Yourlawyer.com (Natrecor News)

Feds Join Lawsuit Alleging Natrecor was Illegally Marketed

Fri, 20 Feb 2009 00:00:00 -0800

The United States Justice Department (DOJ) just announced that it is joining in two whistleblower lawsuits against drug maker Scios Inc. and Johnson & Johnson Inc. (J&J); J&J is Scios’ parent company. The lawsuits allege the drug makers marketed cardiac drug Natrecor for a use not approved by the U.S. Food and Drug Administration (FDA), said the DOJ. Both suits were filed in the Northern District of California.

The San Francisco Gate reported that the lawsuits allege that J&J defrauded Medicare and other federal health programs and that the drug makers collected hundreds of millions of dollars in reimbursements for unapproved uses of Natrecor.

The DOJ explained that the False Claims Act allows for whistleblower—qui tam—in the Northern District of California and allows for private persons to file such suits to provide the government information about wrongdoing. If it is found that a person has submitted or caused others to submit false or fraudulent claims to the U.S.—such as federal health care programs and Medicare—the government can recover treble damages and $5,500 to $11,000 for every false or fraudulent claim filed. Whistle-blowers can receive 15-to-25 percent of damages awarded, said the SF Gate. The marketing, according to the lawsuits, caused false and fraudulent claims to be submitted to the federal health care programs.

Physicians are permitted to prescribe medications off-label; however, off-label marketing is illegal. The DOJ explained that under the Food, Drug and Cosmetic Act, a company must specify the intended uses of a product in its new drug application to the FDA. Before approval, the FDA must determine a drug’s safety and efficacy and, once approved, the drug company may not market or promote the drug off-label. FiercePharma reported that the DOJ intends to fight for reimbursement of money Medicare spent on unapproved uses and noted that if state attorneys general choose to join in the suits, they might also seek Medicaid renumeration.

In August 2001, the FDA approved Natrecor for "the intravenous treatment of patients with acutely decompensated congestive heart failure [CHF] who have dyspnea [shortness of breath] at rest or with minimal activity," said the DOJ, which explained that the study upon which approval was based involved hospitalized patients with severe CHF and who received Natrecor infusions over an average 36-hour period. The government’s investigation revealed that just after the 2001 approval, Scios began an aggressive campaign to market Natrecor for scheduled, serial outpatient infusions for patients with less severe CHF, an off-label use not included in the FDA approval. Patients were prescribed Natrecor infusions for less than six hours on a scheduled basis over an extended time.

Medicare does not cover drugs used for off-label uses unless such off-label use is established to be medically necessary. Federal health care programs, Medicare in particular, paid what the DOJ described as substantial amounts for serial outpatient off-label Natrecor use.

In mid-2005, a panel of prominent cardiologists told Scios to stop promoting the scheduled, serial outpatient use of Natrecor; Scios sent letters to healthcare providers acknowledging that there was insufficient clinical evidence supporting the safety and efficacy of Natrecor for such treatment, said the DOJ. In 2007, Scios released the results of a clinical study confirming there were no significant benefits of the off-label treatment.

The two separate qui tam actions were filed by former Scios sales managers against Scios and J&J. And, while the qui tams contain additional allegations, the U.S. is only intervening with regard to allegations that Scios marketed Natrecor for serial infusions in the outpatient setting. The investigation was conducted by the Civil Division of the U.S. DOJ, the U.S. Attorney’s Office for the Northern District of California, the Federal Bureau of Investigation, and the Offices of Inspector General of the Department of Health and Human Services, the FDA, the Department of Veterans Affairs, the Office of Personnel Management, and the Department of Defense.

Natrecor a Drag on Johnson & Johnson since Reports of Kidney Failure, Deaths

Thu, 06 Dec 2007 00:00:00 -0800

Natrecor side effect reports have taken a toll on the finances of Johnson & Johnson. Natrecor was considered a potential hit in 2001 when the Food and Drug Administration (FDA) approved it for treating severe heart failure. So great was this potential, that in 2003, Johnson & Johnson paid $2.4 billion for Natrecor's developer, biologics company Scios. However, a lot has changed since then, and last night, Johnson & Johnson reported it would record a $440 million write-down to account for Natrecor's declining revenue. Although Natrecor sales reached about $400 million in 2004, the company said sales declined significantly since outside medical researchers raised questions in 2005 about the possible risk of kidney problems and death associated with Natrecor. In a regulatory filing with the Securities and Exchange Commission, Johnson & Johnson maintained that Natrecor was an important clinical option for heart failure treatment and is safe when used correctly.

When Natrecor was originally reported to increase kidney problems and death rates among patients, Johnson & Johnson announced it had agreed with the FDA to revise labeling for the drug to include the data underlying those reports.

Natrecor is FDA approved to intravenously treat severe cases of acute heart failure, which typically require hospitalization; however, it has been widely used "off-label" in outpatient clinics where patients arrive for regular infusions, although the drug has not been tested for that use. Some cardiologists have raised questions about whether the drug is safe enough to be used so frequently while others claim regular treatments help. While legal, regular treatments are not a federally approved use of the drug

Physicians' off-label prescribing of powerful drugs approved for specified limited conditions is posing serious life-safety risks. Given that physicians are so intimately under the influence of drug sales reps, perhaps it is time to reconsider the freedom U.S. physicians enjoy based on assumptions that their judgment is always in the best interest of the patient. Natrecor's use beyond emergency treatment to weekly maintenance is, in the view of some doctors, another example of the pharmaceutical industry's ongoing search for broader markets for drugs with FDA approval for specific and narrow usage. Speaking in terms of dollars, Natrecor has been used by over 600,000 patients in the U.S. since the FDA approved it in 2001. Infusions-without physician examination fees-run about $600 a session. Most of the cost is billed to Medicare, thus taxpayers are being bilked. Operating a Natrecor infusion clinic can be lucrative. About 80 percent of patients who receive the drug are 65 or over, and therefore eligible for Medicare-which fully covers Natrecor in many states because it is an infusion therapy.

Several states' insurers that provide Medicare coverage have refused to pay for the outpatient use. In May 2005, a group of cardiologists recommended the use of Natrecor be banned or severely limited recommending Natrecor be prescribed by cardiologists, or top intensive care doctors, and only in its recommended dosage on congestive heart failure patients admitted to the hospital whose medical condition had rapidly deteriorated.

Many doctors contend that much cheaper alternatives to Natrecor-such as nitroglycerin and Lasix and its generics-can work just as well as an emergency treatment for heart failure.

Off-label drug marketing: Missing the mark

Sun, 22 Oct 2006 00:00:00 -0700

The heart-failure drug Natrecor seemed sure to become a blockbuster after Scios of Fremont put it on the market in 2001.

Besides its use in hospitalized patients, many clinics began giving it to walk-in patients in weekly sessions dubbed ``tuneups.'' Some people including prominent heart specialist Dr. Eric Topol say Scios encouraged this with a hotline and brochure explaining how to bill Medicare for the sessions.

There was only one problem: Some medical experts contend Natrecor was never approved for such tuneups. Some also say it may not be as safe as initially thought.

Scios says studies show the drug is safe. And it has launched a campaign to clarify to doctors that the drug is not recommended for repeated use in patients in a clinic setting.

Nevertheless, the drug's sales have sagged and the company is under investigation by the U.S. attorney in San Francisco for allegedly engaging in ``off-label'' marketing, promoting drugs for uses not approved by the government.

Since this case came to light, critics in two major medical journals have cited Natrecor as an example of how easy it is for drug companies to peddle their medicines for unapproved purposes. Although doctors are allowed to prescribe drugs for off-label treatments, companies are forbidden from promoting their drugs for such uses.

``The system is faulty, and there are numerous leaks in the pipe,'' said Aaron Kesselhelm, one of three Harvard medical specialists who published an article this summer in the journal Health Affairs that criticized the use of Natrecor for tuneups.

But executives at Scios which Johnson & Johnson bought for $2.4 billion in 2003 maintain they and Natrecor have been unfairly tarnished.

Scios spokeswoman Chris Ernst wouldn't comment about the off-label claims, except to say the company is cooperating with the federal probe. But she stressed that ``patients are our first priority'' and noted that 15 studies of Natrecor in people turned up no cause to believe the drug is risky.

Nonetheless, Scios said in June it will do another massive study over the next couple of years to definitively assess Natrecor's safety.

The U.S. Food and Drug Administration approved Natrecor for treating patients with congestive heart failure who have trouble breathing even while doing minimal activity or resting. It has been given to hundreds of thousands of people and its sales hit $395 million in 2004. But since then, the drug has run into trouble.

After reanalyzing past studies of Natrecor, New York heart specialist Dr. Jonathan Sackner-Bernstein published two reports in 2005, warning the drug seemed linked to worrisome rates of kidney problems and death.

In disputing Sackner-Bernstein's conclusions, Scios has reported finding only a slightly increased death rate among those taking Natrecor after 30 days. Moreover, after tracking some Natrecor patients over six months, the company said it found virtually no difference in their death rate compared with patients on other medicine.

Although many patients are given drugs for off-label uses, the practice worries some critics. Doctors often prescribe medicines for purposes not approved by the government based on preliminary studies suggesting they might be effective for such uses. But one expert has said the evidence supporting off-label use is questionable.

A study published in May by Dr. Randall Stafford, an associate professor of medicine at Stanford University, found about 20 percent of the drugs in a national prescription database were given for off-label purposes. And in most of those cases, he determined, there was little or no evidence the drug was effective for those uses.

Companies, on the other hand, can face heavy fines for promoting drugs for off-label purposes. But the FDA's ability to halt abuses is limited, said Dr. Sidney Wolfe, who directs Public Citizen's Health Research Group.

``They do not have anywhere near the budget they should,'' Wolfe said. ``That is a major reason the drug industry is able to get away with what they do.''

FDA and Justice Department officials said they don't track how many companies have been prosecuted for off-label marketing. But Ioana Petrou, chief of major crimes for the U.S. attorney in San Francisco, said federal authorities have been paying increasing attention to such practice, given the grave danger it can pose to the public.

``In the vast majority of the cases prosecuted, there are misleading statements being made to the medical community by the pharmaceutical companies,'' she said. ``So the patients can't rely on their doctors to tell them what is safe and effective.''

Petrou said the first off-label case the Justice Department ever prosecuted involved Protropin, made by Genentech of South San Francisco. Although Protropin was approved for treating children with a growth hormone deficiency, the company was accused of promoting it for healthy short children. Genentech denied the charges, but paid $50 million to settle the case in 1999.

Now Genentech is under investigation for off-label marketing again, this time over Rituxan. In 1997, the FDA approved the drug for treating non-Hodgkin's lymphoma and in February this year also approved its use for rheumatoid arthritis.

It's unclear what the current investigation by the U.S. Attorney in Philadelphia involves. But a lawsuit by a former Genentech employee has accused the firm and its partner, Biogen Idec, of promoting Rituxan for rheumatoid arthritis before it was approved for that purpose.

Genentech spokeswoman Caroline Pecquet said the company is cooperating with prosecutors, who she said are expected to call current and former Genentech employees before a grand jury.

``We are committed to ethical and legal promotional practices,'' Pecquet added.

Yet another Bay Area company accused of off-label marketing is InterMune of Brisbane. In July, its executives announced they had created a $30 million reserve in hopes of settling a federal investigation into claims the firm improperly promoted Actimmune. The drug is approved for treating a bone disorder and a condition that makes people prone to infections. But InterMune also was accused of marketing it as a treatment for lung disease.

InterMune spokeswoman Pam Lord said the probe focuses on former employees.

The marketing of Natrecor has aroused particular concern because of questions about its safety, especially given the claims that people were receiving repeated injections of the drug in tuneups.

Using Natrecor occasionally to treat people in out-patient clinics wouldn't necessarily be considered an off-label use of the drug, said Dr. Norman Stockbridge, who directs an FDA division overseeing heart and kidney drugs. But he said giving such patients frequent doses of Natrecor would be an unapproved use.

Responding to the criticism, Scios convened a panel of medical experts last year to review Natrecor's safety. The group concluded more studies of the drug were warranted. But until then, it recommended that Natrecor should be given only to the seriously ill in hospitals and not in frequent doses to people in outpatient clinics.

Since the Natrecor controversy erupted last year, doctors familiar with the drug say its use has dropped dramatically. That troubles some doctors who swear by Natrecor, also known as nesiritide.

``I am absolutely enthusiastic,'' said Dr. John Luber Jr., a Tacoma, Wa. heart specialist involved in a Scios-sponsored study this year that found Natrecor lessened the likelihood of death among heart surgery patients.

But in the New England Journal of Medicine last year, Topol, former chair of the Cardiovascular Medicine Department at the Cleveland Clinic in Ohio, cited Natrecor as an example of a serious and widespread public health issue.

``We need a tuneup of our procedures to eliminate indiscriminate use of drugs, such as nesiritide, when there is not proper evidence of their safety,'' he warned.

Scios to Conduct Safety Study of Natrecor

Thu, 01 Jun 2006 00:00:00 -0700

Scios Inc. announced on Thursday that it would spend more than $100 million to conduct a safety and effectiveness study of its controversial heart failure drug, Natrecor.

The trial is designed to address safety issues swirling around the drug since last year when other studies suggested Natrecor can lead to increased risk of kidney problems and a higher risk of mortality within the first month of treatment than traditional medicines. Patient enrollment is slated to begin in the first quarter of next year and will involve 7,000 people in the United States, Canada and Europe, Scios said.

Scios, a division of Johnson & Johnson, still has to select the lead researchers for the study. The company doesn't know how long the trial will take to complete.

Natrecor, an intravenous drug approved in 2001, is designed to treat the breathing problems that often accompany heart failure. Some experts had expressed concern about the drug being used in an outpatient setting instead of only the hospital. J&J received a subpoena from the U.S. Attorney's Office in Boston last year requesting information about the marketing of Natrecor.

Last year, the U.S. Food and Drug Administration told Scios to add more information about the risk of death from Natrecor on the package insert for doctors.

Scios convened a panel of experts to provide recommendations about Natrecor in the wake of the negative publicity. The panel, organized last June, endorsed Scios' plan to conduct several trials of the drug.

Dr. Roger Mills, Scios' vice president for medical affairs, said it has taken a year to announce the study because the company wanted to insure it was appropriately designed and answered all the questions raised.

J&J doesn't break out Natrecor's sales but Scios spokesman Chris Ernst said its revenue has fallen since last spring when the safety concerns emerged.

Heart failure drug maker relays new deaths

Tue, 03 Jan 2006 00:00:00 -0800

The manufacturer of the heart failure drug Natrecor reported two additional deaths in patients involved in a study carried out three years ago but said it was confident the cases don't mean an increased risk.

The deaths had not been previously reported to Natrecor's manufacturer, Scios Inc., a Johnson & Johnson subsidiary, company spokesman Mark Wolfe said Tuesday.

The two cases bring to seven the number of patients who died within 30 days of treatment with Natrecor, also known as nesiritide. One patient treated with placebos, or dummy pills, died during that time.

Dr. Jonathan Sackner-Bernstein, a New York cardiologist and lead author of an April 2005 report published in the Journal of the American Medical Association that was critical of Natrecor, said the drug should be withdrawn.

"What it says to me is the information we published, if anything, understates the risks associated with the drug," Sackner-Bernstein said.

The cases are contained in an interim report being submitted to the Food and Drug Administration. The final version of the report, slated for completion by April 1, will measure how patients treated with Natrecor fared compared with those given placebos in the 30 days after treatment began.

The authors of a report on the original study, published in October 2005 in the Journal of Emergency Medicine, will submit an update that includes the two additional deaths, Scios said in a statement. The October report found no statistically significant difference in the outcomes of patients treated with Natrecor or a placebo.

Natrecor was approved in 2001 to treat serious breathing problems that often accompany heart failure.

Early last year, the FDA ordered that more information about the risk of death from Natrecor be added to the package insert for doctors, but the agency said it still believes the drug is a useful treatment.

The warning label on nesiritide already mentioned the potential for low blood pressure, kidney problems and more deaths than are seen with nitroglycerin.

Natrecor sales had declined significantly, Johnson & Johnson said in October, blaming media reports that the drug was being used too much on outpatients.

The intravenous drug has been given to more than 600,000 patients nationwide.

A Growing Clamor over J&J's Natrecor

Thu, 06 Oct 2005 00:00:00 -0700

The furor over Johnson & Johnson (NYSE: JNJ - news) 's (JNJ) controversial heart failure drug Natrecor shows no signs of abating.

In a letter in the Oct. 6 issue of the New England Journal of Medicine, two physicians who had authored papers raising questions about the drug's safety are now calling for the Food & Drug Administration to withdraw Natrecor. "There is a new acting commissioner [Andrew C. von Eschenbach] at the FDA," says Dr. Jonathan Sackner-Bernstein, one of the authors. "This is a terrific litmus test to see whether he is really concerned about the safety of drugs that are on the market."

Dr. Robert J. Temple, associate director of medical policy at the FDA says the papers that have raised safety questions about Natrecor don't take into account all the trials conducted on it. And he says there hasn't been any new information on Natrecor since its approval in 2001 that would cause the FDA to revisit its decision to approve the drug.

In a statement, Scios, the J&J unit that markets Natrecor, said the drug is one of the few options doctors have for treating patients who are suffering episodes of severe breathing difficulty associated with heart failure. "The call for the withdrawal of Natrecor is based on a hypothesis rather than hard scientific facts," Scios said.

"LEADERSHIP STRIFE." Still, the clamor for the drug's withdrawal is likely to bring more unwanted attention to the controversy surrounding Natrecor. Earlier this year Sackner-Bernstein co-authored a paper that showed it might be linked to kidney problems. That was followed by a second paper that raised questions about whether Natrecor is associated with a higher death rate than standard treatments.

The drug is drawing other vocal critics as well. Among them: Dr. Eric J. Topol, chief of cardiovascular medicine at the Cleveland Clinic Foundation. Topol, who was an early critic of Merck's (MRK) now-withdrawn painkiller Vioxx, also believes Natrecor should be pulled. But he says, "With all the leadership strife at FDA and the unwillingness of those people who were involved to admit the potential of being too lenient [in approving the drug], I'm not optimistic."

The FDA's Temple rejects any suggestion that the agency would resist pulling the drug simply to avoid looking bad. "The way you look most stupid is by failing to recognize a problem when it should be recognized," Temple insists.

UNAPPROVED USE. Certainly J&J has been in damage-control mode for months. In April it convened a panel of outside experts led by noted Harvard Medical School professor Dr. Eugene Braunwald to review Natrecor's safety and give guidance on what sort of additional clinical trials needed to be done. In June the panel made a series of recommendations, including urging Scios to move ahead on a planned large trial aimed at answering questions about the drug's impact on death rates. A Scios spokesman says the company is in the process of designing and seeking FDA guidance on such a study.

The panel also urged Scios to limit the ways in which Natrecor was being used. It was originally studied in hospitalized heart-failure patients who were suffering from labored breathing. But in recent years some physicians have given Natrecor on a regular basis to heart-failure patients who weren't suffering from serious breathing problems in the hope it would prevent them from landing in the hospital. Most of the data on that sort of use are anecdotal, and that use wasn't approved by the FDA.

Scios says it hasn't promoted that sort of use, but its marketing practices are under scrutiny. In July, Scios received a subpoena from the U.S. Attorney's office in Boston asking for documents related to Natrecor's sales and marketing. Scios says it's cooperating with the request.

Still, the J&J panel clearly wants Scios to steer doctors away from prescribing Natrecor for those regularly scheduled treatments. In August, it rolled out a program to retrain its sales force, and it began running ads in medical journals aimed at ensuring the drug is being used appropriately. But as more voices call for Natrecor's withdrawal, it looks like these efforts won't be enough to keep calm the critics.

How Johnson & Johnsons Strategy to Turn Natrecor into a Blockbuster Failed

Thu, 25 Aug 2005 00:00:00 -0700

In the world of pharmaceuticals, a “blockbuster” is the term reserved for a prescription drug which has annual sales in the billion-dollar plus range (with the emphasis on “plus”).

While annual sales in the $500 million range are nothing to sneeze at, the many drugs that attain that level are looked upon as revenue producers. The blockbusters are looked upon as king-makers.

Thus, when drug has the potential to attain the elusive “10-figure” status, some very questionable marketing strategies take place. These include:

•    Failing to disclose or report negative test or clinical trial results;
•    Failing to report adverse reactions;
•    Failing to finalize post-approval testing or reporting;
•    Spending more on advertising a drug than on developing and testing it;
•    Withholding negative information from doctors or using questionable incentives to encourage the writing of prescriptions for a specific drug;
•    Indirectly engineering a campaign to stimulate (while not actually promoting) one or more “off-label” uses of a drug that may actually generate more income for that drug than the approved uses. (The “off-label” market will be described below.)

These revenue-driven strategies do not make a drug better or safer. In fact, every case is little more than marketing winning out over science, safety, and even ethical considerations. In the case of Natrecor nothing good can be said concerning the manner in which the drug was promoted and marketed.

Natrecor, or nesiritide, was approved by the FDA in 2001 to treat congestive heart failure or acute decompensating heart failure in which patients experience shortness of breath and the heart fails to adequately pump blood to other organs in the body. The drug works by mimicking a hormone-like molecule that dilates vessels to prevent blood from gathering in the heart and lungs thereby allowing the patient to breathe.

Natrecor is manufactured by Scios, a company which was bought by Johnson & Johnson in 2003. As many as 600,000 patients have been treated with the drug since its approval.

Natrecor was, and still is, supposed to be used for the sole purpose of treating hospitalized patients with the aforementioned heart conditions. Despite this express limitation on its approved use; Natrecor has become an increasingly popular option in outpatient clinics nationwide where it is used for far longer periods than it was originally approved for.

Some outpatient clinics even administer Natrecor twice weekly for up to 12 weeks. This type of use is considered to be extremely dangerous as no study has been conducted to confirm whether long-term use is either safe or effective.

This “off-label” use of Natrecor has lead to the discovery of severe side-effects and a subsequent push from medical experts and consumer advocates for the manufacturer to conduct further large-scale, longitudinal studies of the drug.

The off-label prescribing of drugs beyond the scope of their approval by the FDA has become a serious concern in recent years. Dosage levels, medical conditions, and treatment durations for which drugs were never intended or tested make the entire area of off-label use problematic at best. At its worst, the practice can be downright deadly.

It is for this reason that the FDA regularly discourages and even warns against such uses of drugs. This has been especially true in the case of powerful drugs like antipsychotics, heart medications, and antidepressants.

The incredibly strange thing about off-label use, however, is that doctors may prescribe drugs to treat conditions for which the FDA has even denied approval. Thus, while a manufacturer cannot market a drug for an unapproved off-label use, a doctor may prescribe the drug for that use.

Thus, if a pharmaceutical company is able to subtly (or, even not so subtly) stimulate off-label use of one of its drugs, the return in unanticipated profits can be quite significant. In fact, a clever marketing scheme can turn a restricted approval drug with limited sales potential into a billion-dollar blockbuster.

Many times, off-label use of a drug is stimulated by doctors themselves who are acting more like marketing agents than as responsible health professionals.

Dr. Jonathan Sackner-Bernstein, a cardiologist at North Shore University Hospital in New York and an avid opponent of the overuse of Natrecor, co-wrote several journal articles that provide data which links Natrecor to kidney problems and elevated death rates.

Sackner-Bernstein’s patients taking Natrecor were 80% more likely to die within the next 30 days than patients who had received other treatments such as diuretics or vasodilators.

The issues relating to kidney safety were known prior to and during the process of FDA approval of the drug and are specifically noted in the drug’s labeling. Yet the increased risk of mortality was not entirely known or appreciated until the drug became widely used in outpatient clinics for extended periods of time.

Although Scios argued that the Sackner-Bernstein paper included studies done at higher doses than are advised on the drug’s label, those higher doses are precisely what patients are being exposed to when they receive the treatment outside of hospitals.

Natrecor was never approved to be used as frequently as it is being used in outpatient clinics. Sackner-Bernstien and other experts, including fellow cardiologist Keith Aaronson, have attempted to show that Natrecor should not be administered in outpatient settings and that the drug’s label should indicate the serious problems associated with unrestricted off-label usage.

In the July 14 edition of the New England Journal of Medicine, Dr. Eric Topol of the Cleveland Clinic was highly critical of the way in which Scios was marketing Natrecor and he even went so far as to state that the drug should be off the market because the FDA was never given sufficient data upon which to have based its approval.

Natrecor has been aggressively marketed with sales of the drug now reaching almost $700 million this year. This is because Natrecor is an expensive option, costing nearly 50 times more than standard therapy options.

Natrecor is billed to insurance companies at up to $700 per session. When used in hospitals for emergency situations, as intended, the cost, while high, is controllable. However, when patients are receiving this treatment dozens of times in outpatient clinics, the cost quickly spirals out of control.

In addition to other questionable marketing strategies, Scios provided doctors with promotional materials advising them on how to bill Medicare for Natrecor uses that are clearly not approved by the FDA.

The Scios reimbursement guide, also available through a toll-free number, told doctors to use Medicare codes that treat Natrecor like chemotherapy allowing them to bill for lager Medicare reimbursements.

As a result, Medicare managers became concerned that reimbursements for Natrecor treatments in outpatient clinics would skyrocket as a result of the information that Scios has been giving to medical professionals.

In May 2005, Johnson & Johnson announced that in compliance with the FDA, it would revise the labeling for Natrecor to include data indicating an increased risk of mortality within 30 days for Natrecor patients compared with patients taking a placebo or other treatments.

This was a good start but doctors and other medical professionals were still advocating further studies of Natrecor to determine the health risks associated with the drug. Milton Packer, a cardiologist at the University of Texas, Southwestern, is concerned that Scios, like Vioxx maker Merck, has not done adequate studies to make sure that its drug is safe. Although the FDA approved the drug in 2001, many doctors argue that today the vote might be closer and Natrecor would probably wind up with a tougher label.

Then, in May of this year, an independent expert panel, convened by Johnson & Johnson itself, recommended that Natrecor be restricted to severely ill hospitalized patients. Most experts also agreed that a large-scale clinical trial is needed in order to determine the risks of Natrecor.

Although a spokesperson for Scios argued that the company could not control how doctors prescribe the drug, Scios itself greatly contributed (or even created) the problem by affirmatively providing doctors with information on how to maximize their billing of Natrecor for off-label uses.

Many experts consider it ethically irresponsible for a pharmaceutical company to promote an off-label (and potentially harmful) use of a medication for no other apparent reason than financial gain.

Such questionable conduct could have caused significant problems for Scios and Johnson & Johnson if the drug does prove to be as dangerous as it appears to be and it continued to be prescribed in outpatient settings as opposed to hospital situations where it is a life-or-death situation.

In June, the panel of cardiologists convened by Johnson & Johnson and headed by the highly respected heart researcher, Harvard’s Dr. Eugene Braunwald, recommended strict limitations on Natrecor, including not using it for scheduled “tune-ups” or even administering it outside the hospital.

The panel specifically recommended that Natrecor only be used in cases of an acute type of heart failure when the patient actually shows up at the hospital; that it should not be used in place of diuretics, the first-line treatment for heart failure; and never used for outpatients, scheduled appointments, or to improve kidney function.

Furthermore, the panel believed that: “Scios should immediately undertake a proactive educational program to inform physicians regarding the conditions and circumstances in which [Natrecor] should and should not be used.”

A member of the panel, Barry Massie (professor of medicine at University of California in San Francisco) also expressed disapproval of the manner in which doctors flagrantly engage in the off-label prescribing of drugs. He believes it is important for doctors to take responsibility for their actions and only prescribe drugs for their approved uses. “It shouldn’t all be blamed on the pharmaceutical companies, no matter what they do to encourage unproven indications.”

On July 20, Johnson & Johnson acknowledged it had received a subpoena from the United States Attorney’s office in Boston requesting documents related to the sales and marketing of Natrecor.

As a result of this virtual tidal wave of disapproval concerning the questionable tactics associated with the marketing of Natrecor, Johnson & Johnson added a clear disclaimer to its hotline used by doctors seeking information on how to charge Medicare and insurance carriers for the drug. The disclaimer clearly seeks to discourage the heretofore rampant off-label use of Natrecor.

The disclaimer warns of the “lack of clinical data” regarding off-label use of the drug and that Scios “does not recommend Natrecor for this use.” Johnson & Johnson now plans to follow up on the panel’s suggestions.

Fortunately, in the case of Natrecor, the often ineffective checks and balances in the healthcare system finally worked to forever deprive Natrecor of the blockbuster status its manufacturers had so desperately attempted to achieve.

Scios Heart Drug Curbed

Sat, 06 Aug 2005 00:00:00 -0700

Fremont biotechnology firm Scios Inc. is taking the first of a series of steps to curb prescribing of its heart drug Natrecor for uses not approved by the Food and Drug Administration.

The company, a unit of Johnson & Johnson, had been accused of promoting those unapproved uses by a prominent Cleveland heart disease expert. Its Natrecor marketing records were subpoenaed in July by federal prosecutors in Boston. Scios denies promoting the off-label use.

Natrecor was approved by the FDA in 2001 for a type of acute congestive heart failure accompanied by shortness of breath. In the July 14 edition of the New England Journal of Medicine, Dr. Eric Topol of the Cleveland Clinic charged that Scios was aggressively marketing Natrecor for repeated administration in outpatient settings for a "tune-up.'' Topol said Scios was showing doctors how to bill Medicare for the off-label treatments. He said the regimen used nearly 10 times the amount of the drug administered to acute-care patients in hospitals and resulted in fees of as much as $700 per dose to the doctors.

Physicians can legally prescribe off-label, but FDA regulations forbid drug companies from promoting such uses.

A Scios telephone hot line for doctors now leads off with a recorded disclaimer advising that due to a "lack of clinical trial data,'' Natrecor is not recommended as a scheduled series of infusions in outpatient clinics or doctors' offices.

Company spokesman Mark Wolfe said the recorded message is just the first of a series of measures Scios will take at the recommendation of a panel of experts it had commissioned in April to evaluate safety concerns about Natrecor. The drug has been linked to kidney malfunctions, and some clinical trials have shown a higher death rate among patients receiving it compared with those given a placebo.

The expert panel on June 13 recommended that Natrecor be used only when patients come to the hospital suffering from acutely decompensated congestive heart failure and labored breathing when at rest. Doctors should consider whether other remedies could give the same relief from shortness of breath, the panel said, and should not administer Natrecor repeatedly in outpatient settings. The panel urged Scios to convey those guidelines to doctors through an educational campaign, and to conduct further clinical trials on the impact of Natrecor on kidney function and death rates.

Topol said Natrecor should be off the market because the FDA lacked sufficient data on its safety and efficacy when it granted approval.

Wolfe said the FDA's decision was well supported. "More information is available on Natrecor from gold-standard clinical trials than there is for any other therapy available for acutely decompensated congestive heart failure,'' he said.

Cardiologist: Stop Marketing of Heart Drug

Thu, 14 Jul 2005 00:00:00 -0700

The government should halt sales of the congestive heart failure drug Natrecor until a large study proves it significantly benefits fragile patients, a leading cardiologist said.

Aggressive marketing has put sales of the drug on track to double this year to $700 million, even though it costs 50 times more than standard therapy and increases patients' risk of death and kidney damage, Dr. Eric J. Topol wrote in a commentary published today in the New England Journal of Medicine.

Natrecor ''has not yet met the minimal criteria for safety and efficacy," wrote Topol, chair of the Cleveland Clinic's department of cardiovascular medicine.

Topol, who submitted the article at the request of the journal's editors, earlier raised concerns about such new-generation painkillers as Vioxx, which Merck & Co. stopped selling last fall due to safety concerns.

In today's article, Topol criticized Scios Inc., a subsidiary of Johnson & Johnson, for promotion that included advising doctors how to bill Medicare for Natrecor uses not approved by the Food and Drug Administration. He faulted the agency for setting a ''low threshold" for approval, not warning patients of increased risks and not pressuring Scios to conduct definitive safety trials.

The FDA approved the drug in 2001 for intravenous use in hospitalized patients whose condition is so grave they gasp for breath while at rest or during minimal activity. Approval was based on a trial of 489 patients that compared Natrecor, whose generic name is nesiritide, to placebo and intravenous nitroglycerin. It showed that within three hours the drug reduced breathing problems caused by fluid buildup in the lungs and improved a measure of cardiac function thought to be significant at the time.

But Topol's commentary said the same study also showed people receiving Natrecor had lengthier hospital stays and higher death rates 30 days after using the drug.

FDA's rapid approval process for Natrecor contrasts with the strategy of European drug regulators who are waiting for the results of a 1,900-patient trial before deciding whether to allow the drug's sale. A similar study also should be conducted in the United States to prove Natrecor reduces death rates or has other durable clinical value, Topol said.

''The question is why should it be given at all right now when we don't even know its safety," he said in an interview.

The FDA said a halt in sales is unlikely, and an agency official said delaying approval until Scios could prove the drug's impact on mortality would not have been reasonable.

''A short-term treatment with nesiritide is expected to improve the increased symptoms of decompensated heart failure," said Dr. Robert Temple, FDA's associate director of medical policy. ''A long-term effect on survival would be nice, but symptomatic improvement is of value by itself."

Temple said the FDA knew before approving the drug that some trials raised questions about Natrecor's impact on kidneys and mortality, but ''it did not appear to represent a real risk," he said. ''Had we thought it did, we would have asked for additional data."

The criticism from Topol comes as Medicare managers worry about ballooning reimbursements for Natrecor in outpatient clinics where people can receive dozens of treatments costing taxpayers at least $500 per session. Hospitalized patients typically receive the drug a few times as stopgap therapy to relieve their symptoms and to give doctors time to consider long-term treatments.

Scios's reimbursement guide suggests doctors use Medicare codes that treat the heart drug like chemotherapy. That permits them to bill for larger Medicare reimbursements. They can include a professional fee that amounts to an additional $172 for the first hour the drug is given to a patient, and they are allowed to bill $408 for eight hours of observation, Topol noted in the article.

He said that through its marketing Scios has placed Natrecor in a drug class of its own.

''Cardiologists have never made revenue by giving a drug to a patient," he said in an interview. ''This is a new, new thing."

Johnson & Johnson spokesman Mark Wolfe said the company ''absolutely takes issue" with the assertion that it promoted regular, scheduled outpatient use of Natrecor. He also said such use does not significantly benefit the company.

Halting Natrecor sales would hold it to a higher standard than other drugs, like nitroglycerin, that without clinical proof are used to treat the same gravely ill patients, Wolfe said.

Boston University's Dr. Wilson S. Colucci said he has used Natrecor in a clinical trial, as well as for select University Medical Center patients. He reviewed the drug's safety data in June as a member of a panel that met at the urging of Scios.

''I very much want to be sure that we get it right," said Colucci, chief of cardiovascular medicine. He said there has been ''excessive abuse" of Natrecor by some doctors, but fears there may be an overreaction to the problem.

''When used in the right patients, in the right way, it's an important" treatment option, Colucci said.

Dr. Clyde W. Yancy, a University of Texas Southwest Medical Center professor of medicine, called Topol ''a strong voice in cardiology," but he defended Natrecor's effectiveness.

Yancy is now leading a clinical trial involving 900 patients to test Natrecor's safety and efficacy as an outpatient treatment.

Medical journal articles critical of Natrecor published this spring slowed patient recruitment rates for the trial during May, Yancy said.

Nesiritide Not Verified

Thu, 14 Jul 2005 00:00:00 -0700

How can a drug that is associated with higher rates of both renal dysfunction and death than placebo and that costs 50 times as much as standard therapies and for which there are no meaningful data on relevant clinical end points be given to more than 600,000 patients and be promoted throughout the United States for serial outpatient use, an indication not listed on the label?1,2,3,4,5 The answer to this question can be discerned, at least in part, from a review of the clinical development and marketing of nesiritide: recombinant human brain natriuretic peptide.

On May, 17, 2005, the New York Times reported that tens of thousands of patients around the country are receiving nesiritide treatment once or more per week, over a period of several months, for what is described as an outpatient "tune-up." This application of nesiritide — which costs approximately $500 per dose, as compared with less than $10 for nitroglycerin or nitroprusside — is the subject of an aggressive marketing campaign by the manufacturer, Scios, which is encouraging physicians to start their own "infusion centers" for whose services they can bill Medicare as if they were providing chemotherapy. But when nesiritide was approved by the Food and Drug Administration (FDA) in 2001, it was designated for the treatment of acute, decompensated congestive heart failure. Moreover, it had apparent safety problems and no proven clinical advantage over existing treatments in terms of the key end points of improved survival and prevention of subsequent hospitalizations.

In a 2000 report, Colucci and colleagues concluded that "nesiritide would be a valuable addition to the initial treatment of patients admitted to the hospital for decompensated congestive heart failure."1 But their placebo-controlled, dose-ranging trial was focused on short-term monitoring of the pulmonary-capillary wedge pressure. Follow-up data on these subjects, which were not part of the study design as reported in that article, suggested that nesiritide may have had an adverse effect on 30-day mortality, which was 7.1 percent in the nesiritide group, as compared with 4.8 percent in the placebo group (P=0.62).2 Over this longer period of follow-up, the incidence of substantial deterioration of renal function was more than three times as high among patients treated with nesiritide as among those given placebo (P=0.04).3

The data from that trial were reviewed by an FDA advisory panel in January 1999. Despite the panel's recommendation that the drug be approved for the reduction of pulmonary-capillary wedge pressure, the FDA decided that more data were required. A larger trial, Vasodilatation in the Management of Acute Congestive Heart Failure (VMAC), was conducted in 498 hospitalized patients who had dyspnea at rest.4 Nesiritide was compared with intravenous nitroglycerin or placebo. Since there were statistically significant improvements in both the reduction of pulmonary-capillary wedge pressure (a difference of 4 mm Hg) and the self-reported dyspnea rating with nesiritide as compared with placebo, nesiritide was considered to have met the efficacy criteria. The study did not demonstrate any benefit of nesiritide over nitroglycerin in terms of death or the need for repeated hospitalization within 30 days. At a subsequent meeting, in May 2001, the majority of the advisory panel recommended granting approval for nesiritide, and in August 2001, the FDA formally approved this drug for commercial use.

The VMAC trial raised a number of concerns about nesiritide. Only 30 percent of the patients received furosemide or intravenous diuretics before enrollment, although use of these agents is a standard approach to acute decompensated heart failure. The dose of nitroglycerin was not titrated aggressively, and because of the monitoring of the pulmonary-capillary wedge pressure, the "double-blind" assessment was compromised. The length of stay in the hospital was greater among patients who received nesiritide than among those given nitroglycerin (10.0 vs. 8.1 days, P=0.008).5 An elevation of more than 0.5 mg per deciliter (44.2 µmol per liter) in the serum creatinine level occurred in 27 percent of the patients in the nesiritide group, as compared with 21 percent of the controls (P=0.11).3,4 There was no increase in urine output with nesiritide, and subsequent studies have shown that this drug does not have a natriuretic or diuretic effect in patients with decompensated heart failure. Furthermore, the rate of death at 30 days was 8.6 percent in the nesiritide group, as compared with 5.5 percent among the controls (relative risk, 1.56; 95 percent confidence interval, 0.75 to 3.24; P=0.20).2 Indeed, the FDA approval went forward despite an internal reviewer's critical point that VMAC did not rule out a 50 percent increase in the risk of death. A meta-analysis also suggests that the use of nesiritide is associated with an increased frequency of abnormal renal function.3

There have been two different analyses of the effects of nesiritide treatment on mortality, the most important end point in a randomized trial of an intervention for heart failure (see graphs). In one of them, Sackner-Bernstein et al. pooled data from the three trials involving patients whose baseline treatment regimen was not required to include inotropes and for which 30-day mortality data were available. According to this analysis, there was an 81 percent increase in the death rate with nesiritide as compared with placebo.2 In contrast, Scios analyzed seven trials that had 30-day mortality data, including trials involving open-label and outpatient use, but did not take into consideration the baseline treatment regimen. The company reported a 24 percent increase in mortality (P=0.33), and this figure was incorporated into a revised package insert in April 2005.

Mortality at 30 Days among Patients Treated with Nesiritide as Compared with Controls in Randomized Trials.

The relative risk of death with nesiritide as compared with placebo was 1.81 (95 percent confidence interval, 1.02 to 3.27; P=0.04) in the analysis by Sackner-Bernstein et al.3 (Panel A) and 1.26 (95 percent confidence interval, 0.80 to 2.00; P=0.33) in the analysis by Scios (Panel B).

Even in the face of such findings, however, the manufacturer has been actively promoting the use of nesiritide. It has set up a toll-free telephone hotline for "Natrecor Reimbursement Support" and has published a 46-page "Natrecor Reimbursement and Billing Guide." The guide provides physicians with specific Medicare code numbers to be used in billing for a professional fee for nesiritide infusion ($172 for the first hour, $39 for each additional hour, and $408 for eight hours of observation), as one would for chemotherapy. The company justifies this billing practice by noting that the codes for chemotherapy administration include "substances such as monoclonal antibody agents and other biologic response modifiers."

Notwithstanding the fact that only one small, open-label feasibility study has been conducted, outpatient nesiritide use has become widespread, fulfilling sales objectives for the manufacturer and bringing in revenue for physicians. The overall sales figure for nesiritide is projected to be $700 million for 2005, nearly double last year's tally; it represents payment for more than 1.4 million treatments. Given that nearly 10 times as much drug is used for serial administration in outpatients as for the one-time use in hospitalized patients, much of this growth clearly stems from the off-label "tune-up" application.

The nesiritide story reflects some recurring themes: in other recent cases, too, major safety problems have been uncovered after a drug has been approved. Nesiritide was approved on the basis of a single trial in which surrogate end points were assessed three hours after administration. In cardiovascular medicine, we learned long ago that therapies directed at surrogate end points such as the suppression of premature ventricular contractions or, for inotropic agents, an improved ejection fraction can be associated with excess deaths. With the low threshold set for regulatory approval, the FDA did not demand appropriate warnings on the label regarding an increased risk of death or worsened renal function and did not require the performance of trials that would have provided definitive verification of the safety and efficacy of nesiritide.

We practice medicine in an era in which there is one pharmaceutical-company representative for every five physicians and in which companies will stretch the limits in their marketing of drugs. The boundary lines that previously separated industry from the FDA and academia have unfortunately become blurred. Interestingly, the European Agency for the Evaluation of Medicinal Products, the counterpart of the FDA, has still not approved nesiritide and awaits the results of a trial involving 1900 patients before it will even consider doing so.5

In my view, nesiritide has not yet met the minimal criteria for safety and efficacy. Until a trial definitively proves that this drug reduces the risk of death or repeated hospitalization for heart failure, there will be questions about the appropriateness of the drug's use or even commercial availability. We need a tune-up of our procedures to eliminate indiscriminate use of drugs, such as nesiritide, when there is not proper evidence of their safety.

Source Information

Dr. Topol is provost of Cleveland Clinic Lerner College of Medicine of Case Western Reserve University and chair of the Department of Cardiovascular Medicine at the Cleveland Clinic, Cleveland.

An interview with Dr. Topol can be heard at www.nejm.org.

References

Colucci WS, Elkayam U, Horton DP, et al. Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure, N Engl J Med 2000;343:246-53.

Sackner-Bernstein JD, Kowalski M, Fox M, Aaronson K. Short-term risk of death after treatment with nesiritide for decompensated heart failure. JAMA 2005;293:1900-1905.

Sackner-Bernstein JD, Skopicki HA, Aaronson KD. Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation 2005;111:1487-1491.

Publication Committee for VMAC Investigators.
Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA 2002;287:1531-1540. [Erratum, JAMA 2002;288:577.]

Teerlink JR, Massie BM. Nesiritide and worsening of renal function: the emperor's new clothes? Circulation 2005;111:1459-1461.

Heart Drug's Usage Causes Concern Among Some Doctors

Tue, 12 Jul 2005 00:00:00 -0700

Shortly after the Food and Drug Administration in 2001 approved the heart failure drug Natrecor for hospitalized patients, two sales representatives from the manufacturer visited Dr. David L. Brown to promote the use of it elsewhere.

The Scios Inc. reps gave Brown tips on how to set up and publicize outpatient clinics and even provided marketing brochures. ''You can turn it into a profit center," Brown remembers them saying. After they left his office at the Weiler Hospital of the Albert Einstein College of Medicine in New York, Brown threw the material away because he had no interest in opening a clinic. But other doctors have seized the opportunity.

Natrecor is now flooding into outpatient clinics nationwide, being taken for longer periods than what was tested prior to FDA approval. Instead of a stopgap treatment for severe congestive heart failure given in a hospital setting, the use for which the drug was tested, some outpatient clinics intravenously administer Natrecor twice weekly for up to 12 weeks.

Critics say no study has been conducted to confirm whether protracted use is safe or effective.

While individual doctors can prescribe drugs in ways not explicitly approved by the FDA, manufacturers are prohibited from promoting such uses. Prosecutors aided by company whistle-blowers have collected multimillion-dollar settlements from other drug makers because of illegal promotion.

The Natrecor trend has alarmed state Medicare managers. Four years ago, total sales of the drug were just under $12 million, but reimbursements for outpatient use alone soared to $37.6 million in the first nine months of 2004, according to a report issued late last month by the Government Accountability Office. ''The major contributing factor" to the increase was regular use of Natrecor, especially in outpatient clinics, according to the Medicare managers.

The trend worries cardiologists, too, because even limited use of the drug is linked to higher mortality rates and kidney problems. And it has incensed critics of Scios, a division of Johnson & Johnson, who believe the company is aggressively encouraging clinics as a way to generate more money for Scios and doctors.

Dr. Steve Nissen, a Cleveland Clinic cardiologist, notes that Scios distributes a 48-page guide for doctors that includes Medicare reimbursement codes for outpatient use of Natrecor.

''My moral compass went off when I saw this," Nissen said. ''It felt like the company was promoting the use of a drug to profit physicians, rather than to benefit patients."

Another opponent of the overuse of Natrecor, Dr. Jonathan Sackner-Bernstein, regularly prescribed it until a spring 2002 journal article suggested that a slight increase in the amount given increased health risks.

''I read that paper and I said, 'This is not good,' " said Sackner-Bernstein, a cardiologist at North Shore University Hospital in New York.

After digging through data, he co-authored journal articles published this spring that link the drug to kidney problems and higher death rates. The analysis suggests the chance of dying 30 days after Natrecor use is sharply increased. That means that as many as 10,000 to 20,000 more heart patients taking the drug die each year than those on other medications, Sackner-Bernstein said.

''The fact that the Medicare stamp of approval is on this drug is laughable," he said.

Scios and Johnson & Johnson, which in 2003 acquired the Fremont, Calif., biotech company, said they have not encouraged unapproved use of Natrecor. Mark Wolfe, a Johnson & Johnson spokesman, said in a written statement that ''Scios does not promote Natrecor for regular, scheduled outpatient infusions."

But the drug's label does not specify where it should be dispensed. That vagueness has spawned a crop of outpatient clinics that charge about $500 per treatment and can treat patients dozens of times. Natrecor is expected to generate $600 million in sales this year and become a billion-dollar drug in 2006. It is unclear what percentage of that growth is attributable to outpatient clinics. Medicare figures are not up to date and do not include payments from private insurers.

Ray Lipicky, who was director of the FDA's division of cardio-renal drugs when Natrecor was approved, said the agency never intended it to be used in outpatient clinics. ''If we were smart enough," Lipicky said, the label would have read, ''Now, don't you dare use it in any way other than what we have described here."

A panel of prominent cardiologists and heart failure doctors who met at the urging of Scios in June advised the company to conduct a study that would track mortality rates and kidney function in people using Natrecor. The doctors also urged Scios to make it clear to doctors that the drug is for patients whose symptoms are so severe they have go to a hospital.

Darlene P. Horton, Scios senior vice president of clinical research and medical affairs, said a label revision is unlikely. ''That is certainly not the plan," she said.

About 5 million Americans suffer from heart failure. In its acute stage, heart failure is the number one reason for the hospitalization of patients older than 65.

In many instances, Medicare picks up the bill for outpatient treatments. Funding decisions are made at the state level.

For example, in the fourth quarter of last year, New Mexico's allowable outpatient claims for Natrecor totaled $114,307 with 15 treatments per patient. During that same time, Texas allowed $263,017 for patients averaging 20 treatments each in physicians' offices and $4.1 million in allowable claims for hospital outpatient Natrecor use. Those patients averaged 23.1 Natrecor treatments each, according to TrailBlazer Health Enterprises, a Medicare contractor.

Dr. Larry Altschul, who opened the nation's first Natrecor outpatient clinic eight years ago at South Bay Cardiovascular Associates in West Islip, N.Y., has a different opinion. He said he performs 40 to 100 Natrecor weekly treatments, and most of his patients are weaned off the drug after 12 weeks.

Altschul said Natrecor helps insurers save money and patients enjoy a better quality of life.

''We're all being painted as bad guys, but we're not," he said. ''This is a great thing that we're doing."

Panel Advise Limited Use of Heart Drug Natrecor

Wed, 15 Jun 2005 00:00:00 -0700

An independent panel of experts say heart-failure drug Natrecor should be restricted and only used with acutely ill hospitalized patients.

They want drug company Johnson & Johnson to conduct a comprehensive clinical trial, as research indicates that Natrecor may increase the risk of kidney problems and death.

Eugene Braunwald, head of the panel and a Harvard Medical School cardiologist, says the drug is important.

The panel said Natrecor should not be used routinely for heart-failure patients even though there are few similar drugs, until more research is done.

Johnson & Johnson has accepted the panel's recommendations, and are planning a clinical study.

The panel recommend that the drug should be reserved for hospitalized heart-failure patients who have trouble breathing at rest and not outpatients who have breathing problems after mild exertion.

Natrecor is the latest drug to raise safety concerns long after receiving Food & Drug Administration approval.

Merck & Co. and Pfizer Inc. were to forced to pull their respective painkillers, Vioxx and Bextra, off the market after safety concerns arose.

Tug-of-War Over Heart Drug

Mon, 23 May 2005 00:00:00 -0700

A year ago, Michael Chiarello was in a wheelchair, dependent and depressed, helpless as his life was being slowly stolen by heart failure.

The 74-year-old Riverhead man was told that only 25 percent of his heart function remained. Without options and within a whisper of death, Chiarello had run technology's gamut. Then last summer, doctors suggested a new approach: a drug to be infused four hours a day, three days a week. He took the chance.

"I'm 100 percent better," Chiarello said. "I can do anything I want to do; I even feel like I can go and hang wallpaper again," his career of 30 years.

But Natrecor, the drug that transformed Chiarello's life, is at the center of a growing storm, the result of research that uncovered life-threatening dangers linked to its use. Approved as a therapy for hospitalized patients or those rushed to emergency rooms in acute heart failure, the drug increasingly is being administered to outpatients, treatments that critics say may be dangerous and driven by the drug's high-flying price tag. Clinics charge about $500 per infusion, often several times per week.

Natrecor mimics a hormone-like molecule that dilates vessels to prevent blood from pooling in the heart and lungs, easing breathing. More than 600,000 patients have taken the drug since its approval.

'A last resort'

Yet some doctors say the medication should be used with caution. Not only does it cause problems in hospitalized patients, they contend, it may prove even more problematic over the long haul in vast numbers of people receiving it frequently. The drug wasn't approved, they say, to be administered to outpatients multiple times per week.

"We're not saying that it should be pulled from the market," said Dr. Jonathan Sackner-Bernstein, director of clinical research at North Shore University Hospital in Manhasset and chief investigator of two studies that found problems. "We're saying it should be a drug that is used as a last resort."

In one analysis, Sackner-Bernstein found Natrecor increased the likelihood of kidney failure by up to 50 percent. In the other he discovered an elevated risk of dying within 30 days of leaving the hospital for some patients who were administered the drug. Although he could not explain the biochemistry of how the drug might increase mortality, he said the findings should alarm the manufacturer and government regulators. He's calling for a large, randomized placebo-controlled clinical trial to assess the drug's safety.

Natrecor's maker, Scios Inc., a division of Johnson & Johnson, and the Food and Drug Administration say the medication is safe and effective when used according to its label. As for Natrecor's use in outpatient clinics, Johnson & Johnson spokesman Mark Wolfe said even though the drug was not originally tested in outpatients to be administered intermittently, the product label does not say that it should not be.

Moreover, he added, the company can't control how doctors prescribe the drug. And the FDA underscores that doctors are free to prescribe any approved medication "off-label."

"We promote the product based on its FDA-approved indication," Wolfe said. "Decisions regarding how it's used are made by practicing physicians based on their professional medical judgment." Medicare and insurers cover the drug.

Sackner-Bernstein's analysis of kidney problems was reported in March in the journal Circulation. The finding was produced by pooling all available scientific data on the drug.

His second and more startling analysis last month in the Journal of the American Medical Association revealed the 30-day mortality risk. Sackner-Bernstein and colleagues found patients were 80 percent more likely to die in the month after treatment than patients who got standard therapy. The FDA approved Natrecor, also known as nesiritide, in 2001.

Dr. Steven Nissen, vice chairman of cardiology at the Cleveland Clinic, was the lone dissenter on the FDA panel that approved Natrecor. He said he wasn't convinced it was safe.

More patient warnings

An FDA official told Newsday the agency had been aware of Natrecor's potential to increase kidney dysfunction and raise the risk of mortality years ago when Natrecor was first reviewed. Warnings were added to its package insert then. Last month additional death-risk information was added. Earlier this month, Scios sent a "Dear Doctor" letter to health heart specialists nationwide, underlining mortality risks associated with the drug. The FDA did not call for a black-box warning, however, its most potent caution.

"This drug has been a lightning rod for controversy ever since it was introduced," said Dr. Robert Hobbs, a cardiologist and researcher at the Cleveland Clinic and a strong proponent of the drug. He added that Sackner-Bernstein's research was based on older data involving higher Natrecor doses that are no longer used.

"There are physicians who love it and those who hate it," he said. "Most of the people who love it are treating heart-failure patients in the hospital or in the emergency department, and the reason we love it is because it makes people feel better faster."

Hobbs said Natrecor, a genetically engineered drug, is more effective than infused nitroglycerin, a standard medication used for decades.

Another proponent of Natrecor is Dr. Clyde Yancy, director of the heart-failure program at the University of Texas Southwestern Medical Center in Dallas. Yancy and a team of doctors are examining Natrecor in a Scios-sponsored study of nearly 1,000 outpatients to answer questions about frequent use.

Yancy said he has no financial ties to the manufacturer and is interested only in answering medical and scientific questions. He added that the population originally defined for Natrecor might be too narrow. Acute heart failure, also known as decompensated heart failure, the form of the disease for which the drug was approved, may be evident even when patients are not in crisis. The problem is typified by acute shortness of breath.

"There are many patients who remain symptomatic despite being on all the right medications," Yancy said. "In my judgment they may not have acute decompensated heart failure, but chronic decompensated heart failure," he said.

While some heart-failure patients benefit from nitroglycerin, diuretics, pacemakers and other implantable devices, transplantation remains another option. Heart transplants, however, are usually out of the question for people older than 60 because these patients are considered too old and often too sick. Yancy believes Natrecor offers a life-sustaining option.

William Morrisey, 72, of Brooklyn, said Natrecor has renewed his strength. He has a history of heart disease and underwent quintuple bypass surgery more than a decade ago. "Before this [drug] I couldn't make more than two steps at a time," the retired machine-parts salesman said about ascending the stairs to his home. "Now I can go up the whole flight of 15 steps. I wouldn't call it a miracle drug, it doesn't cure anything it just helps."

Doctors opposed to outpatient Natrecor infusions say no one has established how often the drug should be administered or when patients should be weaned. Chiarello, a patient in Stony Brook University Hospital's heart-failure program, has been weaned from three weekly infusions to one. He hopes to soon be free of the drug.

Millions affected

Heart failure is a growing public health issue, said Dr. Norbert Moskovits of Maimonides Medical Center in Brooklyn. He calls heart failure the No.1 cardiac affliction among people 65 and older. In the disease, an enlarged heart no longer pumps efficiently. An estimated 5 million people are affected nationwide.

Dr. Robert Phillips, chairman of medicine at Lenox Hill Hospital in Manhattan, said Sackner-Bernstein's analyses suggest the need for more research on Natrecor's safety.

"At this point in time the ethical position that any physician or researcher should take is that the drug should be tested in a randomized placebo-controlled clinical study," Phillips said. "Even though this study [Sackner-Bernstein's] raises concerns, if the drug is useful, we need to know this and how to use it most effectively."

Nesiritide May Be Associated With Increased Risk of Mortality

Mon, 23 May 2005 00:00:00 -0700

The U.S. Food and Drug Administration (FDA) and Scios, Inc., have alerted healthcare professionals via letter of several published reports that suggest nesiritide (Natrecor) may have adverse effects on survival and kidney function compared with control agents such as nitroglycerin and diuretics, according to an alert sent from MedWatch, the FDA's safety information and adverse event reporting system.

Nesiritide was approved by the FDA in 2001 for the intravenous treatment of patients with acutely decompensated congestive heart failure who have dyspnea at rest or with minimal activity.

The approval was based on the results of studies showing that nesiritide reduced pulmonary capillary wedge pressure and improved dyspnea in this population. Although the mortality rate associated with nesiritide therapy in these studies was somewhat greater than that of comparator groups, it was not clear at that time that the increase could be drug related.

The current revision of nesiritide safety information to include 30-day mortality data were based on an analysis of results from seven controlled studies involving 1,700 patients. Three of the studies were used in a meta-analysis that recently appeared in the April 20, 2005, issue of JAMA and in the March 29, 2005, issue of Circulation.

In the seven clinical trials, nesiritide was associated with an increased mortality rate compared with other standard medications (5.3% vs 4.3%). In the four trials that measured long-term mortality, the 180-day mortality rate was also increased in patients receiving nesiritide, relative to standard medications (21.7% vs 21.5%). None of the mortality differences reached statistical significance.

The FDA notes that due to the small number of deaths, confidence limits around the hazard ratios for mortality are wide. Furthermore, the small size of the studies allows the presence of potentially important baseline imbalances among the treatment groups of which the effects cannot be ascertained.

Nesiritide may also affect renal function and cause azotemia in patients with severe heart failure whose renal function is dependent on the activity of the renin-angiotensin-aldosterone system.

In clinical studies, initiation of nesiritide at doses more than 0.01 g/kg per minute (0.015 and 0.03 g/kg/minute) was associated with an increased rate of serum creatinine elevation to more than 0.5 mg/dL above baseline compared with other therapies. No increases were observed in rates of acute renal failure or dialysis requirements.

However, nesiritide was associated with a higher number of patients requiring first-time dialysis during a 30-day follow-up period compared with nitroglycerin therapy (9 [3%] vs 5 patients [2%]).

According to the letter, the company will be convening a panel of experts to review all available studies and advise the company on their clinical significance; additional information will be available pending the review.

RADAR Finds Drug Reactions

Wed, 04 May 2005 00:00:00 -0700

Researchers in Chicago reported Wednesday they have found a large number of previously unknown and often fatal reactions to 14 commonly prescribed drugs and to drug-coated cardiac stents.

The report in the Journal of the American Medical Association is one of the results of an independent pharmaceutical surveillance program known as RADAR (Research on Adverse Drug Events and Reports Project), which looks at the safety of drugs already on the market.

The scientists from Northwestern University scoured academic journals, reports by pharmaceutical companies, and the U.S. Food and Drug Administrations database for information about adverse reactions to common drugs.

They identified reactions that affected nearly 1,700 patients, and divided them into three groups of effects: death, severe organ failure, or cases requiring major interventions like CPR or liver transplantation.

The results show that 170 people died from adverse drug reactions. One novel cancer drug alone is associated with 67 deaths.

"RADAR has proved to be a powerful new instrument that supplements existing FDA surveillance systems and has helped save hundreds to thousands of patient lives," said Charles L. Bennett, program director.

The FDA has come under fire recently for not adequately policing the safety of marketed drugs. Several drugs have been withdrawn from the market or re-labeled to warn of additional side-effects.

"Its the FDAs responsibility to make sure that the drugs which go on the market are safe and effective," said Elizabeth Boehm, a senior research analyst with Forrester.

New Jersey-based Merck withdrew its COX-2 inhibitor Vioxx on September 30, after studies showed the arthritis drug caused heart problems. Pfizer followed suit on April 7 with Bextra, and Biogen Idec and Elan suspended sales of multiple sclerosis drug Tysabri on February 28.

Suspicion has also been cast over common painkillers such as Advil, Motrin, and Aleve, as well as Scios heart drug Natrecor, and Novartis epilepsy drug Trileptal.

These have prompted calls for post-market monitoring of drugs by independent groups of scientists, such as those involved in RADAR.

According to Ms. Boehm, some drugs are approved after a very short period of testing on the condition that they are continually monitored while on the market.

"Its the follow-up on that which is under-resourced. Thats the most politically sensitive way I can put it," she said. "The FDA is not staffed to monitor all of these drugs over the long haul."

Currently, its largely up to drug companies to report safety issues once a drug is already for sale. "For good business reasons, they arent going out there to seek out every adverse drug event," added Ms. Boehm.

FDA Orders Heart-Risk Info on Drugs

Mon, 25 Apr 2005 00:00:00 -0700

The Food and Drug Administration is ordering that more information about the risk of death from a heart failure drug be added to the package insert for doctors.

The expanded data on nesiritide, sold as Natrecor, includes findings from seven studies with pooled results suggesting the drug might increase patients' risk of death within 30 days of treatment. Four of the studies found an increased risk of death compared with other treatments, and three found a decreased risk.

The drug is given intravenously and has been used by more than 600,000 patients in the United States since it was approved in 2001 to treat serious breathing problems that often accompany heart failure.

The revision, required for the professional label doctors are supposed to read, also adds information on 180-day death rates, showing virtually no increased risk of death with Natrecor. The revision notes that the studies were small, with relatively few deaths.

The labeling information had already mentioned a potential for low blood pressure and kidney problems, along with data from one study showing more deaths with Natrecor than nitroglycerin.

The FDA listed the required changes in a letter sent Wednesday to Scios Inc., the Johnson & Johnson subsidiary that makes Natrecor.

Scios spokesman Doug Arbesfeld said Monday that the company had agreed to the new labeling. He said the studies listed in the revised data will be reviewed by a company panel examining the drug's safety.

A study in the April 20 Journal of the American Medical Association said hospitalized patients given Natrecor appeared more likely to die in the first month after treatment than those given traditional medication or dummy pills.

Dr. Robert Temple, director of FDA's drug evaluation office, said he was not convinced that Natrecor increases patients' risks of dying and that the FDA still believes it is a useful drug.

Scientists Issue Warning On Heart-Failure Drug

Wed, 20 Apr 2005 00:00:00 -0700

A drug designed to rescue heart-failure patients from crisis may instead dramatically increase their risk of dying within 30 days of leaving the hospital, medical experts said yesterday.

In an analysis of documents from the Food and Drug Administration as well as the pooled results of three studies, researchers found that nesiritide, an intravenous medication approved amid fanfare in 2001, does little to help patients and may even make them worse, researchers say.

The medication, produced by Scios Inc., a Johnson & Johnson subsidiary, and sold under the brand name Natrecor, is not cheap. The drug costs about $500 per infusion and patients are usually hospitalized. However, doctors have begun a new, off-label use of the drug in which patients are treated on an outpatient basis, a practice critics say may also increase the danger. An estimated 600,000 people have been treated with the drug since approval.

Led by Dr. Jonathan Sackner-Bernstein, director of clinical research at North Shore University Hospital's heart failure center in Manhasset, researchers found that patients on the drug were more likely to die after release from the hospital than those prescribed standard therapy or placebos.

For decades diuretics and nitroglycerin have been the medications of choice for severe heart failure, a condition in which the organ has lost the capacity to pump enough blood. The disorder's symptoms are shortness of breath, extreme fatigue and fluid build-up.

The drug is a genetically engineered version of a hormone that eases breathing. Doctors do not know how the drug may contribute to death.

"Nesiritide is a drug used during the period of time when symptoms are out of control," Sackner-Bernstein said, "and it can be used for several hours or several days.

"We estimated the risk of dying within 30 days of being treated with nesiritide is 80 percent higher," Sackner- Bernstein said, than for patients on standard therapy or dummy pills. He added that further study is needed.

Johnson & Johnson spokesman Mark Wolfe said the study, in today's Journal of the American Medical Association, is inaccurate. "Natrecor is highly effective for patients with acutely decompensated heart failure, a life-threatening condition for which there are limited treatment options."Wolfe said an extensive review of the drug soon will get under way.

But with the threat of death so apparent in previous work on the drug, Sackner-Bernstein said, patients should be administered the medication only as second- or third-line therapy. The current study is the second in a month to warn about the drug. The first, reported in the journal Circulation, showed that nesiritide also substantially increased the risk of kidney problems.

Dr. Steven Nissen, vice chairman of cardiology at the Cleveland Clinic, the lone dissenting member on the FDA panel that approved the drug in 2001, said it's time to reassess nesiritide. "I was very concerned about this drug from the very beginning and I made very strong statements about it," Nissen said yesterday. "I was opposed to its approval because of the safety issues."

In the studies reviewed by Sackner-Bernstein and his colleagues, 35 of 485 patients on nesiritide died within 30 days of treatment while only 15 of 377 patients on other treatments died.

Nissen hailed the study, saying Sackner-Bernstein "did the classic analysis."

QUOTES:

'I was very concerned about this drug from the very beginning and I made very strong statements about it. I was oppposed to its approval because of the safety issues.'

Dr. Steven Nissen, the lone dissenting member on the FDA panel that approved the drug in 2001

Researchers Question Safety of Heart Drug

Wed, 20 Apr 2005 00:00:00 -0700

A genetically engineered drug made by a Fremont biotechnology company that was hailed as a breakthrough in the treatment of heart failure when it was approved in 2001 might actually raise patients' risk of dying soon after treatment, researchers say.

Pooling results from three studies, the researchers found that hospitalized patients given nesiritide appeared much more likely to die in the first month after treatment than those given traditional medication such as nitroglycerin or dummy pills.

The intravenous drug has been given to more than 600,000 patients nationwide. Nesiritide, sold as Natrecor, is made by Scios, a Fremont company that became a Johnson & Johnson subsidiary in 2003.

``The public should be very alarmed,'' said Dr. Jonathan D. Sackner-Bernstein, a cardiologist at North Shore University Hospital in Manhasset, N.Y., and lead author of the study, which appears in today's Journal of the American Medical Association. He said a large, rigorous study is needed to answer safety questions.

Johnson & Johnson spokesman Mark Wolfe called the analysis inconclusive and said nesiritide is safe and highly effective.

Dr. Robert Temple, director of the Food and Drug Administration's drug evaluation office, said there is ``not a convincing case for increased mortality, but we will be looking at all available data.''

The researchers acknowledged that the studies were small and not designed to examine increased death risks, so it is possible the results were just a chance finding.

They said they considered the possibility that nesiritide simply prolonged the lives of patients who would have otherwise died earlier, and they do not believe that explains their findings.

The analysis follows a study last month linking nesiritide to an increased risk of kidney problems. Scios announced last week that it is convening a panel of outside experts to review those concerns.

The FDA saw much of the data on higher death rates before it approved the drug. The warning label on nesiritide already mentions the potential for low blood pressure, kidney problems and more deaths than are seen with nitroglycerin.

In the pooled analysis, 35 of 485 nesiritide patients, or 7.2 percent, died within 30 days of treatment, compared with 15 of 377 patients, or 4 percent, given other drugs. That 80 percent increased risk of death is higher than found in previous studies and would translate into thousands of deaths nationwide, Sackner-Bernstein said.

Sackner-Bernstein has done consulting work for GlaxoSmithKline, which owns rights to market nesiritide in Europe. His daughter owns stock in Johnson & Johnson.

Natrecor was the first new drug in a decade approved to treat heart failure, which affects about 5 million Americans and is diagnosed in more than half a million people nationwide each year. It is designed to treat the frightening breathing problems that often accompany heart failure and is a laboratory version of a hormone hearts produce to ease breathing. Skeptics say it is unclear whether nesiritide is better than old standbys like nitroglycerin.

Dr. Steven Nissen, a Cleveland Clinic heart specialist who said he was the lone dissenter on an FDA advisory committee that recommended approval of the drug, said: ``If it really does increase the risk of death, then this is a major public health issue.''

Dr. Rose Marie Robertson, chief science officer for the American Heart Association, said the AHA would review the latest findings. But she added: ``I don't think there's sufficient data here to alarm patients or to alarm physicians.''

J&J Drug Raises Safety Concerns

Wed, 20 Apr 2005 00:00:00 -0700

Patients given a Johnson & Johnson drug for congestive heart failure may face an 80 percent higher risk of dying within a month of treatment, according to an article in this week's issue of the Journal of the American Medical Association.

As a result, the authors recommended a long-term safety study of Natrecor, an expensive medication that was touted as a breakthrough when it became available four years ago and is now a widely used treatment in hospital emergency rooms.

"The data suggests the best approach is to reserve Natrecor as a drug of last resort and not to use it as freely as it is currently used," Jonathan Sackner-Bernstein, one of the journal authors and a cardiologist at North Shore University Hospital in Manhasset, N.Y., said.

The findings are the latest controversy surrounding Natrecor, which prompted safety concerns in 2001 when regulators were deciding whether to approve the drug. Last month, a separate study indicated Natrecor may pose a 50 percent greater risk of worsening kidney function.

The back-to-back journal articles have also drawn Johnson & Johnson into the harsh spotlight focused on the safety of prescription medicines, which erupted over the hazards posed by antidepressants and painkillers, notably Merck's Vioxx.

The latest article was actually not a new clinical trial. Instead, the authors reviewed three older clinical studies, which dated back to 2002 and involved 862 patients who were given Natrecor or older therapies, such as diuretics.

Although Natrecor has not been proven to cause excessive harm, Sackner-Bernstein, who also was a co-author of the article showing greater kidney risk, said Johnson & Johnson should have investigated the risk of death sooner, given earlier safety concerns.

Mark Wolfe, a spokesman for Johnson & Johnson, the health- care giant based in New Brunswick, disagreed with the latest study and insisted the benefits offered by Natrecor outweigh the risks. He added 600,000 people have been treated with the medication.

"A review of the full data set does not show a statistically significant difference in mortality," he said. "With patient safety as our top priority, an external review of our existing data and our clinical development program is underway."

Johnson & Johnson, which is perhaps best-known for Band-Aids and baby shampoo, inherited Natrecor as part of its $2.4 billion purchase two years ago of Scios, a high-flying biotechnology company based in Fremont, Calif.

Natrecor, which is administered intravenously, helps people suffering from acute heart failure to breathe easier. One doctor yesterday said he has used Natrecor successfully many times and is concerned its benefits are being overlooked.

"I've used this medication and had favorable outcomes," Robert Takla, an emergency room physician in Detroit who had been a member of the Scios speakers' bureau, said. "I'd use it on my own father, who was recently diagnosed with congestive heart failure."

Last year, the medication generated $375 million in revenue, a fraction of Johnson & Johnson's 2004 sales of $47.3 billion. But Natrecor has moved the company into a lucrative market there are about 550,000 cases of congestive heart failure each year in the United States.

Moreover, the medication costs up to $500 a day, according to Steve Nissen, a cardiologist at the Cleveland Clinic, who added that Johnson & Johnson's Scios unit has been very aggressively marketing Natrecor, but has been slow to respond to safety concerns.

"The safety concerns are all happening just when the use of the drug is exploding. There are clinics popping up all over the place offering outpatient therapy," Nissen, who sat on the 2001 regulatory panel and argued in favor of a long- term safety study, said.

Johnson & Johnson's Wolfe maintained Natrecor marketing doesn't violate any regulatory guidelines. And he noted the company last week named Eugene Braunwald, a Harvard Medical School cardiologist, to convene a panel to assess clinical-trial data.

However, Nissen dismissed the effort as "damage control. It's an attempt to recover from a public relations disaster," he said. "Right now, we have a gap in our knowledge because the company never did a mortality trial. It's a serious omission."

New Heart Drug Carries Risks

Wed, 20 Apr 2005 00:00:00 -0700

About 1 million people are hospitalized every year for acutely decompensated heart failure (heart failure in which symptoms get suddenly worse) and about 100,000 of these patients are given the relatively new drug nesiritide, sold by Scios Inc. as Natrecor, and usually given intravenously.

The drug was approved by the Food and Drug Administration in 2001 to treat shortness of breath that accompanies heart failure and was touted for its ability to improve patients' condition within three hours. But researchers from Chicago, New York, and Ann Arbor, Mich., say the drug may harm patients more than it helps them.

What the researchers wanted to know: Is nesiritide safer than traditional therapies for heart failure?

What they did: The researchers reanalyzed data from three previous studies on the drug. In all, they looked at the files from 862 patients, 485 of whom received nesiritide intravenously after an episode of heart failure. They looked at death rates for patients who were given nesiritide compared with patients who were given more-traditional medications such as diuretics, which help reduce the buildup of fluid in the body, and vasodilators, which open up blood vessels.

What they found: The researchers found that nesiritide increased a person's chance of dying by 86 percent compared with traditional medications. Thirty-five of the 485 patients (7.2 percent) who received nesiritide died within 30 days, and 15 of 337 patients (4.0 percent) who did not receive the medication died within 30 days. Because of the increased risk of death, the researchers concluded that nesiritide "may not be an optimal choice" as the first medication given after acute heart failure. Instead, traditional medications should be used firstespecially since they cost much less. The researchers did not rule out the possibility that nesiritide could be used if other medications did not work. A spokesman for the company that manufactures nesiritide said that internal data do not show any increase in death rates compared with traditional therapies, though a separate paper published several weeks ago suggested the drug might harm the kidneys. Scios says it is convening an independent safety panel to look into the questions raised by that study.

What it means to you: If you are a heart-failure patient, it might be a good idea to talk to your doctor about the risks and benefits of different treatments given during acute episodes. Given that kidney failure could be a major risk of nesiritide, it would also be a good idea to monitor the Scios website and the FDA's Center for Drug Evaluation and Research to keep up on any new safety studies.

Caveats: Because the researchers got their data from other studies, they didn't have full information on all of the patients, including exactly when they died or why. The authors say they regard this paper as a hypothesis and say that other studies should be done to confirm their results.

3 Major Studies Point To Risk of Heart-Failure Drug Natrecor

Tue, 19 Apr 2005 00:00:00 -0700

Researchers challenged the safety of the heart-failure drug Natrecor for the second time in two months, reporting it could raise patients' risk of dying within a month of treatment.

Given intravenously to about 10% of people who are hospitalized for heart failure, the drug dilates blood vessels, reduces stress on the heart and relieves such frightening symptoms as shortness of breath. Natrecor is made by Scios Inc., a subsidiary of Johnson & Johnson.

The study, published in today's Journal of the American Medical Association, found that Natrecor, the trade name for nesiritide, raised the risk of death in the first month after treatment by 80% compared with other heart-failure drugs. The researchers based their conclusions on an analysis of three major studies of Natrecor involving 485 patients and 377 controls.

"The individual studies were not powerful enough to look at mortality. Only by doing this analysis does real risk emerge," says researcher Keith Aaronson of the University of Michigan, who worked with doctors at North Shore University Hospital and St. Luke's-Roosevelt Hospital Center in New York. Only a long-term study of the drug's risks would resolve the safety questions his research raised, he says.

In the March Circulation, the same researchers reported a 40% to 50% increased risk of kidney problems with Natrecor.

"We take any question about the safety of Natrecor seriously," says Mark Wolfe of Johnson & Johnson.

"At the same time, a review of Scios' full data set does not show a statistically significant difference in (death rates) between patients treated with Natrecor and those treated with traditional heart-failure therapies."

On April 12, Scios announced it would convene an external panel of heart experts to evaluate the drug's safety. Wolfe says the company would not comment further, and his statement did not address whether Scios would carry out the kind of study that Aaronson has proposed.

"When a question like this is raised, it has to be addressed," says Rose Marie Robertson, the American Heart Association's chief science officer.

Robertson says the critics' study is hampered by its reliance on information from studies that involved different patient populations and different drug dosages. She says only a study designed to weigh the drug's risks can resolve safety questions.

The heart association receives funding from Scios to inform doctors and the public about heart-failure treatments and would incorporate new information into the organization's programs, Robertson says.

A Food and Drug Administration review of Natrecor in 2001 says the company's data could not "rule out a 50% increased risk" of death among patients given Natrecor. "We have not reviewed the JAMA article and cannot answer specific questions at this point," the FDA's Laura Alvey says.

Natrecor had nearly $400 million in sales last year, quadruple the total for 2001, when the drug was introduced, reports IMS Health, a firm that tracks drug sales.

Heart Failure Drug Associated with Higher Risk of Death in First Month

Tue, 19 Apr 2005 00:00:00 -0700

A drug that helps heart failure patients survive a crisis may actually increase their risk of dying in the first month after they leave the hospital, according to a new study that will be published April 20 in the Journal of the American Medical Association.

In fact, the analysis shows, patients treated with the intravenous drug nesiritide were 80 percent more likely to die in the next month than patients who received traditional drugs for acute heart failure symptoms, such as diuretics and vasodilators. The study analyzed clinical trial data obtained from the manufacturer of the drug, which is marketed as Natrecor, and from the U.S. Food & Drug Administration. All the clinical trials were conducted by the manufacturer, Scios, a unit of Johnson & Johnson.

The studys authors, from North Shore University Hospital in New York and the University of Michigan Cardiovascular Center, also published findings in March showing that nesiritide is associated with a much higher risk of kidney dysfunction.

But, Sackner-Bernstein adds, This new meta-analysis estimating the risk of death to be increased by 80 percent serves as a compelling argument for a randomized, controlled clinical trial to be performed, to define the risks associated with nesiritide prior to its widespread use. To date, the company has not initiated any trial that will address these concerns about the link between nesiritide therapy and the risk of worsening kidney failure or higher risk of death reported in this analysis.

The new finding was made using data from three carefully designed clinical trials involving 862 heart failure patients who required urgent treatment for acute decompensation, or sudden worsening of symptoms. The 485 randomly assigned to receive nesiritide had a higher risk of death than the 377 randomized to traditional non-inotropic drugs. The size of the risk was much larger than a prior FDA estimate.

The authors acknowledge that their study can't give definitive proof of harm, but note that these are the only data that evaluate the safety of nesiritide in randomized, double-blind controlled trials.

All the other data available are from sources that are less rigorous and less reliable. Therefore, clinical decisions need to rest on the understanding that these, the best data available, suggest that nesiritide is likely to be associated with important risk,” says Sackner-Bernstein.

Co-investigator Keith Aaronson, M.D., associate professor of cardiovascular medicine at the U-M Medical School and medical director of the U-M heart transplant program, notes that the increased mortality risk was seen even when the researchers focused on data from the two clinical trials that used the starting dose of nesiritide that is now recommended to physicians.

Aaronson hopes the new finding will give physicians better perspective on the risks of nesiritide, which is perceived as being more effective and safer than dobutamine, an inotropic (heart strength-enhancing) drug that carries a substantial risk of increased mortality.

The analysis of all three clinical trials, he says, suggests that the safety of nesiritide may have been over-estimated especially compared with diuretics and vasodilators, which are also much less expensive. Doctors should remember that theres no data showing that nesiritide is any better at calming acute symptoms than diuretics and vasodilators, Aaronson says.

When the FDA approved nesiritide, they acknowledged that it could be associated with a 50 percent increased risk of death, he adds. But it seems the FDA believed that physicians could judge how to balance the risks and benefits for individual patients. Our meta-analysis demonstrates that the risk may be even higher. In view of the relatively modest symptomatic benefit this drug provides, a death risk of this size should take precedence in a physician treatment decision.

With that in mind, he says, the first choice for treatment should be diuretics, which aren't perfect but which are effective and cost pennies in comparison with hundreds of dollars for nesiritide. And he questions the intermittent outpatient use of nesiritide, which is covered by Medicare in several states. That approach infuses patients with the drug up to three times a week, to ease ongoing non-acute symptoms.

Although the outpatient use of nesiritide is now being explored in a Scios-funded trial, we're concerned the study will not be large enough to allow for risks to be seen if they are present, says Aaronson.

In addition, nesiritide is currently being used in patients who have had open-heart surgery, but this too is likely to be a misguided approach, the authors say. Very few patients require a vasodilator after open-heart surgery, but kidney dysfunction is a major concern post-operatively, Sackner-Bernstein says. In addition to this mortality risk in patients with acutely decompensated heart failure, the meta-analysis we reported last month contradicted the perception that nesiritide protects the kidneys. Between these two analyses, and in the absence of a randomized controlled clinical trial, its hard to see any rationale for the use of nesiritide in patients post-operatively.

The new analysis used data from the NSGET, VMAC and PROACTION trials. Nine other studies were not included because they were not randomized, double-blind trials, meaning that their results could be biased. The team pored over FDA and company data, looking closely at the risk of death within 30 days of treatment. They controlled for concurrent dobutamine use in the VMAC study.

The authors noted the statement released on April 12 by Scios, stating that the company will convene an expert panel headed by Eugene Braunwald, M.D., to evaluate the risks of nesiritide.

"We certainly welcome the forthcoming outside expert review and trust they will conclude, as we have, that there is a pressing need for a prospective, randomized clinical trial that is large enough to accurately assess kidney and mortality risks from nesiritide, says Sackner-Bernstein. We regret that a kidney safety review was not undertaken sooner, as those data were available to them since 2001. With the disclosure of increased risk of death associated with nesiritide use in the current issue of JAMA, based on data available to Scios since 2002, the data support the need for further action.

Acutely decompensated heart failure results in nearly one million hospitalizations annually, and is the most common reason for hospitalization among people over age 65. Nearly 10 percent of such patients receive nesiritide. More than 4.9 million Americans have heart failure, a gradual worsening of heart function that often begins after a heart attack weakens the heart muscle.

Hospitalizations for acutely decompensated heart failure cost Medicare $3.6 billion in 1999. Typically, patients are hospitalized with organ congestion, an indicator that there is excess fluid present. Symptoms can include severe shortness of breath, especially with activity or when lying down. The cornerstone of therapy is the use of diuretics.

In addition to Sackner-Bernstein and Aaronson, the study’s authors are Marcin Kowalski, M.D., and Marshal Fox, M.D., of St. Lukes-Roosevelt Hospital Center.

Natrecor Heart Failure Lawyers

Tue, 19 Apr 2005 00:00:00 -0700

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Injured by Natrecor?

In a study published in the April 2005 issue of the Journal of the American Medical Association, a team of researchers assert that Natrecor users suffered from a higher death rate than cardiac patients on other drugs, such as diuretics and vasodilators, based on data from three past Natrecor clinical trials. "In conclusion, Nesiritide may be associated with an increased risk of death within the first month after its use for the treatment of decompensated heart failure when compared to noninotrope-based therapies," the researchers wrote. The Natrecor study was conducted by researchers Dr. Jonathan Sackner-Bernstein, of the North Shore University Hospital in Manhasset, N.Y; Drs. Marcin Kowalski and Marshal Fox, of St. Luke's-Roosevelt Hospital Center in New York; and Dr. Keith Aaronson, of the University of Michigan. Some of the researchers involved in the JAMA study also published a similar study in the medical journal Circulation in March 2005. In that analysis, the researchers said that Natrecor could hasten renal failure in some patients. On January 3, 2006, Johnson & Johnson informed U.S. regulators that a previously unreported two additional patients died 30 days after taking Natrecor, adding to uncertainty about the drug's safety.

Natrecor (Generic: Nesiritide) was approved by the Food and Drug Administration in 2001 to treat a severe form of heart disease called decompensated heart failure, for which there are few available treatments. Many patients are treated with diuretics and vasodilators. Natrecor's label already warns it can cause kidney problems in certain users. The drug is marketed by Scios Inc., a wholly-owned unit of Johnson & Johnson.

A Food and Drug Administration review of Natrecor in 2001 said the company's data could not "rule out a 50% increased risk" of death among patients given Natrecor. Statements from Dr. Nissen at the FDA Advisory Committee hearing on Nesiritide:

DR. Nissen: Jim, I have a series of sort of interrelated questions, and the hypothesis to be tested here was that this agent was effective in the background of standard of care, and so I'm interested in exploring with you this whole issue of standard of care. Now, as I understand this, these were Class IV patients, dyspneic at rest with acute decompensation; respiratory rates in the low to mid-20s; a pretty sick group.

In my experience, if a patient like that comes in the emergency room, before I've answered my page, someone has given them a big slug of IV furosemide, and I'm very troubled here by slide number 73, if you want to put that up, because it suggests something about this study was somehow biased toward not providing standard of care. I mean, here is only 30 percent of the Natrecor patients got an IV diuretic within six hours before they began these infusions, and only a little more than half got an IV diuretic within 24 hours before.

And so it looks to me like somebody was withholding diuretic therapy, withholding standard of care therapy in order to set these patients up for the drugs to be used, and I need to understand what happened here to be able to properly interpret the data.

Dr. Nissen: Yeah, I wonder if you could put up slide 112. I want to talk with you about that. the question I have relates to this issue of what I think is a somewhat narrow therapeutic index for this drug, and I was very struck by the fact that a dose increase from .01 to .015 is really associated with about a doubling of the risk of symptomatic hypotension, and then there's even another large increase when the dose gets higher.

And so I had several questions that relate to this that I think are important, and let me make sure you understand why I am asking this question. You know, one of the reasons that IV nitroglycerine is very popular is that it has a very wide range of doses. We give as little as ten micrograms and I've certainly given as much a 1,000 or more micrograms.

So it's a drug that we know we can use over a very broad range. So whenever I see a drug with a narrow therapeutic index, I worry. And so the next question I wanted to ask is given the fact that I assume you agree with me that it is a narrow therapeutic index, what do we know about the pharmacokinetics of this drug?

For example, how exactly is it metabolized or eliminated? What kinds of patients might we have to worry about as clinicians that might accumulate the drug at greater levels because if presumably a 50 percent increase in dose is associated with a big increase in risk of hypotension, then I've got to know more about the variability in the kinetics here to have comfort about this, and I wonder if you could address that for me.

If you or a loved one took Natrecor and suffered side effects, please fill out the form at the right for a free case evaluation by a qualified drug side effects attorney.