapable of being the sole guardian of drug safety and that without the information supplied by liability litigation, “the American public would be deprived of a vital deterrent against pharmaceutical company misconduct.”

The opinion was submitted to the Supreme Court as a friend-of-the-court brief in the matter of Wyeth v. Levine, a case expected to be heard later this year. According to the AP story, the case involves Diana Levine, a guitarist who lost her right arm below the elbow after an injection of Phenergan. She sued the drug’s manufacturer, Wyeth, alleging the company had not adequately warned consumers of the risks associated with its product. The case was tried in Vermont, and the court agreed, awarding Levine $7 million.

Wyeth is appealing the case, saying the FDA had approved the drug, and that the state court could not overrule the FDA’s judgment.

However, the editors of the New England Journal of Medicine sided with 47 state attorneys general and two former FDA commissioners in supporting Levine’s position, the AP report states.

The FDA cannot identify a patient population in which the use of Trasylol (aprotinin) outweighs the risk, Dr. John K. Jenkins, director of the FDA’s Office of New Drugs, said at an early morning news conference Monday.

However, he added, “The suspension will include a slow phase-out of Trasylol from the marketplace, to decrease the possibility of shortages of the alternative drugs.” And he added that Bayer could continue to supply the drug if physicians can identify specific patients who would benefit from it.

“Studies have found that Trasylol can increase the risk of kidney damage compared with other drugs,” Dr. Gerald Dal Pan, the FDA’s director of the Office of Surveillance and Epidemiology, said during the news conference.

In 2006, he added, the FDA limited the use of Trasylol and strengthened its warnings. Subsequently, he said, studies found that Trasylol increased the risk of in-hospital death among patients undergoing cardiac bypass surgery. In addition, Dal Pan said, two studies this year found that the drug increased the long-term mortality of patients who had undergone bypass surgery.

The suspension follows news last month that a major Canadian trial of the drug was terminated because of an increase in deaths for cardiac surgery patients using it.

The trial was designed to show that Trasylol was better than other drugs in controlling bleeding, Dal Pan said. “That study was halted because Trasylol appeared to increase the risk for death compared with two other drugs,” he said.

Based on these findings, the FDA requested last week that Bayer suspend Trasylol pending further review, Dal Pan added.

In a company statement on its Web site Monday, Bayer stressed that the suspension was temporary. “Bayer believes that the totality of the available data continue to support a favorable risk-benefit profile for Trasylol when used according to labeling,” the statement said.

The FDA also said Monday that it plans to do a detailed review of the preliminary results from the Canadian trial before deciding whether to allow Trasylol back on the U.S. market.

Trasylol was first approved by the FDA in 1993, and has had a checkered history since then.

In the Canadian trial, called BART, an elevated 30-day and overall death risk caused the study’s Data Safety Monitoring Board (DSMB) to recommend stopping patient enrollment. The trial had been set to recruit about 3,000 adults who were candidates for a variety of cardiac surgeries and were at high risk of bleeding.

On Sept. 12, a U.S. Food and Drug Administration advisory panel recommended that Trasylol remain on the market, despite mounting evidence that it might have serious side effects.

In February, a study published in the Journal of the American Medical Association found patients on the drug were at greater risk of dying over the next five years than those given two other medications. The same researchers had linked the drug to an increased risk of kidney failure, heart failure and stroke in a study published in 2006.

“Our present findings deal with death,” one of the JAMA study’s authors, Dr. Dennis T. Mangano, said at the time. Mangano, director of the Ischemia Research and Education Foundation, a California-based nonprofit group, said that “the death rate for aprotinin patients far outstrips that for the other two drugs.”

His team’s study tracked the long-term survival of nearly 3,900 heart patients who underwent coronary artery bypass surgery at 62 medical centers worldwide. The researchers tabulated survival at six weeks, six months, and then annually for five years.

The five-year death rate for patients given Trasylol was 20.8 percent, compared to 15.8 percent for those given another drug, aminocaproic acid, and 14.7 percent for those given tranexamic acid. Both alternative drugs are available in generic versions.

After the 2006 report from Mangano’s group, the FDA advised doctors to carefully monitor Trasylol patients for kidney, heart and brain damage — an action taken after Bayer disclosed study data showing that it increased the risk of death, kidney damage, congestive heart failure and stroke.

The drug does have its defenders.

Dr. T. Bruce Ferguson Jr., associate director of cardiothoracic and vascular surgery at East Carolina University, wrote an accompanying editorial to the JAMA study. He said he believed the study “was inadequate to address the question they were asking because of the way the database was designed.”

“The most important factor they were unable to control was why patients got aprotinin,” Ferguson said. “There were no data to address that issue, and therefore it cannot account for physician-related bias.”

For example, the higher rate of death and other complications linked to the drug might be due to aprotinin being prescribed for “higher-risk patients who could be expected to have a worse outcome and higher mortality,” Ferguson said. Other studies have shown that “in carefully selected patients, aprotinin is a good drug,” he said.

The information used in the study was thorough and complete, Mangano countered. “In terms of the database, we had between 7,000 and 10,000 pieces of data per patient from 59 centers in 16 countries, including 23 of the 25 top cardiac centers in the United States,” he said.

“The findings speak for themselves,” Mangano added. “I think they are as accurate as you can get.”

He believes that the drug’s use should be restricted to about 5 percent of patients in whom other drugs could not be used.

Known as BART, the study randomly administered one of three drugs to the patients: Trasylol, Cyklokapron (tranexamic acid) and Amicar (aminocaproic acid).

BART sought to answer questions about Trasylol’s safety and efficacy, despite the fact that the drug has been in use for over twenty years. Was Trasylol more effective than alternative drugs in controlling bleeding during cardiac surgery? And, how did rates of death, organ failure, and other serious complications measure in Trasylol compared to the alternative drugs?

Experts conducting the study found that Trasylol’s safety risks were so high, they ended the trial before its scheduled completion. Death rates among Trasylol patients were alarmingly higher than in patients who were given the alternative therapies. Dr. Paul C. Herbert, a critical care physician at Ottawa Hospital and one of the lead investigators, told BusinessWeek magazine that Trasylol represented a 53% increase in risk in dying compared to the other drugs. That “translates into for every 50 patients treated with aprotinin, one patient would die,” he explained.

Strangely, earlier Trasylol tests were small and not designed to study death. Information about the drug’s toxicity in some patients, therefore, remained hidden.

Dr. Eric J. Topol, director of the Scripps Translational Science Institute and dean of the Scripps School of Medicine, reacted to the results of BART with the same frustration as many North American consumers. In remarks made to BusinessWeek magazine, he wondered “why it takes so long for the truth to come out.”

“How many patients were lost because of this misadventure in therapeutics?” he asked.

Beginning immediately, Trasylol will belong to a class of drugs that require a special protocol for use. Patients who are at a high risk for blood loss during coronary artery bypass graft surgery may receive Trasylol if no alternative therapies are appropriate. In such cases, physicians must follow a special treatment protocol and submit it to the FDA for approval. The physician must show that the benefits of administering Trasylol outweigh the risks.

Trasylol is an antifibrinolytic drug that reduces excessive bleeding by slowing the breakdown of blood clots during heart surgery. In October 2007, the Data Safety Monitoring Board (DSMB) recommended the discontinuation of patient enrollment in a randomized Canadian study of aprotinin. The study was stopped once data suggested an increased risk of death in patients who had received Trasylol.

The FDA will reassess its special treatment protocol for Trasylol once it receives and has reviewed data from the study’s researchers. According to the FDA’s statement, “the FDA oversight requires comprehensive and thorough studies of a drug not only during the pre-market review phase but throughout the drug’s life cycle.” Many critics of the FDA object to the administration’s method of drug approval, which, they argue tests effectiveness of new medicines but not safety.

Trasylol, Bayer’s injectable aprotinin for heart patients, is largely responsible for the gloom that many analysts forecast for Bayer. Approved by the FDA in 1993 for use in controlling blood loss during heart bypass surgery, Trasylol was administered to nearly 5 million patients around the world. However, two extensive studies published last week in the New England Journal of Medicine revealed the risk of death to be dangerously high in patients who had received Trasylol injections. The drug was found to double the risk of liver damage, kidney failure, cardiac arrest, and heart failure. Moreover, it quadrupled the risk of stroke.

Bayer agreed to suspend marketing of Trasylol in November of last year following preliminary results of a Canadian test that indicated the drug’s link to increased risk of death. The FDA is reviewing the test results, but it’s likely that Trasylol is soon to be a thing of the past.

Trasylol controversies are just one of Bayer’s problems right now. Its performance in other markets evokes the image of an Olympic athlete jumping hurdles with a broken leg. A trial for one of Bayer’s next-best things, a drug called Nexavar, revealed that it was ineffective in the treatment of lung cancer. Also pharmaceutical companies Novartis and Novo Nordisk took Bayer to court over the hemophilia drug Kogenate, claiming that the drug infringes on their patents. Kogenate represents well over $1 billion in annual sales for Bayer.

All of these setbacks, it should be noted, are contained within the drug arm of Bayer – a large and diversified company on the brink of celebrating its 150th birthday. In addition to prescription pharmaceuticals, Bayer’s conglomerate includes over-the-counter health care, chemical research and development, and crop protection. The old giant may seem a little too unfocused and clunky to truly compete in the pharmaceutical arena, but its diverse ventures help to safeguard it from the risky and unsteady world of big pharma.