Janet Woodcock

Two studies to find the most effective dose of a widely used drug for treating heart attack patients have found that a high dose can unexpectedly prove unacceptably dangerous.

The trials, sponsored by drug companies, were halted in April because of an unexpectedly high risk of paralyzing and fatal strokes, but doctors are to be publicly warned of the danger only on Monday.

The drug is heparin, a powerful agent that interferes with the body's normal clotting process. Heparin, along with other drugs, is recommended for heart attack patients because it inhibits the formation of blood clots that can lead to a second heart attack. Doctors use a range of doses on hundreds of thousands of heart attack patients, the study leaders said.

A large study established last year that a low dose of intravenous heparin was reasonably safe and effective when given with clot-dissolving drugs. Two large follow-up trials involving patients in more than 365 hospitals in the United States and 12 other countries were then begun, testing a high dose of heparin and a similar but experimental drug.

By this April the answer was clear: the high dose of heparin wrought too much havoc with the clotting process and could cause lethal bleeding in some patients.

The trials were resumed in May with lower doses of both heparin and the experimental drug, hirudin, with approval from Federal officials.

A third study conducted in Germany was halted in June after researchers there, alerted to results of the two American-based studies, found a similar risk of strokes among individuals receiving hirudin. The German study used a low dose of heparin.

There are no clear standards for how quickly the results of clinical trials should be publicly reported.

In recent years Federal health officials have taken to issuing clinical alerts, informing doctors within days of important new therapeutic advances or dangers from federally sponsored research. This is a departure from the academic tradition of allowing all but the most exceptional results to wend a leisurely route through the review and publication schedule of journals.

Findings from the three studies are being reported on Monday in the October issue of Circulation, a medical journal published by the American Heart Association in Dallas.

Dr. Eric J. Topol, chief cardiologist at the Cleveland Clinic Foundation and the head of the largest study, said in an interview that there were many reasons for the six-month delay in disclosing the findings, chiefly the need to avoid causing a panic among doctors who were using heparin at low doses. An editorial in the same issue of the medical journal advised them to continue.

The studies are part of a massive international effort to find the most effective treatment for heart disease, a leading killer, and to fine-tune the doses of the leading drugs and the way some are administered.

To save more lives, Federal health officials earlier this year recommended that people suffering heart attacks should receive clot-dissolving drugs, often including heparin, within 30 minutes of arrival at an emergency room.

The three studies aimed in part at comparing heparin, which was discovered in 1916, and hirudin. Hirudin is made by genetic engineering from the anticoagulant in the saliva of leeches, and it is being intensively studied in the hope that it will prove more effective than heparin.

Participants received either heparin or hirudin along with drugs that can break up blood clots after they form, including streptokinase and TPA, and aspirin, which is also used to prevent clots.

The three studies found that among those receiving either heparin or hirudin with streptokinase or TPA there was "definitive evidence of a catastrophic bleeding complication" that was about twice the expected rate, the heart association said in a news release.

Strokes result from the death of brain cells and can be caused by blood clots or bleeding. The ones in these studies resulted for unknown reasons from bleeding due to a complication of therapy.

In Dr. Topol's study, 26 of 2,564 heart attack patients who received either hirudin or heparin suffered a stroke from bleeding in the brain, a rate of about 1 percent. In the study headed by Dr. Eugene Braunwald and Dr. Elliott M. Antman of Harvard Medical School in Boston, 6 of 345, or 1.7 percent of those receiving hirudin and 7 of 368, or 1.9 percent of patients receiving heparin, suffered strokes from bleeding.

More than half of those with strokes died, and others among the survivors were paralyzed or otherwise disabled and face years of rehabilitation, the association said.

"These are intolerable rates of" stroke from bleeding, said Dr. Topol, who is chairman of cardiology at the Cleveland Clinic Foundation. "It has been a nightmare for us."

Doctors have generally been careful in prescribing heparin because of the well-known bleeding risks. The new findings document the narrow window that exists in prescribing a safe, effective dose because the amount in the American-based studies was only 20 percent higher than that used in an earlier study that had showed the benefit of combined intravenous heparin and therapy using the "clot buster" drugs, thrombolytics.

"We really want to get the word out so that there are not other fiascos like what we ran into," Dr. Topol said. "Physicians need to know they should not be too aggressive, too liberal, in their use of heparin."

Earlier this year, the heart association recommended a regimen for heart attack patients receiving clot buster drugs in which 5,000 units of heparin is injected initially, followed by an infusion of 1000 units per hour. The dose may vary depending on a patient's weight and results of repeated blood monitoring tests.

Dr. Topol said he knew that in everyday practice doctors were prescribing heparin in amounts larger than those in his earlier study.

A spot check of doctors not connected with the studies found that all had used the lower amount of heparin but that none had known that the studies were halted because of the stroke hazard with the higher dose of heparin. Several expressed anger that a warning was delayed.

Dr. Topol said that among the reasons he and his colleagues did not do so was to wait to publish reports in a journal that would reach cardiologists since there was no need to warn patients directly.

The studies were stopped on April 8 when the leaders learned of the problem from independent committee monitoring the safety of both American-based studies. Reports of the two studies were submitted to Circulation on July 7, accepted with revisions on Aug. 15 and are being published in record time, he said.

Dr. Topol said the researchers wanted to be sure of the underlying problems before publishing because they originally had a poor understanding of the many variables involved. But, despite such reservations, the researchers felt they understood the problem well enough to restart the studies in May.

Dr. Topol said the researchers also wanted the reports to be reviewed by peers before being published in a journal. But the experts on the monitoring committee already had analyzed the data, another form of peer review. The researchers then submitted it to the F.D.A. in making its case to resume the studies with lower doses of heparin and hirudin.

Officials at the F.D.A., which had approved the studies, said their focus in reviewing the findings of the three studies was on hirudin because it was the experimental drug being compared with the standard one, heparin, and that they had approved resumption of the hirudin trials because they did not want to inhibit research progress of a potentially important drug.

"The point is well taken: maybe we were remiss in not thinking more about" heparin, Dr. Janet Woodcock, an F.D.A. official, said in an interview, adding that she was surprised to learn that doctors were using heparin in high amounts.

"Dr. Topol never conveyed to us that there was a large section of the population using this dose of heparin" and the researchers' concern about the practice, Dr. Steven Fredd, another F.D.A. official, said.

Both officials said that if Dr. Topol knew that doctors were prescribing heparin in high doses and had informed the F.D.A., the agency would have taken steps to warn doctors. The F.D.A. does not have such data.

The studies were paid for by the Ciba-Geigy Corporation of Summit, N.J.; Boehringer Mannheim of Germany; Advanced Cardiovascular Systems of Mountain View, Calif.; Genentech of South San Francisco; and Behringwerke AG of Marburg, Germany.

THE bleeding stomach ulcer that Secretary of State Warren Christopher suffered as a complication of a nonsteroidal anti-inflammatory drug he took for arthritis vividly illustrates the dangers of such drugs.

Complications of these drugs, referred to by doctors as Nsaid's (pronounced EN-seds), are a significant public health problem. The complications have been described in a medical journal as the most prevalent serious drug toxicity in the United States. Each year such complications lead to about 41,000 hospitalizations and 3,300 deaths, studies show. They are a principal reason for the procedure known as gastroscopy, which Mr. Christopher underwent, in which doctors pass a tube through the mouth into the stomach to diagnose stomach disorders.

Mr. Christopher's ulcer sent him to the intensive care unit of Ottawa Civic Hospital during President Clinton's visit to Canada last month. Doctors there said the ulcer had been caused by complications of Ansaid, a non-steroidal anti-inflammatory drug made by the Upjohn Company of Kalamazoo, Mich. It is one of 25 Nsaid's approved for marketing by the Food and Drug Administration.

On his return to Washington, Mr. Christopher, 69, checked into Georgetown University Hospital for overnight observation. Now back at work, Mr. Christopher is to leave today on a trip to the Middle East. It will be another month before the ulcer is completely healed.

Mr. Christopher was luckier than many who develop a bleeding ulcer due to an Nsaid. The death rate from such complications is about 8 to 10 percent, said Dr. Marie R. Griffin, an expert on the epidemiology of drugs at Vanderbilt University in Nashville who has carried out studies on Nsaid usage.

About 3.4 percent of the 2.2 billion prescriptions written each year are for Nsaid's. Millions more nonprescription Nsaid's are bought as over-the-counter drugs like aspirin, ibuprofen and naproxen, which are often used for short-term use to relieve inflammation and pain from osteoarthritis and rheumatoid arthritis. Nsaid's are among the oldest commercial drugs still on the market; aspirin and another Nsaid, sodium salicylic acid, were developed in the 19th century. In the 1950's, drug companies began marketing the first newer ones and the numbers have been increasing ever since. The latest Nsaid approved was in 1993.

Among people aged 65 and over, half have pain or swelling in at least one joint. Rheumatologists say it would be harder to give patients relief if Nsaid's were not available. Their use is expected to increase as more people live longer.

But some experts say that aggressive marketing practices of drug companies have made Nsaid's too popular and that many people could get as much relief with fewer adverse effects and at less cost if they took milder drugs like acetaminophen (Tylenol), which is not an Nsaid. Some prescription Nsaid's cost 12 times more than over-the-counter ibuprofen.

On any day, 10 to 15 percent of Americans aged 65 and older have a filled prescription for an Nsaid.

Although Nsaid's have merit, they should be prescribed and used cautiously with the risks explained to each patient, said Dr. Janet Woodcock, a rheumatologist and official of the Food and Drug Administration.

Dr. Stuart Nightingale, an associate commissioner of the F.D.A., has cited studies showing that bleeding ulcers develop in about 1 percent of those who use the drugs for three to six months, and from 2 to 4 percent of those who use them for a year.

Studies also have shown that those who use the drugs have a four times greater risk of developing an ulcer than nonusers in all age groups. Complications of the drugs lead to 30 percent of the hospitalizations and deaths from ulcers in people aged 65 and older in this country, Dr. Griffin said. The remaining 70 percent are caused by a bacterium, Helicobacter pylori.

"It appears that you are at about the same risk in the first month of taking an Nsaid as in the 12th or 24th, not getting any worse or better," Dr. Woodcock said. With some drugs, like sulfa or penicillin, the risk of a catastrophic event is highest when it is first taken.

The Arthritis Foundation in Atlanta says, "No single Nsaid is guaranteed to work; you may have to try several types before you find one that works for you."

The foundation advises users of the drugs who are bothered by repeated nausea, vomiting, stomach pain, heartburn, gas, bloating, constipation and diarrhea to check with their doctors.

The Medical Letter, a respected review of drugs and therapeutics published in New Rochelle, N.Y., warns that these drugs may interact to decrease the effectiveness of many other drugs that are used to lower high blood pressure. Doctors also warn that the interaction of Nsaid drugs with alcohol or aspirin can be harmful.

It is not clear whether some drugs in the group are more likely than others to cause complications. Dr. Woodcock said the F.D.A. is studying reports that piroxicam (Feldene) may cause a higher rate of intestinal bleeding than others.

The National Kidney Foundation in New York City has expressed concern about the increased risk of kidney failure from chronic use of the drugs.

Over all, Dr. Griffin said, "the adverse effect rate is pretty high for a drug that is not curative and used mainly to relieve symptoms." She said the complication rate of the drugs was about that of anti-coagulant drugs that are used to prevent blood clots and for which doctors generally exercise greater precaution.

Dr. Gerald Weissmann, a rheumatologist at New York University, said: "All the newer Nsaid's are safer than aspirin and are valuable when used under a doctor's observation for defined inflammatory arthritis," but that they are overused by people who take them for more non-specific reasons.

Most doctors believe that the benefits of daily use outweigh the risks for those who get substantial relief. But studies indicate that many people take more than they need to get relief.

Concern also exists for those who seem to get only a modest or marginal benefit from the drugs and for the many patients who are unclear why they are taking them.

"Many people have a misconception about how good these drugs are," Dr. Griffin said. "For some people they work great, for other people they don't work that well. We and many others who treat elderly people believe that the complication rate is high and that they should probably try acetaminophen first" because it affords about the same relief for osteoarthritis as the prescription and nonprescription medications.

Chronic use of acetaminophen, or Tylenol, however, has its own set of problems.

In criticizing studies of Nsaid's, Dr. P. A. Dieppe and his colleagues from the University of Bristol in England have written in The Lancet, "We still know very little about the causes, diagnosis, natural history, and appropriate management of osteoarthritis."

Most studies of the drugs last only a few weeks, while the pain of the condition is present for months or years in most cases. Few studies have compared the effectiveness of an Nsaid with that of a pure analgesic like Tylenol, and "one of the main reasons for this paucity of comparative studies of simple analgesics and Nsaid's must be the vested interests of the pharmaceutical industry," Dr. Dieppe's team wrote.

Large trials are needed, but the money for them is unlikely to come from drug companies, they said.

A major reason for the widespread use of the drugs is that dealing with arthritis is frustrating for patients and doctors. Many arthritics get incomplete relief of pain, and doctors and patients want to do something to improve their quality of life. So doctors are continually tempted to try new drugs, even when their effect is symptomatic and does not address the root cause of the disease.

Each new drug that comes on the market is advertised as easier on the stomach than its predecessors, leading doctors and patients to try it in the hope that this will be the drug that really helps.

But head-to-head studies have shown little difference in effectiveness between the many available, Dr. Griffin said, and only ibuprofen has been found consistently safer than the other drugs, presumably because individuals take it in smaller amounts than they do the others.

Doctors and patients often overlook many alternatives like exercise, weight loss and measures to relieve the load on affected joints, Dr. Griffin said, adding, "They take much time and are harder to comply with than taking a pill."

Doctors also tend to underestimate the dangers of these drugs, largely because the overwhelming majority of their patients do not have trouble and when they do develop ulcers and other complications they do not always link them to the drugs, Dr. Griffin said.

Dr. Woodcock said that her drug agency was trying to find new ways to provide information about the drugs people use. For many years, she said, "there was a complacency where many people seemed to take all kinds of drugs and consumers did not recognize that they could result in bad adverse reactions."

Correction: March 10, 1995

A table in Science Times on Tuesday about drugs used to treat arthritis and inflammation classified some generic drugs and their proprietary versions incorrectly. The medicines -- Diflusinal (Dolibid), acetaminophen (Tylenol), oxyphenbutazone (Tandearil) and phenylbutazone (Butazolidin) -- are approved by the Food and Drug administration for arthritis but are not classified as nonsteroidal anti-inflammatory drugs.

NOW that thalidomide, the drug that was banned worldwide in the 1960's after it produced 10,000 babies with missing and stunted limbs, is headed for approval by the Food and Drug Administration, Randy Warren has a question: Are the benefits of the world's most notorious sedative worth the risk that just one more baby will be born like him?

Mr. Warren, 36, a Canadian whose mother took the drug when she was pregnant, was born with flipperlike feet where his kneecaps should be, four fingers on each hand and severely deformed ears. He had 24 operations by the time he turned 16; he remains wheelchair bound and unable to perform simple tasks like buttoning up his shirt.

''One baby born for 100 lives extended?'' he asked rhetorically last week, a few days after the F.D.A. announced that it intended to approve thalidomide for leprosy patients. ''If there is a number, I would like to know what it is. How are you going to measure that?''

No one has performed such a cold-hearted risk-benefit analysis, of course, and no one intends to, which is precisely Mr. Warren's point. Yet in the contentious debate over the return of thalidomide, which holds promise as a treatment for maladies as diverse as AIDS, lupus and cancer, there is one point upon which nearly everyone agrees: more deformed babies will be born if the drug comes to market.

''There will be some slip-ups,'' predicted Dr. Norman Fost, who directs the medical ethics program at the University of Wisconsin. ''There is no policy that will produce zero.'' But no one, he added, is willing to answer the most volatile question of all: How many thalidomide babies is too many?

In part, this is because Americans don't like to confront risk, be it the danger of contaminated hamburger meat or automobile air bags. Dr. John Graham, director of the Center for Risk Analysis at Harvard University, says an honest intellectual discussion of thalidomide should include some numbers crunching. But he doesn't expect it: ''We as a society do not want to face up to these numbers and their implications.''

The drug's maker, the Celgene Corporation of Warren, N.J., maintains that it can't crunch any numbers, because no one knows how many babies might be born and the potential uses of thalidomide will grow as scientists discover more diseases for which the drug is useful. Instead, the company has focused on designing a plan to prevent birth defects.

The plan, which has drawn accolades from all sides, including from Mr. Warren, includes a variety of provisions. Pharmacies would register before dispensing the drug, and there would be no automatic refills. Female patients would have to show proof of contraception and undergo regular pregnancy tests, and education for doctors and patients would be mandatory, which experts say is critical given that so many Americans are too young to remember the thalidomide scare.

Still, the company is not foolhardy. ''We have obtained product liability insurance,'' said Celgene's vice president for marketing, Bruce Williams, although he added that he does not believe more deformed babies are inevitable. ''If I believed that,'' he said, ''I would not be doing this.''

Because no drug is 100 percent safe, the F.D.A. always weighs risks and benefits. The difference with thalidomide, according to Dr. Janet Woodcock, who directs the agency's Center for Drug Evaluation and Research, is that the side effects don't injure the patient but another person, namely her child. Dr. Woodcock says the best the agency can do is to monitor thalidomide once it is on the market, and re-evaluate if too many accidents occur.

To Dr. Fost, that answer is not good enough. He would like the agency to confront the numbers question up front. ''If there are 10, 20, 50 or 100 or 200 of these kids five years from now, we will all look back and have heart-wrenching symposia and TV specials on whether the right precautions were taken,'' he said. ''So we should answer that question now.''

Releasing its own survey of doctors who work for the Food and Drug Administration, an advocacy group yesterday accused the agency of lowering its standards for safety and efficacy, working too hastily and approving drugs that should never have been allowed on the market.

The report has drawn a scathing rebuttal from the drug industry, an oblique defense from the agency and criticism from representatives of chronically ill people who advocate swifter drug approval.

But some scientists said the report raised significant concerns.

The survey, announced at a news conference, was conducted by the Public Citizen's Health Research Group of Washington, which is directed by Dr. Sidney Wolfe and was founded by the consumer advocate Ralph Nader in 1971. The organization has criticized the pharmaceutical industry and, more recently, the drug-approval process, which Congress accelerated in 1992 and 1997.

The people surveyed were medical officers, agency employees assigned to oversee individual drugs being evaluated for approval. The survey was anonymous, and completed by only 53 of the 172 people to whom it was mailed.

Among its findings were these:

*Nineteen medical officers identified 27 new drugs that were approved even though the officers thought they should not be.

*Seventeen said the food and drug agency's safety and efficacy standards were lower than in the past.

*Nineteen said they felt more pressure to approve drugs from within the agency and from Congress and the pharmaceutical industry.

But a majority of the medical officers did not answer the survey, and a majority of those who did answer did not complain, making it impossible to tell whether the survey found genuine problems or merely provided malcontents an outlet for gripes.

In a statement, the drug agency said in part, ''The public should rest assured that the F.D.A. maintains the highest standards in the world for approving drugs.''

Agency officials declined to be interviewed, and the statement from Dr. Janet Woodcock, director of the agency's Center for Drug Evaluation and Research, did not specifically address issues raised in the report.

Jeff Trewhitt, a spokesman for an industry group, the Pharmaceutical Research and Manufacturers of America, said, ''It is highly irresponsible to issue a so-called study based on clandestine communications with faceless, anonymous sources.''

Virginia Ladd, president of the American Autoimmune Related Diseases Association, in Detroit, said, ''We worked for F.D.A. reform to speed up the process.'' She said new drugs that became available through speeded approvals were very helpful to her group.

Dr. Kenneth Kaitin, who studies drug regulation at the Tufts University Center for the Study of Drug Development, in Boston, said, ''The research is shoddy, the survey is inconclusive and equivocal, and by no stretch does it support the conclusions.''

But Dr. Charles Flexner, an associate professor of medicine in clinical pharmacology at Johns Hopkins University, said the report raised important issues. Accelerated approvals have helped people with H.I.V. and cancer, he said, but more recently the process has gone too far.

''I think we've lost sight of the valuable role that the F.D.A. serves as a guardian of public health and safety,'' Dr. Flexner said, ''and not simply a regulatory hurdle for bringing new drugs to market.''