A new study suggests that ovarian cancer screening with a technique called transvaginal ultrasonography (TVS) may catch ovarian cancer early, at a more curable stage.
TVS involves using an ultrasound probe placed in the vagina to direct sound waves through the vaginal wall towards the ovaries to detect abnormalities. The new study shows that TVS screening is able to detect ovarian cancers at an earlier stage, perhaps increasing their chances of survival.
The early diagnosis of ovarian cancer is difficult and the disease is often not detected until it has reached an advanced stage. Compared with other gynecologic cancers, ovarian cancer carries a very poor prognosis.
Dr. John R. van Nagell, from the University of Kentucky in Lexington, and colleagues assessed the value of annual TVS screening for ovarian cancer in 25,327 women who were seen between 1987 and 2005.
To be eligible for the study, the women had to be at least 50 years old with no cancer-related symptoms or at least 25 years old with a family history of ovarian cancer.
Overall, 364 women (1.4 percent) had a persistent ovarian tumor on TVS, the authors report in the journal Cancer. Malignant cases included 35 primary invasive ovarian cancers, 9 ovarian tumors of low malignant potential, and 7 "metastatic" cancers that had already spread beyond the ovaries. Most of the contained or "non-metastatic" ovarian tumors were early stage I tumors.
During an average follow-up of about 5 years, 38 women were alive and well, 4 had died of their cancer, and 2 had died from other causes.
The 2-year survival rate in annually TVS screened women approached 90 percent and the 5-year survival rate in screened women was a little over 77 percent.
TVS screening was highly sensitive and specific in detecting ovarian cancer. However, "false-negative" results were obtained in nine women, including three who died of their disease, the investigators note.
Summing up, the researchers say early detection of ovarian cancer could potentially improve treatment efficacy and reduce deaths. "The protective effect of annual sonographic screening on ovarian cancer mortality observed in the current trial should only increase as more specific biomarkers are added to TVS in screening algorithms," they conclude.
SOURCE: Cancer, May 1, 2007.
Monday, May 28, 2007
Lost Chances for Survival, Before and After Stroke
Dr. Diana Fite, a 53-year-old emergency medicine specialist in Houston, knew her blood pressure readings had been dangerously high for five years. But she convinced herself that those measurements, about 200 over 120, did not reflect her actual blood pressure. Anyway, she was too young to take medication. She would worry about her blood pressure when she got older.
Then, at 9:30 the morning of June 7, Dr. Fite was driving, steering with her right hand, holding her cellphone in her left, when, for a split second, the right side of her body felt weak. “I said: ‘This is silly, it’s my imagination. I’ve been working too hard.’ ”
Suddenly, her car began to swerve.
“I realized I had no strength whatsoever in my right hand that was holding the wheel,” Dr. Fite said. “And my right foot was dead. I could not get it off the gas pedal.”
She dropped the cellphone, grabbed the steering wheel with her left hand, and steered the car into a parking lot. Then she used her left foot to pry her right foot off the accelerator. She pulled down the visor to look in the mirror. The right side of her face was paralyzed.
With great difficulty, Dr. Fite twisted her body and grasped her cellphone.
“I called 911, but nothing would come out of my mouth,” she said. Then she found that if she spoke very slowly, she could get out words. So, she recalled, “I said ‘stroke’ in this long, horrible voice.”
Dr. Fite is one of an estimated 700,000 Americans who had a stroke last year, but one of the very few who ended up at a hospital with the equipment and expertise to accurately diagnose and treat it.
Stroke is the third-leading cause of death in this country, behind heart disease and cancer, killing 150,000 Americans a year, leaving many more permanently disabled, and costing the nation $62.7 billion in direct and indirect costs, according to the American Stroke Association.
But from diagnosis to treatment to rehabilitation to preventing it altogether, a stroke is a litany of missed opportunities.
Many patients with stroke symptoms are examined by emergency room doctors who are uncomfortable deciding whether the patient is really having a stroke — a blockage or rupture of a blood vessel in the brain that injures or kills brain cells — or is suffering from another condition. Doctors are therefore reluctant to give the only drug shown to make a real difference, tPA, or tissue plasminogen activator.
Many hospitals say they cannot afford to have neurologists on call to diagnose strokes, and cannot afford to have M.R.I. scanners, the most accurate way to diagnose strokes, for the emergency room.
Although tPA was shown in 1996 to save lives and prevent brain damage, and although the drug could help half of all stroke patients, only 3 percent to 4 percent receive it. Most patients, denying or failing to appreciate their symptoms, wait too long to seek help — tPA must be given within three hours. And even when patients call 911 promptly, most hospitals, often uncertain about stroke diagnoses, do not provide the drug.
“I label this a national tragedy or a national embarrassment,” said Dr. Mark J. Alberts, a neurology professor at the Feinberg School of Medicine at Northwestern University. “I know of no disease that is as common or as serious as stroke and where you basically have one therapy and it’s only used in 3 to 4 percent of patients. That’s like saying you only treat 3 to 4 percent of patients with bacterial pneumonia with antibiotics.”
And the strokes in the statistics are only the beginning. For every stroke that doctors know about, there are 5 to 10 tiny, silent strokes, said Dr. Vladimir Hachinski, the editor of the journal Stroke and a neurologist at the London Health Sciences Centre in Ontario.
“They are only silent because we don’t ask questions,” Dr. Hachinski said. “They do not involve memory, but they involve judgment, planning ahead, shifting your attention from one thing to another. And they also may involve late-life depression.”
They are also warning signs that a much larger stroke may be on the way.
Most strokes would never happen if people took simple measures like controlling their blood pressure. Few do. Many say they forget to take medication; others, like Dr. Fite, decide not to. Some have no idea they need the drugs.
Still, there is much more hope now, said Dr. Ralph L. Sacco, professor and chairman of neurology at the Miller School of Medicine at the University of Miami. Like most stroke neurologists, Dr. Sacco entered the field more than a decade ago, when little could be done for such patients.
Now, Dr. Sacco said, there is a device, an M.R.I. scanner, that greatly improves diagnosis, there is a treatment that works and there are others being tested. “Medical systems have to catch up to the research,” he said.
In medicine, Dr. Sacco said, “stroke is a new frontier.”
Promise Unfulfilled
One Tuesday morning in March, Dr. Steven Warach, chief of the stroke program at the National Institute of Neurological Disorders and Stroke, met with a team from Washington Hospital Center, the largest private hospital in Washington, to review M.R.I. scans of recently admitted patients. They were joined in a teleconference by neurologists at Suburban Hospital in Bethesda, Md., the only other stroke center in the Washington and suburban Maryland area.
There was a 66-year-old woman with a stroke so big the scan actually showed degenerating fibers that carry nerve signals across the brain.
There was a 75-year-old who had trouble moving her right arm and right side in the recovery room after heart surgery. At first doctors thought she was just slow to wake up from the anesthesia. Now, though, it was clear she had suffered a stroke. She had lost the right half of her vision in both eyes and her right side was weak.
There was an 88-year-old who slumped forward at lunch, losing consciousness. When he came to, he had trouble forming words.
There was a middle-age man whose stroke was unforgettable. When Dr. Warach saw his initial M.R.I. scan, in his basement office at his home, he cried out in astonishment so loudly his wife ran downstairs. “I have never seen anything so severe,” Dr. Warach said. None of the three arteries that supplied the man’s right hemisphere were getting any blood.
Now the man lay in a coma, twitching on his left side, paralyzed on his right, breathing with the help of a ventilator. If he survived, he would have severe brain damage.
There was Michael Collins, a 49-year-old police officer who had had a stroke in his police car in Takoma Park, Md. Unlike the others, Mr. Collins seemed mostly recovered. The next few days, though, would determine whether he was among the lucky 10 percent of stroke patients who escape unscathed or whether he would always be weaker on his left side. If that happened, Mr. Collins said, he could never return to his job.
“You have to be able to shoot a gun with either hand,” he explained. But as time passed, Mr. Collins continued to be plagued by numbness in his left hand and on the left side of his face. He wanted to return to work — “I’m doing great,” he said this month — but the Police Department insisted that he retire, telling him, he said, “it’s an officer safety issue.”
The rest of the patients in the stroke units at the two hospitals that day were less fortunate: almost certain to live, but also almost certain to end up with brain damage. Some would have to spend time at a rehabilitation center.
On average, said Dr. Brendan E. Conroy, medical director of the stroke recovery program at the National Rehabilitation Hospital, which is attached to the Washington Hospital Center, a third of the Washington hospital’s stroke patients die, a third go home and a third come to him.
Those whose balance is affected typically spend 20 days learning to deal with a walker or a cane; those who are partly blind or paralyzed must learn to care for themselves. Many functions return, Dr. Conroy said, but rehabilitation also means learning to live with a disability.
But what was perhaps saddest to the neurologists viewing the M.R.I. scans that morning was that tPA, which only recently appeared to be a triumph of medicine, had made not a whit of difference to these patients. They either had not arrived at the hospital in time or had been considered otherwise medically unsuitable to receive it.
Few would have predicted that fate for the drug. In 1995, after 40 years of trying to find something to break up blood clots in the brain, the cause of most strokes, researchers announced that tPA worked. A large federal study showed that, without it, about one patient in five escaped serious injury. With it, one in three escaped.
The drug had a serious side effect — it could cause potentially life-threatening bleeding in the brain in about 6 percent of patients. But the clinical trial demonstrated that the drug’s benefits outweighed its risks.
When the study’s results were announced, Dr. James Grotta of the University of Texas Medical School at Houston expressed the researchers’ elation. “Until today, stroke was an untreatable disease,” Dr. Grotta said.
But the expected sea change did not occur.
One problem was that patients showed up too late. Many had no choice. Strokes often occur in the morning when people are sleeping. They awake with terrifying symptoms, paralyzed on one side or unable to speak.
“That’s the challenge — we have to ask the patient” when the stroke began, said Dr. A. Gregory Sorensen, a co-director of the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital. “If they don’t know or can’t talk, we’re out of luck.”
Another problem is deciding whether a patient is really having a stroke. A person who has trouble forming words could just be confused. Or what about someone whose arm or leg is weak?
“A lot of things can cause weakness,” Dr. Warach said. “A nerve injury can cause weakness; sometimes brain tumors can be suddenly symptomatic. Sometimes people have migraines that can completely mimic a stroke.”
In fact, he said, a quarter of emergency room patients with symptoms suggestive of a stroke are not actually having one.
Most get CT scans, which are useful mostly to rule out hemorrhagic strokes, the less common type that is caused by bleeding in the brain and should not be treated with tPA. Stroke specialists can usually then decide whether the patient is having a stroke caused by a blocked blood vessel and whether it can be treated with tPA.
But most stroke patients are handled by emergency room physicians who often say they are not sure of the diagnosis and therefore hesitate to give tPA.
Dr. Richard Burgess, a member of Dr. Warach’s stroke team, explained the situation: There is no particular penalty for not giving tPA. Doctors are unlikely to be sued if the patient dies or is left with brain damage that could have been avoided. But there is a penalty for giving tPA to someone who is not having a stroke. If that patient bleeds into the brain, the drug not only caused a tragic outcome but the doctor could also be sued. Few emergency room doctors want to take that chance.
Treatment Barriers
There is a way to diagnose strokes more accurately — with a diffusion M.R.I., a type of scan that shows water moving in the brain. During a stroke, the flow of water slows to a crawl as dead and dying cells swell. In one recent study, diffusion M.R.I. scans found five times as many strokes as CT scans, with twice the accuracy.
A diffusion M.R.I. “answers the question 95 percent of the time," Dr. Sorensen said.
It seemed the perfect solution, but it was not.
Most hospitals say they cannot provide such scans to stroke patients. They would need both an M.R.I. technician and an expert to interpret the scans around the clock. They would need an M.R.I. machine near the emergency room. Most hospitals have the huge machines elsewhere, steadily booked far in advance for other patients.
It is simply not practical to demand the scans at every hospital or even every stroke center, said Dr. Edward C. Jauch, an emergency medicine doctor at the University of Cincinnati and a member of the Greater Cincinnati/Northern Kentucky Stroke Team.
“If you made M.R.I. the standard of care before giving tPA, most centers would not be able to comply,” Dr. Jauch said. And if it takes more time to get a scan — as it often does — it might be better to forgo it and give tPA immediately if the patient’s symptoms seem unambiguous.
Doctors do not need an M.R.I. to diagnose and treat stroke, said Dr. Lee H. Schwamm, vice chairman of the department of neurology at Massachusetts General Hospital. But, Dr. Schwamm added, if the question is whether it helps, there is one reply: “By all means.”
It has still not been shown, though, that M.R.I. scans actually improve outcomes. It might depend on the circumstances and the hospital, said Dr. Walter J. Koroshetz, deputy director of the National Institute of Neurological Disorders and Stroke.
But some who use M.R.I. scans, and who have studied them in research, say the system has to change. They say enough is known about the scans to advocate having them at every major medical center that will treat stroke patients.
“All these problems could be solved if there was a will to do it,” Dr. Sorensen said. In his opinion, it comes down to old and outdated assumptions that there is not much to be done for a stroke, to financial considerations and to a medical system that resists change. But the most significant barriers, he said, are financial.
Another approach, stroke specialists say, is to direct all patients with stroke symptoms to designated stroke centers. There, stroke patients would be treated by experienced neurologists and admitted to stroke units for additional care. For the first time, in its newly published guidelines, the American Stroke Association recommended the routing of patients to stroke centers.
But even with such a system in place, many patients end up at hospitals that are not prepared to treat them, as Dr. Grotta discovered in Houston.
He thought he could change stroke care in Houston with the stroke center idea. The first step went well — the city’s ambulance services agreed to take all patients with stroke symptoms to designated stroke centers.
Then, Dr. David E. Persse, the city’s director of emergency medical services, asked every one of Houston’s 25 hospitals if it wanted to be a stroke center. While seven have said yes, others have declined.
Stroke patients, unlike heart attack patients, are not moneymakers. Because of the way medical care is reimbursed, most hospitals either lose money or do little more than break even with stroke care but can often make several thousand dollars opening the arteries of a heart attack patient. And being a stroke center means finding and paying stroke specialists to be available around the clock.
Soon another problem emerged. As many as a third of the patients refused to let the ambulance take them to a stroke center, demanding to go to their local hospital.
“By law in Texas, we cannot take that man to another hospital against his will,” Dr. Persse said. “We could be charged with assault and battery and kidnapping and unlawful imprisonment.”
The Joint Commission, which accredits hospitals, recently started certifying stroke centers, requiring that the hospitals be willing to treat stroke patients aggressively. But only 322 of the 4,280 accredited hospitals in the nation qualify, and most patients and doctors have no idea whether a hospital nearby is among them. (The list is available on the site http://www.jointcommission.org/CertificationPrograms/Disease-SpecificCare/DSCOrgs/ under “primary stroke centers.”) Some states, like New York, Massachusetts and Florida, do their own certifying of stroke centers.
Nonetheless, most ambulances do not consider stroke center designations when they transport patients. And, said John Becknell, a spokesman for the National Association of Emergency Medical Technicians, national programs can be difficult because every community has its own rules for which ambulances pick up patients and where they take them.
As a result, most stroke patients have no access to the recommended care and even fewer get M.R.I.’s, a situation Dr. Warach said he found appalling.
“How can it ever be in the patient’s best interest to have an inferior diagnosis?” he asked. “It borders on malpractice that given a choice between two noninvasive tests, one of which is clearly superior, the worse test is the one that is preferred.”
Averting Catastrophe
In those awful moments when she realized she had had a stroke, Dr. Fite, unlike most patients, knew what to do. She told the ambulance crew to take her to Memorial Hermann Hospital, even though it was about an hour away. She knew that it was one of the Houston stroke centers, that Dr. Grotta worked there, and that its doctors had experience diagnosing strokes and giving tPA.
When she arrived, Dr. Grotta asked if she was sure she wanted the drug. Did she want to risk bleeding in the brain? Dr. Fite did not hesitate. The stroke, she said, “was just so devastating that I would rather die of a hemorrhage in the brain than be left completely paralyzed in my right side.”
“In my horrible voice, I said, ‘Yes, I want the tPA,’ ” Dr. Fite said.
Within 10 to 15 minutes, the drug started to dissolve the clot.
“I had weird spasms as nerves started to work again,” Dr. Fite said. “An arm would draw up real quick, a leg would tighten up. It hurt so bad I was crying because of the pain. But it was movement, and I knew something was going on.”
Now, she looks back with dismay on her cavalier attitude toward high blood pressure. She knew very well how to prevent a stroke but, like many patients and despite her medical training, she found it all too easy to deny her own risk.
Researchers have known for years the conditions that predispose a person to stroke — smoking, diabetes, high cholesterol and an irregular heartbeat known as atrial fibrillation. But the major one is high blood pressure.
“Of all the modifiable risk factors, high blood pressure leads the list,” Dr. Sacco said. “With heart disease, you think more of cholesterol; with stroke you think of high blood pressure.”
The reason, Dr. Sacco said, is that with high blood pressure, the tiny blood vessels in the brain clamp down so much and so hard to protect the brain that they can become rigid. Then they get blocked. The result is a stroke.
Often, people decide they do not need their blood pressure medication or simply forget to take it because they feel well. But, Dr. Sacco said, patients are not solely to blame. Doctors may not have time to work with patients, monitoring blood pressure, telling them about changes in their diet and exercise that might help, or trying different drugs and combining them if necessary.
And it is not so simple for people to keep track of their blood pressure. Machines in drugstores and supermarkets are not always accurate. Doctors may require appointments to check blood pressure.
Even when people do try to control their pressure, doctors may not prescribe enough drugs or high enough doses.
“They’re on a couple of drugs, and the doctor doesn’t want to push it,” said Dr. Jeffrey A. Cutler, a consultant to the National Heart, Lung and Blood Institute and a retired director of its clinical applications and prevention program.
The result is that no more than half the people with high blood pressure have it under control, Dr. Cutler said. He estimated that half of all strokes could be prevented if people kept their blood pressure within the recommended range.
Another lost opportunity to prevent strokes is the undertreatment of atrial fibrillation, in which the two upper chambers of the heart quiver. Blood can pool in the heart and clot, and those clots can be swept into the brain, lodge in a small blood vessel and cause a stroke.
Strokes from atrial fibrillation can largely be prevented with anticlotting drugs like warfarin. Yet many who have the condition do not know it and many who know they have it were never given or do not take an anticlotting drug.
Some strokes can also be prevented by procedures to open obstructed arteries in the neck that supply blood to the brain.
As for Dr. Fite, she completely recovered. And she has changed her ways.
She was sobered by the cost of her treatment and brief hospital stay — $96,000, most of which was paid by her insurance company. But she was even more sobered by how close she came to catastrophe.
Now, Dr. Fite takes three blood pressure pills, a drug to prevent blood clots and a cholesterol-lowering drug. She plans to take those drugs every day for the rest of her life.
“I was so stupid,” she said. “Boy, when you go through this, you never want to go through it again.”
“I have been given that precious second chance,” she said. “I was so blessed.”
Then, at 9:30 the morning of June 7, Dr. Fite was driving, steering with her right hand, holding her cellphone in her left, when, for a split second, the right side of her body felt weak. “I said: ‘This is silly, it’s my imagination. I’ve been working too hard.’ ”
Suddenly, her car began to swerve.
“I realized I had no strength whatsoever in my right hand that was holding the wheel,” Dr. Fite said. “And my right foot was dead. I could not get it off the gas pedal.”
She dropped the cellphone, grabbed the steering wheel with her left hand, and steered the car into a parking lot. Then she used her left foot to pry her right foot off the accelerator. She pulled down the visor to look in the mirror. The right side of her face was paralyzed.
With great difficulty, Dr. Fite twisted her body and grasped her cellphone.
“I called 911, but nothing would come out of my mouth,” she said. Then she found that if she spoke very slowly, she could get out words. So, she recalled, “I said ‘stroke’ in this long, horrible voice.”
Dr. Fite is one of an estimated 700,000 Americans who had a stroke last year, but one of the very few who ended up at a hospital with the equipment and expertise to accurately diagnose and treat it.
Stroke is the third-leading cause of death in this country, behind heart disease and cancer, killing 150,000 Americans a year, leaving many more permanently disabled, and costing the nation $62.7 billion in direct and indirect costs, according to the American Stroke Association.
But from diagnosis to treatment to rehabilitation to preventing it altogether, a stroke is a litany of missed opportunities.
Many patients with stroke symptoms are examined by emergency room doctors who are uncomfortable deciding whether the patient is really having a stroke — a blockage or rupture of a blood vessel in the brain that injures or kills brain cells — or is suffering from another condition. Doctors are therefore reluctant to give the only drug shown to make a real difference, tPA, or tissue plasminogen activator.
Many hospitals say they cannot afford to have neurologists on call to diagnose strokes, and cannot afford to have M.R.I. scanners, the most accurate way to diagnose strokes, for the emergency room.
Although tPA was shown in 1996 to save lives and prevent brain damage, and although the drug could help half of all stroke patients, only 3 percent to 4 percent receive it. Most patients, denying or failing to appreciate their symptoms, wait too long to seek help — tPA must be given within three hours. And even when patients call 911 promptly, most hospitals, often uncertain about stroke diagnoses, do not provide the drug.
“I label this a national tragedy or a national embarrassment,” said Dr. Mark J. Alberts, a neurology professor at the Feinberg School of Medicine at Northwestern University. “I know of no disease that is as common or as serious as stroke and where you basically have one therapy and it’s only used in 3 to 4 percent of patients. That’s like saying you only treat 3 to 4 percent of patients with bacterial pneumonia with antibiotics.”
And the strokes in the statistics are only the beginning. For every stroke that doctors know about, there are 5 to 10 tiny, silent strokes, said Dr. Vladimir Hachinski, the editor of the journal Stroke and a neurologist at the London Health Sciences Centre in Ontario.
“They are only silent because we don’t ask questions,” Dr. Hachinski said. “They do not involve memory, but they involve judgment, planning ahead, shifting your attention from one thing to another. And they also may involve late-life depression.”
They are also warning signs that a much larger stroke may be on the way.
Most strokes would never happen if people took simple measures like controlling their blood pressure. Few do. Many say they forget to take medication; others, like Dr. Fite, decide not to. Some have no idea they need the drugs.
Still, there is much more hope now, said Dr. Ralph L. Sacco, professor and chairman of neurology at the Miller School of Medicine at the University of Miami. Like most stroke neurologists, Dr. Sacco entered the field more than a decade ago, when little could be done for such patients.
Now, Dr. Sacco said, there is a device, an M.R.I. scanner, that greatly improves diagnosis, there is a treatment that works and there are others being tested. “Medical systems have to catch up to the research,” he said.
In medicine, Dr. Sacco said, “stroke is a new frontier.”
Promise Unfulfilled
One Tuesday morning in March, Dr. Steven Warach, chief of the stroke program at the National Institute of Neurological Disorders and Stroke, met with a team from Washington Hospital Center, the largest private hospital in Washington, to review M.R.I. scans of recently admitted patients. They were joined in a teleconference by neurologists at Suburban Hospital in Bethesda, Md., the only other stroke center in the Washington and suburban Maryland area.
There was a 66-year-old woman with a stroke so big the scan actually showed degenerating fibers that carry nerve signals across the brain.
There was a 75-year-old who had trouble moving her right arm and right side in the recovery room after heart surgery. At first doctors thought she was just slow to wake up from the anesthesia. Now, though, it was clear she had suffered a stroke. She had lost the right half of her vision in both eyes and her right side was weak.
There was an 88-year-old who slumped forward at lunch, losing consciousness. When he came to, he had trouble forming words.
There was a middle-age man whose stroke was unforgettable. When Dr. Warach saw his initial M.R.I. scan, in his basement office at his home, he cried out in astonishment so loudly his wife ran downstairs. “I have never seen anything so severe,” Dr. Warach said. None of the three arteries that supplied the man’s right hemisphere were getting any blood.
Now the man lay in a coma, twitching on his left side, paralyzed on his right, breathing with the help of a ventilator. If he survived, he would have severe brain damage.
There was Michael Collins, a 49-year-old police officer who had had a stroke in his police car in Takoma Park, Md. Unlike the others, Mr. Collins seemed mostly recovered. The next few days, though, would determine whether he was among the lucky 10 percent of stroke patients who escape unscathed or whether he would always be weaker on his left side. If that happened, Mr. Collins said, he could never return to his job.
“You have to be able to shoot a gun with either hand,” he explained. But as time passed, Mr. Collins continued to be plagued by numbness in his left hand and on the left side of his face. He wanted to return to work — “I’m doing great,” he said this month — but the Police Department insisted that he retire, telling him, he said, “it’s an officer safety issue.”
The rest of the patients in the stroke units at the two hospitals that day were less fortunate: almost certain to live, but also almost certain to end up with brain damage. Some would have to spend time at a rehabilitation center.
On average, said Dr. Brendan E. Conroy, medical director of the stroke recovery program at the National Rehabilitation Hospital, which is attached to the Washington Hospital Center, a third of the Washington hospital’s stroke patients die, a third go home and a third come to him.
Those whose balance is affected typically spend 20 days learning to deal with a walker or a cane; those who are partly blind or paralyzed must learn to care for themselves. Many functions return, Dr. Conroy said, but rehabilitation also means learning to live with a disability.
But what was perhaps saddest to the neurologists viewing the M.R.I. scans that morning was that tPA, which only recently appeared to be a triumph of medicine, had made not a whit of difference to these patients. They either had not arrived at the hospital in time or had been considered otherwise medically unsuitable to receive it.
Few would have predicted that fate for the drug. In 1995, after 40 years of trying to find something to break up blood clots in the brain, the cause of most strokes, researchers announced that tPA worked. A large federal study showed that, without it, about one patient in five escaped serious injury. With it, one in three escaped.
The drug had a serious side effect — it could cause potentially life-threatening bleeding in the brain in about 6 percent of patients. But the clinical trial demonstrated that the drug’s benefits outweighed its risks.
When the study’s results were announced, Dr. James Grotta of the University of Texas Medical School at Houston expressed the researchers’ elation. “Until today, stroke was an untreatable disease,” Dr. Grotta said.
But the expected sea change did not occur.
One problem was that patients showed up too late. Many had no choice. Strokes often occur in the morning when people are sleeping. They awake with terrifying symptoms, paralyzed on one side or unable to speak.
“That’s the challenge — we have to ask the patient” when the stroke began, said Dr. A. Gregory Sorensen, a co-director of the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital. “If they don’t know or can’t talk, we’re out of luck.”
Another problem is deciding whether a patient is really having a stroke. A person who has trouble forming words could just be confused. Or what about someone whose arm or leg is weak?
“A lot of things can cause weakness,” Dr. Warach said. “A nerve injury can cause weakness; sometimes brain tumors can be suddenly symptomatic. Sometimes people have migraines that can completely mimic a stroke.”
In fact, he said, a quarter of emergency room patients with symptoms suggestive of a stroke are not actually having one.
Most get CT scans, which are useful mostly to rule out hemorrhagic strokes, the less common type that is caused by bleeding in the brain and should not be treated with tPA. Stroke specialists can usually then decide whether the patient is having a stroke caused by a blocked blood vessel and whether it can be treated with tPA.
But most stroke patients are handled by emergency room physicians who often say they are not sure of the diagnosis and therefore hesitate to give tPA.
Dr. Richard Burgess, a member of Dr. Warach’s stroke team, explained the situation: There is no particular penalty for not giving tPA. Doctors are unlikely to be sued if the patient dies or is left with brain damage that could have been avoided. But there is a penalty for giving tPA to someone who is not having a stroke. If that patient bleeds into the brain, the drug not only caused a tragic outcome but the doctor could also be sued. Few emergency room doctors want to take that chance.
Treatment Barriers
There is a way to diagnose strokes more accurately — with a diffusion M.R.I., a type of scan that shows water moving in the brain. During a stroke, the flow of water slows to a crawl as dead and dying cells swell. In one recent study, diffusion M.R.I. scans found five times as many strokes as CT scans, with twice the accuracy.
A diffusion M.R.I. “answers the question 95 percent of the time," Dr. Sorensen said.
It seemed the perfect solution, but it was not.
Most hospitals say they cannot provide such scans to stroke patients. They would need both an M.R.I. technician and an expert to interpret the scans around the clock. They would need an M.R.I. machine near the emergency room. Most hospitals have the huge machines elsewhere, steadily booked far in advance for other patients.
It is simply not practical to demand the scans at every hospital or even every stroke center, said Dr. Edward C. Jauch, an emergency medicine doctor at the University of Cincinnati and a member of the Greater Cincinnati/Northern Kentucky Stroke Team.
“If you made M.R.I. the standard of care before giving tPA, most centers would not be able to comply,” Dr. Jauch said. And if it takes more time to get a scan — as it often does — it might be better to forgo it and give tPA immediately if the patient’s symptoms seem unambiguous.
Doctors do not need an M.R.I. to diagnose and treat stroke, said Dr. Lee H. Schwamm, vice chairman of the department of neurology at Massachusetts General Hospital. But, Dr. Schwamm added, if the question is whether it helps, there is one reply: “By all means.”
It has still not been shown, though, that M.R.I. scans actually improve outcomes. It might depend on the circumstances and the hospital, said Dr. Walter J. Koroshetz, deputy director of the National Institute of Neurological Disorders and Stroke.
But some who use M.R.I. scans, and who have studied them in research, say the system has to change. They say enough is known about the scans to advocate having them at every major medical center that will treat stroke patients.
“All these problems could be solved if there was a will to do it,” Dr. Sorensen said. In his opinion, it comes down to old and outdated assumptions that there is not much to be done for a stroke, to financial considerations and to a medical system that resists change. But the most significant barriers, he said, are financial.
Another approach, stroke specialists say, is to direct all patients with stroke symptoms to designated stroke centers. There, stroke patients would be treated by experienced neurologists and admitted to stroke units for additional care. For the first time, in its newly published guidelines, the American Stroke Association recommended the routing of patients to stroke centers.
But even with such a system in place, many patients end up at hospitals that are not prepared to treat them, as Dr. Grotta discovered in Houston.
He thought he could change stroke care in Houston with the stroke center idea. The first step went well — the city’s ambulance services agreed to take all patients with stroke symptoms to designated stroke centers.
Then, Dr. David E. Persse, the city’s director of emergency medical services, asked every one of Houston’s 25 hospitals if it wanted to be a stroke center. While seven have said yes, others have declined.
Stroke patients, unlike heart attack patients, are not moneymakers. Because of the way medical care is reimbursed, most hospitals either lose money or do little more than break even with stroke care but can often make several thousand dollars opening the arteries of a heart attack patient. And being a stroke center means finding and paying stroke specialists to be available around the clock.
Soon another problem emerged. As many as a third of the patients refused to let the ambulance take them to a stroke center, demanding to go to their local hospital.
“By law in Texas, we cannot take that man to another hospital against his will,” Dr. Persse said. “We could be charged with assault and battery and kidnapping and unlawful imprisonment.”
The Joint Commission, which accredits hospitals, recently started certifying stroke centers, requiring that the hospitals be willing to treat stroke patients aggressively. But only 322 of the 4,280 accredited hospitals in the nation qualify, and most patients and doctors have no idea whether a hospital nearby is among them. (The list is available on the site http://www.jointcommission.org/CertificationPrograms/Disease-SpecificCare/DSCOrgs/ under “primary stroke centers.”) Some states, like New York, Massachusetts and Florida, do their own certifying of stroke centers.
Nonetheless, most ambulances do not consider stroke center designations when they transport patients. And, said John Becknell, a spokesman for the National Association of Emergency Medical Technicians, national programs can be difficult because every community has its own rules for which ambulances pick up patients and where they take them.
As a result, most stroke patients have no access to the recommended care and even fewer get M.R.I.’s, a situation Dr. Warach said he found appalling.
“How can it ever be in the patient’s best interest to have an inferior diagnosis?” he asked. “It borders on malpractice that given a choice between two noninvasive tests, one of which is clearly superior, the worse test is the one that is preferred.”
Averting Catastrophe
In those awful moments when she realized she had had a stroke, Dr. Fite, unlike most patients, knew what to do. She told the ambulance crew to take her to Memorial Hermann Hospital, even though it was about an hour away. She knew that it was one of the Houston stroke centers, that Dr. Grotta worked there, and that its doctors had experience diagnosing strokes and giving tPA.
When she arrived, Dr. Grotta asked if she was sure she wanted the drug. Did she want to risk bleeding in the brain? Dr. Fite did not hesitate. The stroke, she said, “was just so devastating that I would rather die of a hemorrhage in the brain than be left completely paralyzed in my right side.”
“In my horrible voice, I said, ‘Yes, I want the tPA,’ ” Dr. Fite said.
Within 10 to 15 minutes, the drug started to dissolve the clot.
“I had weird spasms as nerves started to work again,” Dr. Fite said. “An arm would draw up real quick, a leg would tighten up. It hurt so bad I was crying because of the pain. But it was movement, and I knew something was going on.”
Now, she looks back with dismay on her cavalier attitude toward high blood pressure. She knew very well how to prevent a stroke but, like many patients and despite her medical training, she found it all too easy to deny her own risk.
Researchers have known for years the conditions that predispose a person to stroke — smoking, diabetes, high cholesterol and an irregular heartbeat known as atrial fibrillation. But the major one is high blood pressure.
“Of all the modifiable risk factors, high blood pressure leads the list,” Dr. Sacco said. “With heart disease, you think more of cholesterol; with stroke you think of high blood pressure.”
The reason, Dr. Sacco said, is that with high blood pressure, the tiny blood vessels in the brain clamp down so much and so hard to protect the brain that they can become rigid. Then they get blocked. The result is a stroke.
Often, people decide they do not need their blood pressure medication or simply forget to take it because they feel well. But, Dr. Sacco said, patients are not solely to blame. Doctors may not have time to work with patients, monitoring blood pressure, telling them about changes in their diet and exercise that might help, or trying different drugs and combining them if necessary.
And it is not so simple for people to keep track of their blood pressure. Machines in drugstores and supermarkets are not always accurate. Doctors may require appointments to check blood pressure.
Even when people do try to control their pressure, doctors may not prescribe enough drugs or high enough doses.
“They’re on a couple of drugs, and the doctor doesn’t want to push it,” said Dr. Jeffrey A. Cutler, a consultant to the National Heart, Lung and Blood Institute and a retired director of its clinical applications and prevention program.
The result is that no more than half the people with high blood pressure have it under control, Dr. Cutler said. He estimated that half of all strokes could be prevented if people kept their blood pressure within the recommended range.
Another lost opportunity to prevent strokes is the undertreatment of atrial fibrillation, in which the two upper chambers of the heart quiver. Blood can pool in the heart and clot, and those clots can be swept into the brain, lodge in a small blood vessel and cause a stroke.
Strokes from atrial fibrillation can largely be prevented with anticlotting drugs like warfarin. Yet many who have the condition do not know it and many who know they have it were never given or do not take an anticlotting drug.
Some strokes can also be prevented by procedures to open obstructed arteries in the neck that supply blood to the brain.
As for Dr. Fite, she completely recovered. And she has changed her ways.
She was sobered by the cost of her treatment and brief hospital stay — $96,000, most of which was paid by her insurance company. But she was even more sobered by how close she came to catastrophe.
Now, Dr. Fite takes three blood pressure pills, a drug to prevent blood clots and a cholesterol-lowering drug. She plans to take those drugs every day for the rest of her life.
“I was so stupid,” she said. “Boy, when you go through this, you never want to go through it again.”
“I have been given that precious second chance,” she said. “I was so blessed.”
Breast cancer: Four more genes linked to "silent killer"
Scientists on Sunday announced they had uncovered four more genes that play a role in breast cancer, widening the portrait of one of the stealthiest slayers of women.
Until now, only about 25 percent of the genes that are suspected to cause inherited breast cancer have been identified.
The new culprits -- flawed versions of genes called FGFR2, TNRC9, MAP3K1 and LSP1 -- are believed to account for an additional four percent.
British-led researchers found them after sifting through through the DNA of nearly 50,000 women, half of them healthy and half of them patients with breast cancer.
Telltale "tags" of DNA code among the breast cancer group highlighted the four genes.
Their study is published by Nature, the British science journal.
Genetic causes account for between five and 10 percent of breast cancer cases, with "lifestyle factors" such as smoking and environmental factors accounting for the rest.
Flawed versions of the four genes are common in the general population, the paper said.
The good news, though, is that the genes are considered a relatively low hazard, meaning that women who have them run a comparatively small risk of developing cancer.
By contrast, the notorious breast cancer genes BRCA1 and BRCA2 are relatively rare in the population but women who have them run a high risk of the disease.
Diagnostic tests for BRCA1 and BRCA2 are helping to save many lives, as they alert women at risk to have regular breast scans.
Because the four newly-identified genes are so common yet relatively low-risk, individual tests for them may be unsuitable, Cancer Research UK, whose scientists led the massive investigation, said in a press release.
However, "as more of these 'low-risk' genes are found it may be possible to design tests for a combination of genes," it said. "This could help doctors make decisions about prevention, diagnosis and treatment for women who inherit faults in one or more of these genes."
Much remains to be learnt about the four genes, especially whether they react with each other or with lifestyle factors in a way that boosts the risk for some women, it added.
Breast cancer is the commonest cancer to strike women, the World Health Organisation said in February 2006.
In 2005, breast cancer caused 502,000 deaths, accounting for seven percent of all cancer mortalities and almost one percent of all deaths worldwide.
Until now, only about 25 percent of the genes that are suspected to cause inherited breast cancer have been identified.
The new culprits -- flawed versions of genes called FGFR2, TNRC9, MAP3K1 and LSP1 -- are believed to account for an additional four percent.
British-led researchers found them after sifting through through the DNA of nearly 50,000 women, half of them healthy and half of them patients with breast cancer.
Telltale "tags" of DNA code among the breast cancer group highlighted the four genes.
Their study is published by Nature, the British science journal.
Genetic causes account for between five and 10 percent of breast cancer cases, with "lifestyle factors" such as smoking and environmental factors accounting for the rest.
Flawed versions of the four genes are common in the general population, the paper said.
The good news, though, is that the genes are considered a relatively low hazard, meaning that women who have them run a comparatively small risk of developing cancer.
By contrast, the notorious breast cancer genes BRCA1 and BRCA2 are relatively rare in the population but women who have them run a high risk of the disease.
Diagnostic tests for BRCA1 and BRCA2 are helping to save many lives, as they alert women at risk to have regular breast scans.
Because the four newly-identified genes are so common yet relatively low-risk, individual tests for them may be unsuitable, Cancer Research UK, whose scientists led the massive investigation, said in a press release.
However, "as more of these 'low-risk' genes are found it may be possible to design tests for a combination of genes," it said. "This could help doctors make decisions about prevention, diagnosis and treatment for women who inherit faults in one or more of these genes."
Much remains to be learnt about the four genes, especially whether they react with each other or with lifestyle factors in a way that boosts the risk for some women, it added.
Breast cancer is the commonest cancer to strike women, the World Health Organisation said in February 2006.
In 2005, breast cancer caused 502,000 deaths, accounting for seven percent of all cancer mortalities and almost one percent of all deaths worldwide.
Sunday, May 27, 2007
Wikis, blogs and podcasts: a new generation of Web-based tools for virtual collaborative clinical practice and education
We have witnessed a rapid increase in the use of Web-based 'collaborationware' in recent years. These Web 2.0 applications, particularly wikis, blogs and podcasts, have been increasingly adopted by many online health-related professional and educational services. Because of their ease of use and rapidity of deployment, they offer the opportunity for powerful information sharing and ease of collaboration. Wikis are Web sites that can be edited by anyone who has access to them. The word 'blog' is a contraction of 'Web Log' – an online Web journal that can offer a resource rich multimedia environment. Podcasts are repositories of audio and video materials that can be "pushed" to subscribers, even without user intervention. These audio and video files can be downloaded to portable media players that can be taken anywhere, providing the potential for "anytime, anywhere" learning experiences (mobile learning).
Wikis, blogs and podcasts are all relatively easy to use, which partly accounts for their proliferation. The fact that there are many free and Open Source versions of these tools may also be responsible for their explosive growth. Thus it would be relatively easy to implement any or all within a Health Professions' Educational Environment. Paradoxically, some of their disadvantages also relate to their openness and ease of use. With virtually anybody able to alter, edit or otherwise contribute to the collaborative Web pages, it can be problematic to gauge the reliability and accuracy of such resources. While arguably, the very process of collaboration leads to a Darwinian type 'survival of the fittest' content within a Web page, the veracity of these resources can be assured through careful monitoring, moderation, and operation of the collaborationware in a closed and secure digital environment. Empirical research is still needed to build our pedagogic evidence base about the different aspects of these tools in the context of medical/health education.
If effectively deployed, wikis, blogs and podcasts could offer a way to enhance students', clinicians' and patients' learning experiences, and deepen levels of learners' engagement and collaboration within digital learning environments. Therefore, research should be conducted to determine the best ways to integrate these tools into existing e-Learning programmes for students, health professionals and patients, taking into account the different, but also overlapping, needs of these three audience classes and the opportunities of virtual collaboration between them. Of particular importance is research into novel integrative applications, to serve as the "glue" to bind the different forms of Web-based collaborationware synergistically in order to provide a coherent wholesome learning experience.
SEE LINK BELOW
http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16911779
Wikis, blogs and podcasts are all relatively easy to use, which partly accounts for their proliferation. The fact that there are many free and Open Source versions of these tools may also be responsible for their explosive growth. Thus it would be relatively easy to implement any or all within a Health Professions' Educational Environment. Paradoxically, some of their disadvantages also relate to their openness and ease of use. With virtually anybody able to alter, edit or otherwise contribute to the collaborative Web pages, it can be problematic to gauge the reliability and accuracy of such resources. While arguably, the very process of collaboration leads to a Darwinian type 'survival of the fittest' content within a Web page, the veracity of these resources can be assured through careful monitoring, moderation, and operation of the collaborationware in a closed and secure digital environment. Empirical research is still needed to build our pedagogic evidence base about the different aspects of these tools in the context of medical/health education.
If effectively deployed, wikis, blogs and podcasts could offer a way to enhance students', clinicians' and patients' learning experiences, and deepen levels of learners' engagement and collaboration within digital learning environments. Therefore, research should be conducted to determine the best ways to integrate these tools into existing e-Learning programmes for students, health professionals and patients, taking into account the different, but also overlapping, needs of these three audience classes and the opportunities of virtual collaboration between them. Of particular importance is research into novel integrative applications, to serve as the "glue" to bind the different forms of Web-based collaborationware synergistically in order to provide a coherent wholesome learning experience.
SEE LINK BELOW
http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16911779
List of Medical Wikis
David Rothman has assembled a comprehensive list of medical wikis which seems to be growing longer every day. He will need to reorder them in categories soon.If you click through the entries on the list, you will notice that many wikis are still in early stage with just a few entries. Many of them will not make it and will eventually fade into oblivion. It is a normal process similar to natural selection. The most popular wikis (with most contributors/readers) will survive.We have discussed several times with the founders of AskDrWiki that the main challenge for a wiki manager is getting people to contribute. Doctors are busy and few of them have time (and desire) to create quality content for free.
SEE LINK BELOW
http://davidrothman.net/list-of-medical-wikis/
SEE LINK BELOW
http://davidrothman.net/list-of-medical-wikis/
AskDrWiki -- A Collaborative Medical Encyclopedia
AskDrWiki.com is a medical encyclopedia based on a wiki platform. The authors were one of the first to use YouTube to upload medical videos. Dean Giustini and I discussed this fact a few weeks ago, and he wrote about it in his landmark BMJ editorial How Web 2.0 is changing medicine, linking to AskDrWiki.com.
Ganfyd is another medical Wiki community, created in November 2005 by a group of doctors working in the UK. It is intended to become a large on-line textbook of medicine (source: Wikipedia).Graham shares his concerns about medical wikis in his post "I Will Never Trust Dr. Wiki… because I will never trust malicious teenagers."
SEE LINK BELOW
http://www.askdrwiki.com/mediawiki/index.php?title=Main_Page
Ganfyd is another medical Wiki community, created in November 2005 by a group of doctors working in the UK. It is intended to become a large on-line textbook of medicine (source: Wikipedia).Graham shares his concerns about medical wikis in his post "I Will Never Trust Dr. Wiki… because I will never trust malicious teenagers."
SEE LINK BELOW
http://www.askdrwiki.com/mediawiki/index.php?title=Main_Page
The Web 2.0 DEFINITION
Web 2.0, a phrase coined by O'Reilly Media in 2003 [1] and popularized by the first Web 2.0 conference in 2004,[1] refers to a perceived second-generation of Web based communities and hosted services such as social networking sites, wikis and folksonomies that facilitate collaboration and sharing between users. O'Reilly Media titled a series of conferences around the phrase, and it has since become widely adopted.
Though the term suggests a new version of the Web, it does not refer to an update to World Wide Web technical specifications, but to changes in the ways systems developers have used the web platform. According to Tim O'Reilly, "Web 2.0 is the business revolution in the computer industry caused by the move to the internet as platform, and an attempt to understand the rules for success on that new platform." [2]
Some technology experts, notably Tim Berners-Lee, have questioned whether one can use the term in a meaningful way, since many of the technology components of "Web 2.0" have existed since the beginnings of the World Wide Web.[3]
SEE EXEMPLE BELOW
http://www.youtube.com/watch?v=X4n90pO-kRk
Though the term suggests a new version of the Web, it does not refer to an update to World Wide Web technical specifications, but to changes in the ways systems developers have used the web platform. According to Tim O'Reilly, "Web 2.0 is the business revolution in the computer industry caused by the move to the internet as platform, and an attempt to understand the rules for success on that new platform." [2]
Some technology experts, notably Tim Berners-Lee, have questioned whether one can use the term in a meaningful way, since many of the technology components of "Web 2.0" have existed since the beginnings of the World Wide Web.[3]
SEE EXEMPLE BELOW
http://www.youtube.com/watch?v=X4n90pO-kRk
Saturday, May 26, 2007
At the Center of Rosiglitazone Storm, Steven Nissen, M.D., Focuses on Safety
CLEVELAND, May 25 -- Here, there, and everywhere this week, it was hard to miss Steven E. Nissen, M.D., the Cleveland Clinic cardiologist who revealed heart risks associated with still another prescription drug.His latest target was rosiglitazone (Avandia), and earlier he set his sights on muraglitazar (Pargluva), a once promising diabetes drug that Dr. Nissen help derail when it was a hair away from FDA approval, and rofecoxib (Vioxx) the Cox-2 inhibitor that was eventually withdrawn from the market.
As director of cardiovascular medicine at the Cleveland Clinic, which is rated as the top heart center in the U.S. by U.S. News and World Report, Dr. Nissen is no stranger to a camera and a microphone. He, personally, is number 72 on Time magazine's list of the 100 most influential people in our world.
But the dustup created this week by his meta-analysis of published data from 42 randomized controlled trials of rosiglitazone has placed him squarely in the glare of critics who charge that Dr. Nissen is an anti-pharmaceutical crusader.
The analysis found a 43% increase in the relative risk of myocardial infarction among diabetics randomized to rosiglitazone (P=0.03). There was also an increase in the number of cardiovascular deaths in the rosiglitazone group, but that didn't reach statistical significance (P=0.06).
Nothing, Dr. Nissen said, could be farther from the truth. "I'm actually a great believer in the value of drugs," he said. "I've devoted most of my life to studying the biology of cardiovascular drugs in an attempt to find new, effective agents."
But at the same time, he has been a leading critic of the Prescription Drug User Fee Act (PDUFA), that allows the FDA to charge drug companies user fees that the agency then uses to pay for its research into drug safety.
Congress is slated to re-authorize PDUFA this year and Dr. Nissen is one of a number of physician-researchers who have been pressing the Democratic majority to re-work the legislation to allow for tougher post-marketing surveillance of new drugs.
To that end, the rosiglitazone study is likely to be cited as a textbook example of the need for more and better FDA safety studies, a point that was not missed by Rep. Henry Waxman (D-Calif.) who announced that he would hold hearings into the FDA handling of rosiglitazone on June 6.
Dr. Nissen, 58, the son of doctor, once entertained thoughts of a career in journalism.
A glimpse into his background explains a lot. As an undergraduate during the turbulent 1960s at the University of Michigan, he was "on the eight-year plan," a long road to graduation, with a minor in the antiwar movement.
"A political leader, really," he described himself, "and I was also editor of the daily paper -- a very good college paper."
His years as a campus activist left him with an entrenched commitment to righting wrongs and a willingness to challenge the status quo, attributes that he has integrated into his medical career. And he never forgot the power of the press.
In 2001 he was the first physician to link rofecoxib to an increased risk of heart attacks and strokes. When the Journal of the American Medical Association published his study detailing those risks, he was roundly criticized by Merck, the maker of Vioxx, and a number of physicians who praised the drug.
Three years later Merck pulled Vioxx from the market when additional studies confirmed that daily, long-term use of the drug could increase the risk of heart attacks and strokes.
In October 2005, Dr. Nissen again blew his whistle. This time the drug was muraglitazar (Pargluva), a drug in the same class as rosiglitazone.
When the FDA published clinical trial data about the drug, Dr. Nissen immediately spotted something amiss. All the "cardiovascular markers were going in the wrong direction. There were increases in heart attacks, stroke, and cardiovascular death."
One look told him that an FDA advisory panel charged with reviewing the same documents would not approve the drug. But he was surprised when the panel, which met in September 2005, recommended by an 8-1 vote that the FDA give it a thumbs-up.
Dr. Nissen said he dropped everything and began an in-depth analysis of the Pargluva data.
Working nonstop with a Cleveland Clinic statistician and with co-author Eric Topol, M.D., who was then the chairman of the department of cardiovascular medicine, Dr. Nissen finished his analysis in record time.
JAMA published the muraglitazar analysis online on Oct. 20, just two days after the FDA had sent the drug's makers an "approvable letter" that said muraglitazar could be approved if the company supplied more cardiovascular safety data.
On Oct. 27, Bristol-Myers Squibb announced that it would terminate its muraglitazar development agreement with Merck. The drug was dead.
Asked about the stunning reversal of fortune for muraglitazar, Dr. Nissen said, "I'm not a crusader, I just want the balance between safety and efficacy to be favorable."
Dr. Nissen, who was elected president of American College of Cardiology in 2006, was born in Toledo, Ohio, where his father was a general practitioner. He recalls reciting the clinical names for all the bones in the body, a skill his father taught him when he was just three or four. He would regularly be called upon to show off for his father's colleagues.
When Dr. Nissen was a child, his father moved the family to Baltimore so that the elder Nissen, at age 40, could shift specialties to become an obstetrician-gynecologist. Later, the Nissens moved to Fullerton, Calif.,, where Dr. Nissen's father developed a successful private practice.
After medical school at Michigan, the younger Dr. Nissen went to the University of California at Davis for a residency. There he met his mentor, Anthony DiMaria, M.D., then a rising star in the world of heart disease research. When Dr. DiMaria was asked to head up a struggling cardiovascular disease research program at the University of Kentucky in Lexington, he asked Dr. Nissen to come along to be the first cardiology fellow.
During his time in Lexington, Dr. Nissen was approached by a company that was trying to develop an "ultrasound transducer that would fit inside a coronary artery," Dr. Nissen recalled. At the time the "smallest ultrasound transducer was the size of a fist," he said.
But Dr. Nissen quickly realized that an imaging technique that could look at the arteries from the inside out could provide critical information about the real nature of atherosclerosis.
By spring 1990, animal experiments had moved to humans. He unveiled intravascular ultrasound imaging (IVUS) at the American College of Cardiology meeting, showing that the tiny device could be threaded into the beating heart to reveal the exact composition of atheromas. These days, IVUS is often used in percutaneous coronary interventions.
But Dr. Nissen decided that IVUS would be even more useful as a tool to evaluate the real efficacy of drugs aimed at treating coronary artery disease. This is the research that he has doggedly pursued since he joined the Cleveland Clinic in 1993.
As his reputation has grown, so have offers from the pharmaceutical industry, a fact that led Dr. Nissen to a decision that smacks of the 1960s anti-establishment activist he once was.
"In order to be sure that I can be absolutely free of conflict of interest I won't accept any money under any circumstances."
He notes in his disclosure statements that he does work on pharmaceutical industry studies but all funds are given directly to the Cleveland Clinic research institute. He does not claim pharmaceutical funding, honoraria, or grants as income and he claims no tax deduction for moneys given in his name to charity.
That decision has "undoubtedly cost me some income," but Dr. Nissen said he has no regrets.
As cardiologist Mehmet Oz, M.D., of Columbia University wrote in the Time profile of Dr. Nissen, "Nissen's intravascular ultrasound lab has become so powerful that it lures industry leaders back-even if the service they receive sometimes includes more brutal honesty than they want. The activist continues to crusade, but these days lots of folks are listening."
As director of cardiovascular medicine at the Cleveland Clinic, which is rated as the top heart center in the U.S. by U.S. News and World Report, Dr. Nissen is no stranger to a camera and a microphone. He, personally, is number 72 on Time magazine's list of the 100 most influential people in our world.
But the dustup created this week by his meta-analysis of published data from 42 randomized controlled trials of rosiglitazone has placed him squarely in the glare of critics who charge that Dr. Nissen is an anti-pharmaceutical crusader.
The analysis found a 43% increase in the relative risk of myocardial infarction among diabetics randomized to rosiglitazone (P=0.03). There was also an increase in the number of cardiovascular deaths in the rosiglitazone group, but that didn't reach statistical significance (P=0.06).
Nothing, Dr. Nissen said, could be farther from the truth. "I'm actually a great believer in the value of drugs," he said. "I've devoted most of my life to studying the biology of cardiovascular drugs in an attempt to find new, effective agents."
But at the same time, he has been a leading critic of the Prescription Drug User Fee Act (PDUFA), that allows the FDA to charge drug companies user fees that the agency then uses to pay for its research into drug safety.
Congress is slated to re-authorize PDUFA this year and Dr. Nissen is one of a number of physician-researchers who have been pressing the Democratic majority to re-work the legislation to allow for tougher post-marketing surveillance of new drugs.
To that end, the rosiglitazone study is likely to be cited as a textbook example of the need for more and better FDA safety studies, a point that was not missed by Rep. Henry Waxman (D-Calif.) who announced that he would hold hearings into the FDA handling of rosiglitazone on June 6.
Dr. Nissen, 58, the son of doctor, once entertained thoughts of a career in journalism.
A glimpse into his background explains a lot. As an undergraduate during the turbulent 1960s at the University of Michigan, he was "on the eight-year plan," a long road to graduation, with a minor in the antiwar movement.
"A political leader, really," he described himself, "and I was also editor of the daily paper -- a very good college paper."
His years as a campus activist left him with an entrenched commitment to righting wrongs and a willingness to challenge the status quo, attributes that he has integrated into his medical career. And he never forgot the power of the press.
In 2001 he was the first physician to link rofecoxib to an increased risk of heart attacks and strokes. When the Journal of the American Medical Association published his study detailing those risks, he was roundly criticized by Merck, the maker of Vioxx, and a number of physicians who praised the drug.
Three years later Merck pulled Vioxx from the market when additional studies confirmed that daily, long-term use of the drug could increase the risk of heart attacks and strokes.
In October 2005, Dr. Nissen again blew his whistle. This time the drug was muraglitazar (Pargluva), a drug in the same class as rosiglitazone.
When the FDA published clinical trial data about the drug, Dr. Nissen immediately spotted something amiss. All the "cardiovascular markers were going in the wrong direction. There were increases in heart attacks, stroke, and cardiovascular death."
One look told him that an FDA advisory panel charged with reviewing the same documents would not approve the drug. But he was surprised when the panel, which met in September 2005, recommended by an 8-1 vote that the FDA give it a thumbs-up.
Dr. Nissen said he dropped everything and began an in-depth analysis of the Pargluva data.
Working nonstop with a Cleveland Clinic statistician and with co-author Eric Topol, M.D., who was then the chairman of the department of cardiovascular medicine, Dr. Nissen finished his analysis in record time.
JAMA published the muraglitazar analysis online on Oct. 20, just two days after the FDA had sent the drug's makers an "approvable letter" that said muraglitazar could be approved if the company supplied more cardiovascular safety data.
On Oct. 27, Bristol-Myers Squibb announced that it would terminate its muraglitazar development agreement with Merck. The drug was dead.
Asked about the stunning reversal of fortune for muraglitazar, Dr. Nissen said, "I'm not a crusader, I just want the balance between safety and efficacy to be favorable."
Dr. Nissen, who was elected president of American College of Cardiology in 2006, was born in Toledo, Ohio, where his father was a general practitioner. He recalls reciting the clinical names for all the bones in the body, a skill his father taught him when he was just three or four. He would regularly be called upon to show off for his father's colleagues.
When Dr. Nissen was a child, his father moved the family to Baltimore so that the elder Nissen, at age 40, could shift specialties to become an obstetrician-gynecologist. Later, the Nissens moved to Fullerton, Calif.,, where Dr. Nissen's father developed a successful private practice.
After medical school at Michigan, the younger Dr. Nissen went to the University of California at Davis for a residency. There he met his mentor, Anthony DiMaria, M.D., then a rising star in the world of heart disease research. When Dr. DiMaria was asked to head up a struggling cardiovascular disease research program at the University of Kentucky in Lexington, he asked Dr. Nissen to come along to be the first cardiology fellow.
During his time in Lexington, Dr. Nissen was approached by a company that was trying to develop an "ultrasound transducer that would fit inside a coronary artery," Dr. Nissen recalled. At the time the "smallest ultrasound transducer was the size of a fist," he said.
But Dr. Nissen quickly realized that an imaging technique that could look at the arteries from the inside out could provide critical information about the real nature of atherosclerosis.
By spring 1990, animal experiments had moved to humans. He unveiled intravascular ultrasound imaging (IVUS) at the American College of Cardiology meeting, showing that the tiny device could be threaded into the beating heart to reveal the exact composition of atheromas. These days, IVUS is often used in percutaneous coronary interventions.
But Dr. Nissen decided that IVUS would be even more useful as a tool to evaluate the real efficacy of drugs aimed at treating coronary artery disease. This is the research that he has doggedly pursued since he joined the Cleveland Clinic in 1993.
As his reputation has grown, so have offers from the pharmaceutical industry, a fact that led Dr. Nissen to a decision that smacks of the 1960s anti-establishment activist he once was.
"In order to be sure that I can be absolutely free of conflict of interest I won't accept any money under any circumstances."
He notes in his disclosure statements that he does work on pharmaceutical industry studies but all funds are given directly to the Cleveland Clinic research institute. He does not claim pharmaceutical funding, honoraria, or grants as income and he claims no tax deduction for moneys given in his name to charity.
That decision has "undoubtedly cost me some income," but Dr. Nissen said he has no regrets.
As cardiologist Mehmet Oz, M.D., of Columbia University wrote in the Time profile of Dr. Nissen, "Nissen's intravascular ultrasound lab has become so powerful that it lures industry leaders back-even if the service they receive sometimes includes more brutal honesty than they want. The activist continues to crusade, but these days lots of folks are listening."
Test of Drug for Diabetes in Jeopardy
A large clinical study meant to test the heart safety of the diabetes treatment Avandia may be in jeopardy as a result of recent reports of the drug’s risks, according to an executive at its maker, GlaxoSmithKline.
Dr. Ronald L. Krall, the medical director for GlaxoSmithKline, said in a telephone interview yesterday that some of the 4,450 patients enrolled in the drug trial, called Record, have dropped out this week because of safety concerns about Avandia.
Dr. Krall said he did not yet know how many patients have withdrawn, but said Glaxo was now worried about whether it could complete the drug trial, which has been scheduled to run through next year. The company has been counting on a successful outcome from the study to dispel widespread concerns that Avandia carries a higher risk of heart attacks than other diabetes drugs.
Now, though, the independent research committees overseeing the study “are concerned about the ability of the study to continue” and are “considering what to do to prevent people from dropping out of the trial,” Dr. Krall said.
The safety concerns were ignited by an analysis published Monday in The New England Journal of Medicine suggesting that Avandia, used to treat Type 2 diabetes, carries an increased risk of heart attack, estimated at 43 percent, compared with other diabetes drugs or placebos.
In response to the medical journal article, the Food and Drug Administration, issued a safety alert for Avandia and advised patients who take it to consult their doctors.
Avandia, which was approved by the F.D.A. in 1999, has been used by an estimated seven million people, six million of them in the United States.
Yesterday, the F.D.A. said its own recent analysis of more than 40 clinical studies of Avandia seemed to confirm the findings in The New England Journal of Medicine’s study, whose lead author was the influential Cleveland Clinic heart specialist Steven E. Nissen.
But an agency spokeswoman yesterday urged caution in interpreting those results.
“Dr. Nissen’s meta-analysis and the F.D.A.’s meta-analysis both arrived at a similar figure of 40 percent” the F.D.A. spokeswoman, Julie Zawisa, wrote in an e-mail message. “But this alone, is not conclusive of anything. What it does mean is that we need to try to reconcile the meta-analysis finding with clinical trial data that DO NOT show this increased risk.”
People with Type 2 diabetes are already at risk of heart attacks, facing a 20.2 percent chance of such an attack over seven years. One of the main reasons for controlling blood sugar in diabetic patients is to manage that risk.
But if Dr. Nissen’s analysis is an accurate reflection of Avandia’s increased risk, it appears the drug would do more cardiovascular harm than good. Diabetics taking Avandia would run a 28.9 percent chance of heart attack over the same seven-year period, according to his analysis.
GlaxoSmithKline’s own meta-analysis, submitted to the F.D.A. last August, showed a slightly lower 31 percent increased risk of heart attack.
A meta-analysis, which involves comparing the results of disparate clinical trials, is not considered as definitive as a uniform, controlled patient study of the sort GlaxoSmithKline has been counting on with its Record trial. Both GlaxoSmithKline and the F.D.A. have said that the meta-analyses indicating a heart risk with Avandia are contradicted by an interim look at Record, as well as data from an analysis of more than 20,000 patients enrolled in a UnitedHealthcare plan.
But neither GlaxoSmithKline nor the F.D.A. has released results from that interim assessment of Record, which was conducted within the last month.
The F.D.A. has received heavy criticism this week from Capitol Hill, where members of Congress have suggested that Avandia is shaping up as another Vioxx — a painkiller that became a bestseller, despite periodic questions about its safety, before being taken off the market in 2004 when its heart risks became irrefutable.
The F.D.A. plans to ask an advisory panel to review the Avandia data. Such panels, if they find safety risks with a drug, can recommend that the agency require a stronger warning label or ban the drug altogether.
Avandia is Glaxo’s second-largest selling drug, with more than $3 billion in sales last year worldwide. The company’s American depository receipts fell nearly $5 this week on news of safety concerns about the drug. The shares closed yesterday at $52.43.
GlaxoSmithKline has urged regulators and the public not to rush to judgment based on the New England Journal of Medicine article and has said that the Record trial, which began in 2000, would be a more reliable way to estimate the drug’s cardiovascular risks.
In that study, half of the 4,450 patients are being treated with Avandia in combination with another diabetes drug, while the others are being treated with two other drugs.
The trial is designed to determine whether patients taking Avandia are more likely to have a range of cardiovascular problems, including heart attack and stroke.
Dr. Ronald L. Krall, the medical director for GlaxoSmithKline, said in a telephone interview yesterday that some of the 4,450 patients enrolled in the drug trial, called Record, have dropped out this week because of safety concerns about Avandia.
Dr. Krall said he did not yet know how many patients have withdrawn, but said Glaxo was now worried about whether it could complete the drug trial, which has been scheduled to run through next year. The company has been counting on a successful outcome from the study to dispel widespread concerns that Avandia carries a higher risk of heart attacks than other diabetes drugs.
Now, though, the independent research committees overseeing the study “are concerned about the ability of the study to continue” and are “considering what to do to prevent people from dropping out of the trial,” Dr. Krall said.
The safety concerns were ignited by an analysis published Monday in The New England Journal of Medicine suggesting that Avandia, used to treat Type 2 diabetes, carries an increased risk of heart attack, estimated at 43 percent, compared with other diabetes drugs or placebos.
In response to the medical journal article, the Food and Drug Administration, issued a safety alert for Avandia and advised patients who take it to consult their doctors.
Avandia, which was approved by the F.D.A. in 1999, has been used by an estimated seven million people, six million of them in the United States.
Yesterday, the F.D.A. said its own recent analysis of more than 40 clinical studies of Avandia seemed to confirm the findings in The New England Journal of Medicine’s study, whose lead author was the influential Cleveland Clinic heart specialist Steven E. Nissen.
But an agency spokeswoman yesterday urged caution in interpreting those results.
“Dr. Nissen’s meta-analysis and the F.D.A.’s meta-analysis both arrived at a similar figure of 40 percent” the F.D.A. spokeswoman, Julie Zawisa, wrote in an e-mail message. “But this alone, is not conclusive of anything. What it does mean is that we need to try to reconcile the meta-analysis finding with clinical trial data that DO NOT show this increased risk.”
People with Type 2 diabetes are already at risk of heart attacks, facing a 20.2 percent chance of such an attack over seven years. One of the main reasons for controlling blood sugar in diabetic patients is to manage that risk.
But if Dr. Nissen’s analysis is an accurate reflection of Avandia’s increased risk, it appears the drug would do more cardiovascular harm than good. Diabetics taking Avandia would run a 28.9 percent chance of heart attack over the same seven-year period, according to his analysis.
GlaxoSmithKline’s own meta-analysis, submitted to the F.D.A. last August, showed a slightly lower 31 percent increased risk of heart attack.
A meta-analysis, which involves comparing the results of disparate clinical trials, is not considered as definitive as a uniform, controlled patient study of the sort GlaxoSmithKline has been counting on with its Record trial. Both GlaxoSmithKline and the F.D.A. have said that the meta-analyses indicating a heart risk with Avandia are contradicted by an interim look at Record, as well as data from an analysis of more than 20,000 patients enrolled in a UnitedHealthcare plan.
But neither GlaxoSmithKline nor the F.D.A. has released results from that interim assessment of Record, which was conducted within the last month.
The F.D.A. has received heavy criticism this week from Capitol Hill, where members of Congress have suggested that Avandia is shaping up as another Vioxx — a painkiller that became a bestseller, despite periodic questions about its safety, before being taken off the market in 2004 when its heart risks became irrefutable.
The F.D.A. plans to ask an advisory panel to review the Avandia data. Such panels, if they find safety risks with a drug, can recommend that the agency require a stronger warning label or ban the drug altogether.
Avandia is Glaxo’s second-largest selling drug, with more than $3 billion in sales last year worldwide. The company’s American depository receipts fell nearly $5 this week on news of safety concerns about the drug. The shares closed yesterday at $52.43.
GlaxoSmithKline has urged regulators and the public not to rush to judgment based on the New England Journal of Medicine article and has said that the Record trial, which began in 2000, would be a more reliable way to estimate the drug’s cardiovascular risks.
In that study, half of the 4,450 patients are being treated with Avandia in combination with another diabetes drug, while the others are being treated with two other drugs.
The trial is designed to determine whether patients taking Avandia are more likely to have a range of cardiovascular problems, including heart attack and stroke.
More Than 30% of US Stroke Survivors Receive Outpatient Rehabilitation
May 25, 2007 — Slightly more than 30% of stroke survivors in a sample of US states received outpatient rehabilitation, according to the results of a study reported in the May 25 issue of the Morbidity and Mortality Weekly Report. Prevalence of outpatient stroke rehabilitation was higher among men, non-Hispanic blacks, unemployed or retired adults, and persons living in the center city of a metropolitan statistical area (MSA) than in comparison groups."Approximately 700,000 persons in the United States have a new or recurrent stroke each year; among those who survive, only 10% recover completely, and many of the remaining survivors need rehabilitation because of resulting impairments," write J. Xie, MD, PhD, and colleagues from the Division for Heart Disease and Stroke Prevention, National Center for Chronic Disease Prevention and Health Promotion, US Centers for Disease Control and Prevention (CDC). "Long-term disability not only affects functional status and social roles among stroke survivors but also results in substantial costs; the combined direct and indirect costs of stroke are projected to be $62.7 billion in the United States in 2007. "Although studies have established that timely and intensive rehabilitation can substantially improve patients' functional outcomes and quality of life after an acute stroke, few studies have provided population-based estimates of the prevalence of acute stroke rehabilitation," the authors write. The CDC analyzed data from the 2005 Behavioral Risk Factor Surveillance System (BRFSS) survey on stroke survivors in 21 states and the District of Columbia (DC). The BRFSS is a state-based, random-digit–dialed telephone survey of the noninstitutionalized, US civilian population aged 18 years and older. The median response rate, based on Council of American Survey and Research Organizations (CASRO) guidelines, was 51.3% (range, 34.6% - 66.7%). The median cooperation rate, defined as the proportion of all respondents interviewed among all eligible persons who were contacted, was 74.3% (range, 63.2% - 85.3%). Of 129,761 survey respondents, 4689 (2.6%; 95% confidence interval [CI], 2.5 - 2.8) reported ever having a stroke.Analysis of the BRFSS data showed that 30.7% of the stroke survivors (n = 1297; 95% CI, 28.5 - 33.1) received outpatient rehabilitation, which was lower than would be expected if clinical practice guideline recommendations for all stroke patients had been followed.Stroke survivors in all 3 age groups had a similar prevalence of outpatient stroke rehabilitation, but the age-adjusted prevalence of receiving outpatient stroke rehabilitation was higher in men than in women (adjusted odds ratio [AOR], 1.31; 95% CI, 1.05 - 1.63). Compared with non-Hispanic whites, non-Hispanic blacks had a higher prevalence of outpatient stroke rehabilitation (AOR, 1.49; 95% CI, 1.10 - 2.00). Compared with stroke survivors who were employed at the time of the survey, respondents who were unemployed (AOR, 1.59; 95% CI, 1.16 - 2.18) or retired (AOR, 1.45; 95% CI, 1.01 - 2.09) were more likely to receive stroke rehabilitation. Adults living in a non-MSA had a lower prevalence of outpatient stroke rehabilitation than did those living in the center city of an MSA (AOR, 0.72; 95% CI, 0.55 - 0.93). Marital status, education level, income level, or insurance status did not significantly affect receipt of outpatient stroke rehabilitation. "Increasing the number of stroke survivors who receive needed outpatient rehabilitation might lead to better functional status and quality of life in this population," the authors write. An accompanying editorial note identifies several study limitations: lack of data on inpatient rehabilitation services or referral to rehabilitation services; inability to calculate nationwide prevalence of outpatient stroke rehabilitation; lack of data on disease severity and patient medical status; employment status determined at the time of the survey, not at the time of stroke; self-report of stroke and stroke rehabilitation; and low BRFSS response rate."Availability of and access to rehabilitation facilities and specialized staff in the community, policies encouraging family support, and physician and patient education might improve [the] rehabilitation rate among stroke survivors," the editorial note concludes. "In addition, more research is needed to assess the prevalence of referral and receipt of both inpatient and outpatient stroke rehabilitation at the state and national levels. Public health measures should continue focusing on improving systems of care, from stroke onset through final rehabilitation, to improve overall outcomes among stroke patients." MMWR Morb Mortal Wkly Rep. 2007;56(20):504-507.
Increased Coffee Consumption May Reduce Risk for Gout in Men
May 25, 2007 — Long-term consumption of coffee is associated with reduced risk for gout in men older than 40 years, according to the results of a prospective study reported in the June issue of Arthritis & Rheumatism.
"Coffee is one of the most widely consumed beverages in the world and may affect the risk of gout via various mechanisms," write Hyon K. Choi, MD, DrPH, from the University of British Columbia in Vancouver, Canada, and colleagues. "A study of a nationally representative sample of US adults showed that coffee consumption was associated with a lower serum level of uric acid and a lower frequency of hyperuricemia."
The study cohort from the Health Professionals Follow-Up Study consisted of 45,869 men with no history of gout at baseline. Validated questionnaires were used to measure intake of coffee, decaffeinated coffee, tea, and total caffeine every 4 years for 12 years, and a supplementary questionnaire was used to determine whether participants met the American College of Rheumatology survey criteria for gout.
During the 12-year study, there were 757 confirmed incident cases of gout. Increasing coffee intake was inversely associated with the risk for gout, with multivariate relative risks (RRs) for incident gout of 1.00, 0.97, 0.92, 0.60 (95% confidence interval [CI], 0.41 - 0.87), and 0.41 (95% CI, 0.19 - 0.88) for coffee consumption categories of 0, less than 1, 1 to 3, 4 to 5, and 6 or more cups per day, respectively (P for trend = .009).
For decaffeinated coffee, the multivariate RRs for 0, less than 1, 1 to 3, and 4 or more cups per day were 1.00, 0.83, 0.67 (95% CI, 0.54 - 0.82), and 0.73 (95% CI, 0.46 - 1.17), respectively (P for trend = .002).
These associations were independent of dietary and other risk factors for gout such as body mass index, age, hypertension, diuretic use, alcohol consumption, and chronic renal failure. Total caffeine from all sources and tea intake were not associated with the risk for gout.
"These prospective data suggest that long-term coffee consumption is associated with a lower risk of incident gout," the authors write.
Study limitations include self-report of coffee consumption, restriction to male healthcare professionals in the cohort, observational design, and inability to rule out the possibility that unmeasured factors might contribute to the observed associations.
The National Institutes of Health and TAP Pharmaceuticals supported this study. Some of the authors have disclosed various financial relationships with TAP and/or Savient Pharmaceuticals.
"Coffee is one of the most widely consumed beverages in the world and may affect the risk of gout via various mechanisms," write Hyon K. Choi, MD, DrPH, from the University of British Columbia in Vancouver, Canada, and colleagues. "A study of a nationally representative sample of US adults showed that coffee consumption was associated with a lower serum level of uric acid and a lower frequency of hyperuricemia."
The study cohort from the Health Professionals Follow-Up Study consisted of 45,869 men with no history of gout at baseline. Validated questionnaires were used to measure intake of coffee, decaffeinated coffee, tea, and total caffeine every 4 years for 12 years, and a supplementary questionnaire was used to determine whether participants met the American College of Rheumatology survey criteria for gout.
During the 12-year study, there were 757 confirmed incident cases of gout. Increasing coffee intake was inversely associated with the risk for gout, with multivariate relative risks (RRs) for incident gout of 1.00, 0.97, 0.92, 0.60 (95% confidence interval [CI], 0.41 - 0.87), and 0.41 (95% CI, 0.19 - 0.88) for coffee consumption categories of 0, less than 1, 1 to 3, 4 to 5, and 6 or more cups per day, respectively (P for trend = .009).
For decaffeinated coffee, the multivariate RRs for 0, less than 1, 1 to 3, and 4 or more cups per day were 1.00, 0.83, 0.67 (95% CI, 0.54 - 0.82), and 0.73 (95% CI, 0.46 - 1.17), respectively (P for trend = .002).
These associations were independent of dietary and other risk factors for gout such as body mass index, age, hypertension, diuretic use, alcohol consumption, and chronic renal failure. Total caffeine from all sources and tea intake were not associated with the risk for gout.
"These prospective data suggest that long-term coffee consumption is associated with a lower risk of incident gout," the authors write.
Study limitations include self-report of coffee consumption, restriction to male healthcare professionals in the cohort, observational design, and inability to rule out the possibility that unmeasured factors might contribute to the observed associations.
The National Institutes of Health and TAP Pharmaceuticals supported this study. Some of the authors have disclosed various financial relationships with TAP and/or Savient Pharmaceuticals.
AUA: Botulinum Toxin Gives Lasting BPH Relief
ANAHEIM, Calif., May 25 -- Injection of botulinum toxin A directly into the prostate provided relief from symptoms of refractory benign prostatic hypertrophy for up to a year, according to a small study.
Three-fourths of patients had at least 30% improvement in urinary symptoms and quality of life, found Yao-Chi Chuang, M.D., of Chang Gung University in Taiwan.
In some cases the improvement persisted for as long as a year, he said at the American Urological Association meeting here. No patient reported any major side effects.
"The results are encouraging because they indicate that Botox could represent a simple, safe, and effective treatment for enlarged prostate that has long-term benefits," commented University of Pittsburgh urologist Michael Chancellor, M.D., an investigator in the study.
Dr. Chuang reported results of a study involving 37 patients with a history of BPH that had responded inadequately to medical therapy. The men had moderate or severe urinary tract symptoms, as reflected by a score of eight or higher on the International Prostate Symptom Scale (IPSS). The patients had a peak urinary flow of less than 12 ml/sec, and all had symptoms that were refractory to medical treatment.
Treatment consisted of single injection session of botulinum toxin A in saline solution. The dose was determined by a patient's prostate volume. Those with a prostate volume of 30 ml or less (n=20) received 100 U administered in divided doses into both lobes of the prostate. Men whose prostate volume exceeded 30 ml (n=17) received 200 U of botulinum toxin administered by two injections into each lobe.
Outcome measures were change in IPSS score, quality of life index (0-6), peak urinary flow (Qmax), post-void residual urine volume, and prostate volume. Follow-up visits occurred one, three, and six months after treatment.
Dr. Chuang said 27 of the 37 men in the study had at least 30% improvement in both the IPSS and quality of life index. At six and 12 months, the average prostate volume had decreased by about 15% in both dose groups.
However, six patients in the 100-U group and five in the 200-U group had no change in prostate volume, the presumed mechanism of action of botulinum toxin A in the prostate. Nonetheless, six of those 11 patients had at least 30% improvement in symptom and quality of life scores.
"The percentage of prostate volume change did not correlate with percentage change in Qmax, lower urinary tract symptoms, or quality of life," said Dr. Chuang.
"The mechanisms of relief of lower urinary tract symptoms through intraprostatic botulinum toxin A injection may involve more than volume shrinkage. The inhibitory effect on the smooth muscle tone, inflammatory process, and aberrant sensory function may plan an important role. Placebo-controlled studies with histology and molecular biology evaluation are needed to prove the mechanisms and confirm the beneficial effect of botulinum toxin A in BPH."
Another Taiwanese study evaluated botulinum toxin A as add-on therapy for men who had large prostates and a history of suboptimal response to combination medical therapy for BPH. Prostate volume exceeded 50 mL in all cases, and the patients had received maximal medical therapy consisting of the combination of an alpha-blocker and a 5-alpha reductase inhibitor.
Thirty patients received botulinum toxin A at doses ranging between 200 and 600 U, depending on prostate volume. Their clinical outcomes were compared against those of 30 other BPH patients who remained on combination medical therapy, according to Hann-Chorng Kuo, M.D., of Buddhist Tzu Chi General Hospital in Hualien, Taiwan. Dr. Kuo was not present to discuss his poster presentation.
Among patients treated with botulinum toxin A, mean prostate volume decreased by an average of 23.5%, mean Qmax by 2.9 mL/sec., and mean PSA level by 35.4%. Three patients were judged to have excellent results and 22 had symptomatic improvement.
The remaining five patients were unchanged. As compared to patients who continued medical therapy, the add-on group had greater improvement in IPSS, quality of life, prostate volume, transition zone index, Qmax, and PSA level. Dr. Kuo reported that 83% of the botulinum toxin A group expressed satisfaction with their treatment compared to 17% of patients who received only combination medical therapy.
The results from the two studies did not meet with universal acceptance. Vanderbilt University urologist Roger Dmochowski, M.D., echoed the sentiments of Dr. Chancellor, particularly with respect to the durability of the symptom relief. On the other hand, Claus Roehrborn, M.D., of the Univeresity of Texas Southwestern Medical Center in Dallas, expressed some reservations about the complete absence of patients with symptom worsening after botulinum toxin injection.
"Are you sure you didn't have a single patient who had a worsening of the symptom score or the flow rate or the quality of life score? Not a single patient?" Dr. Roehrborn asked Dr. Chuang.
Dr. Chuang affirmed that none of his patients had symptom deterioration after the injection therapy.
A 10-patient dose-finding study provided additional evidence that botulinum toxin A might have a role in the treatment of benign prostate hypertrophy and lower urinary tract symptoms. Patients with moderate to severe lower urinary tract symptoms received doses of 100 to 200 U by way of transrectal injection into the prostate and were followed for six months.
Of nine patients who completed follow up, six had significant improvement in the AUA Symptom Scale and peak flow rate; however, four of the six patients had a relapse to baseline symptoms by six months, reported Al Barqawi, M.D., of the University of Colorado in Denver.
Five patients had a significant reduction in prostate volume. No patient developed dose-limiting toxicity, but two patients had episodes of hematospermia, which proved to be self-limiting. Dr. Barqawi noted that a phase II randomized trial is underway to determine the clinical efficacy of botulinum toxin A in a large cohort of patients with benign prostate hypertrophy and lower urinary tract symptoms in the U.S.
Three-fourths of patients had at least 30% improvement in urinary symptoms and quality of life, found Yao-Chi Chuang, M.D., of Chang Gung University in Taiwan.
In some cases the improvement persisted for as long as a year, he said at the American Urological Association meeting here. No patient reported any major side effects.
"The results are encouraging because they indicate that Botox could represent a simple, safe, and effective treatment for enlarged prostate that has long-term benefits," commented University of Pittsburgh urologist Michael Chancellor, M.D., an investigator in the study.
Dr. Chuang reported results of a study involving 37 patients with a history of BPH that had responded inadequately to medical therapy. The men had moderate or severe urinary tract symptoms, as reflected by a score of eight or higher on the International Prostate Symptom Scale (IPSS). The patients had a peak urinary flow of less than 12 ml/sec, and all had symptoms that were refractory to medical treatment.
Treatment consisted of single injection session of botulinum toxin A in saline solution. The dose was determined by a patient's prostate volume. Those with a prostate volume of 30 ml or less (n=20) received 100 U administered in divided doses into both lobes of the prostate. Men whose prostate volume exceeded 30 ml (n=17) received 200 U of botulinum toxin administered by two injections into each lobe.
Outcome measures were change in IPSS score, quality of life index (0-6), peak urinary flow (Qmax), post-void residual urine volume, and prostate volume. Follow-up visits occurred one, three, and six months after treatment.
Dr. Chuang said 27 of the 37 men in the study had at least 30% improvement in both the IPSS and quality of life index. At six and 12 months, the average prostate volume had decreased by about 15% in both dose groups.
However, six patients in the 100-U group and five in the 200-U group had no change in prostate volume, the presumed mechanism of action of botulinum toxin A in the prostate. Nonetheless, six of those 11 patients had at least 30% improvement in symptom and quality of life scores.
"The percentage of prostate volume change did not correlate with percentage change in Qmax, lower urinary tract symptoms, or quality of life," said Dr. Chuang.
"The mechanisms of relief of lower urinary tract symptoms through intraprostatic botulinum toxin A injection may involve more than volume shrinkage. The inhibitory effect on the smooth muscle tone, inflammatory process, and aberrant sensory function may plan an important role. Placebo-controlled studies with histology and molecular biology evaluation are needed to prove the mechanisms and confirm the beneficial effect of botulinum toxin A in BPH."
Another Taiwanese study evaluated botulinum toxin A as add-on therapy for men who had large prostates and a history of suboptimal response to combination medical therapy for BPH. Prostate volume exceeded 50 mL in all cases, and the patients had received maximal medical therapy consisting of the combination of an alpha-blocker and a 5-alpha reductase inhibitor.
Thirty patients received botulinum toxin A at doses ranging between 200 and 600 U, depending on prostate volume. Their clinical outcomes were compared against those of 30 other BPH patients who remained on combination medical therapy, according to Hann-Chorng Kuo, M.D., of Buddhist Tzu Chi General Hospital in Hualien, Taiwan. Dr. Kuo was not present to discuss his poster presentation.
Among patients treated with botulinum toxin A, mean prostate volume decreased by an average of 23.5%, mean Qmax by 2.9 mL/sec., and mean PSA level by 35.4%. Three patients were judged to have excellent results and 22 had symptomatic improvement.
The remaining five patients were unchanged. As compared to patients who continued medical therapy, the add-on group had greater improvement in IPSS, quality of life, prostate volume, transition zone index, Qmax, and PSA level. Dr. Kuo reported that 83% of the botulinum toxin A group expressed satisfaction with their treatment compared to 17% of patients who received only combination medical therapy.
The results from the two studies did not meet with universal acceptance. Vanderbilt University urologist Roger Dmochowski, M.D., echoed the sentiments of Dr. Chancellor, particularly with respect to the durability of the symptom relief. On the other hand, Claus Roehrborn, M.D., of the Univeresity of Texas Southwestern Medical Center in Dallas, expressed some reservations about the complete absence of patients with symptom worsening after botulinum toxin injection.
"Are you sure you didn't have a single patient who had a worsening of the symptom score or the flow rate or the quality of life score? Not a single patient?" Dr. Roehrborn asked Dr. Chuang.
Dr. Chuang affirmed that none of his patients had symptom deterioration after the injection therapy.
A 10-patient dose-finding study provided additional evidence that botulinum toxin A might have a role in the treatment of benign prostate hypertrophy and lower urinary tract symptoms. Patients with moderate to severe lower urinary tract symptoms received doses of 100 to 200 U by way of transrectal injection into the prostate and were followed for six months.
Of nine patients who completed follow up, six had significant improvement in the AUA Symptom Scale and peak flow rate; however, four of the six patients had a relapse to baseline symptoms by six months, reported Al Barqawi, M.D., of the University of Colorado in Denver.
Five patients had a significant reduction in prostate volume. No patient developed dose-limiting toxicity, but two patients had episodes of hematospermia, which proved to be self-limiting. Dr. Barqawi noted that a phase II randomized trial is underway to determine the clinical efficacy of botulinum toxin A in a large cohort of patients with benign prostate hypertrophy and lower urinary tract symptoms in the U.S.
AUA: Testosterone and PSA Intertwined in Prostate Cancer Risk
ANAHEIM, Calif., May 25 -- Testosterone levels appear to have a major influence on PSA values and may warrant watching for patients at high risk of prostate cancer, a large screening program suggests.
Higher PSA values had a near-linear association with rising testosterone levels. said Al Bareqawi, M.D., of the University of Colorado in Denver, at the American Urological Association meeting here.
The strong correlation between the two measures suggests that testosterone might have an impact on the PSA cutoff value for recommending prostate biopsy, he added.
"PSA value by itself is not perfect," said Dr. Bareqawi. "The correlation between PSA and testosterone is very much indicative of a testosterone level that may actually improve our protection against prostate cancer. It may improve the meaning and interpretation of the PSA value."
Yet the results of the study do not mean that testosterone should be measured along with PSA when screening for prostate cancer, he added. That issue needs to be resolved in a validation study that would include prostate biopsy.
The impact of testosterone levels in the setting of PSA screening remains controversial under the best of circumstances, Dr. Barqawi noted.
Androgen stimulation of the prostate likely plays a role in the development of benign prostate hypertrophy and prostate cancer. PSA values are directly related to prostate size and growth in both benign and malignant states.
So the investigators evaluated data from a national prostate screening program in an attempt to clarify the relationship between the two biomarkers,
Dr. Barqawi and colleagues reviewed PSA and testosterone values obtained from 8,794 men who participated in the program in 2004 and 2005. By linear regression analysis, testosterone as a continuous value was analyzed with respect to PSA, age, and age by PSA interaction. Testosterone values were stratified into four ordinal levels (≤150 ng/ml, N=238; 150 to 230 ng/ml, N=896; 230 to 346 ng/ml; and >346 ng/ml, N=5,159). Logistic regression was used to model testosterone level by PSA value and age.
The mean age of the study population was 60.9, and their testosterone level averaged 412.5 ng/mL. Linear and logistic regression revealed a significant positive association between PSA and testosterone values (P<0.001). The correlation remained significant after adjusting for age (P<0.001). Men in the lowest testosterone quartile had a mean PSA value of 1.35 ng/ml, which increased to 1.79 ng/mL for men in the highest testosterone quartile.
The findings clearly suggest implications for PSA testing and prostate cancer screening.
"The arbitrary PSA cutoff value for recommending a prostate biopsy is 4 ng/ml," said Dr. Barqawi. "If a patient has a PSA value of 3.9 ng/ml, for example, the physician and the patient might feel safer than they really should. We know from the Prostate Cancer Prevention Trial that PSA values of 1-2 ng/ml are associated with a 29% risk of a prostate cancer-related diagnosis. The correlation between PSA and testosterone is very much indicative that testosterone could help improve interpretation of PSA values and in the process increase the protection against prostate cancer."
University of Colorado urologist E. David Crawford, M.D., who was senior investigator in the study, said testostereone could easily be included in a standard panel of laboratory tests. Including testosterone in a panel should help hold down the cost of testing, although he emphasized that the role of testosterone in prostate cancer screening remains unclear.
Japanese investigators contributed to the debate with data indicating that testosterone measurement might help distinguish prostate cancer from BPH in at least some patients.
Hiroyoshi Suzuki, M.D., of Chiba University reported that screening test data on 420 men showed that testosterone levels did not differ between men with biopsy-proven prostate cancer and those with BPH. However, in the subset of patients with a PSA <10 ng/mL or a PSA density <0.15 ng/mLl/cc, the pretreatment testosterone level was significantly higher in men with prostate cancer than in those with benign prostate disease (P=0.0198 for PSA, P=0.0362 for PSA density).
In multivariate analysis, serum testosterone was an independent predictor of a positive biopsy in men who had baseline PSA values <10 ng/ml. Dr. Suzuki and colleagues suggested that the prostate cancer screening might be improved by adding testosterone measurement to PSA assessment.
Higher PSA values had a near-linear association with rising testosterone levels. said Al Bareqawi, M.D., of the University of Colorado in Denver, at the American Urological Association meeting here.
The strong correlation between the two measures suggests that testosterone might have an impact on the PSA cutoff value for recommending prostate biopsy, he added.
"PSA value by itself is not perfect," said Dr. Bareqawi. "The correlation between PSA and testosterone is very much indicative of a testosterone level that may actually improve our protection against prostate cancer. It may improve the meaning and interpretation of the PSA value."
Yet the results of the study do not mean that testosterone should be measured along with PSA when screening for prostate cancer, he added. That issue needs to be resolved in a validation study that would include prostate biopsy.
The impact of testosterone levels in the setting of PSA screening remains controversial under the best of circumstances, Dr. Barqawi noted.
Androgen stimulation of the prostate likely plays a role in the development of benign prostate hypertrophy and prostate cancer. PSA values are directly related to prostate size and growth in both benign and malignant states.
So the investigators evaluated data from a national prostate screening program in an attempt to clarify the relationship between the two biomarkers,
Dr. Barqawi and colleagues reviewed PSA and testosterone values obtained from 8,794 men who participated in the program in 2004 and 2005. By linear regression analysis, testosterone as a continuous value was analyzed with respect to PSA, age, and age by PSA interaction. Testosterone values were stratified into four ordinal levels (≤150 ng/ml, N=238; 150 to 230 ng/ml, N=896; 230 to 346 ng/ml; and >346 ng/ml, N=5,159). Logistic regression was used to model testosterone level by PSA value and age.
The mean age of the study population was 60.9, and their testosterone level averaged 412.5 ng/mL. Linear and logistic regression revealed a significant positive association between PSA and testosterone values (P<0.001). The correlation remained significant after adjusting for age (P<0.001). Men in the lowest testosterone quartile had a mean PSA value of 1.35 ng/ml, which increased to 1.79 ng/mL for men in the highest testosterone quartile.
The findings clearly suggest implications for PSA testing and prostate cancer screening.
"The arbitrary PSA cutoff value for recommending a prostate biopsy is 4 ng/ml," said Dr. Barqawi. "If a patient has a PSA value of 3.9 ng/ml, for example, the physician and the patient might feel safer than they really should. We know from the Prostate Cancer Prevention Trial that PSA values of 1-2 ng/ml are associated with a 29% risk of a prostate cancer-related diagnosis. The correlation between PSA and testosterone is very much indicative that testosterone could help improve interpretation of PSA values and in the process increase the protection against prostate cancer."
University of Colorado urologist E. David Crawford, M.D., who was senior investigator in the study, said testostereone could easily be included in a standard panel of laboratory tests. Including testosterone in a panel should help hold down the cost of testing, although he emphasized that the role of testosterone in prostate cancer screening remains unclear.
Japanese investigators contributed to the debate with data indicating that testosterone measurement might help distinguish prostate cancer from BPH in at least some patients.
Hiroyoshi Suzuki, M.D., of Chiba University reported that screening test data on 420 men showed that testosterone levels did not differ between men with biopsy-proven prostate cancer and those with BPH. However, in the subset of patients with a PSA <10 ng/mL or a PSA density <0.15 ng/mLl/cc, the pretreatment testosterone level was significantly higher in men with prostate cancer than in those with benign prostate disease (P=0.0198 for PSA, P=0.0362 for PSA density).
In multivariate analysis, serum testosterone was an independent predictor of a positive biopsy in men who had baseline PSA values <10 ng/ml. Dr. Suzuki and colleagues suggested that the prostate cancer screening might be improved by adding testosterone measurement to PSA assessment.
AUA: ED Drugs May Have Role in Treatment of BPH
ANAHEIM, Calif., May 25 -- Treatments for erectile dysfunction may prove effective against benign prostatic hyperplasia and lower urinary tract symptoms, possibly because they share a common etiologic pathway.
Studies involving all three of the currently available type 5 phosphodiesterase (PDE5) inhibitors showed improvement in BPH and urinary symptoms, regardless of whether the patients had concomitant erectile dysfunction. The three studies, two from the U.S. and one from Germany, were reported at the American Urological Association meeting.
The data reinforce an emerging theoretical and scientific framework that posits a common pathway for development of erectile dysfunction, benign prostatic hyperplasia, and lower urinary tract symptoms, and, the research suggests, possibly overactive bladder, researchers said.
The larger of the two prospective, randomized trials was conducted by Kevin McVary, M.D., of Northwestern University, and colleagues. It involved 369 men who had erectile dysfunction and concomitant lower urinary tract symptoms.
The patients, whose mean age was 60, had about a six-year history of erectile dysfunction and a five-year history of BPH and lower urinary tract symptoms. They were randomized to placebo or to 50 mg of sildenafil (Viagra) taken nightly before bedtime or 1 hour before sexual activity.
Treatment continued for 12 weeks. The primary endpoints were change in the erectile function (EF) domain score of the International Index of Erectile Function, change in the International Prostate Symptom Score (IPSS), and change in maximum urinary flow (Qmax).
Overall, patients treated with sildenafil had a 6.32-point improvement in the IPSS compared to 1.93 for the placebo group (P<0.001). EF domain scores improved by an average of 9.17 in the sildenafil group and 1.86 in the placebo group (P<0.001). Qmax did not differ between groups at baseline or at the end of the study.
Stratification of the data by baseline severity showed that patients with severe (IPSS ≥20) lower urinary tract symptoms improved substantially more compared with placebo than did those with moderate (IPSS 8-19) symptoms (P=0.0619). Among men with severe symptoms at baseline (54% of the cohort), substantially more had mild (16% vs. 4%) or moderate (57% vs. 36%) symptoms compared with placebo at the end of the study, the researchers found.
"The improvement in IPSS correlated with the IIEF changes," said Dr. McVary said. "Patients with more severe symptoms had more improvement, in a sense because they have more room for change."
He noted, however, that the researchers were surprised to find that the improvement did not correspond with the flow rate. "Although we didn't have an active comparator, the improvement looks to be comparable to what we might expect when giving alpha-blockers or a five-alpha reductase inhibitor," he said.
Asked to speculate about the lack of correlation between symptom improvement and flow rate, Dr. McVary said he and his colleagues initially suspected a predominance of urgency symptoms as opposed to obstruction. However, the data showed that both types of symptoms improved to a similar degree.
With respect to potential mechanisms involved in the co-existence of lower urinary tract symptoms and erectile dysfunction and the lack of flow improvement, Dr. McVary said that a pelvic deficiency in nitric oxide remains a viable explanation.
Other possibilities, he said, include an effect on bladder compliance, modulation of potential PDE5 effects on sensory innervation, and perhaps a change in pelvic flow affecting ischemia.
German investigators prospectively evaluated vardenafil (Levitra) as treatment for BPH in a randomized placebo-controlled study involving 222 men with moderate or severe symptoms.
The patients were randomized to placebo or vardenafil 10 mg BID for eight weeks, and the primary endpoints were change in IPSS, UROLIFE (a BPH quality-of-life questionnaire), and the EF domain of the IIEF.
The mean baseline IPSS was 16.8 in both groups. At the end of the study, vardenafil patients had a mean improvement of 5.9 compared with 3.6 for the placebo group (P=0.0013), reported Christian Stief, M.D., of Ludwig-Maximilians University in Munich.
Vardenafil also led to significantly greater improvement in the IPSS subscales for obstructive symptoms (3.2 vs. 1.9, P=0.0081) and irritative symptoms (2.6 vs. 1.7, P=0.0017).
The vardenafil group had significantly greater improvement on the UROLIFE questionnaire (P<0.0001 compared to placebo) and in the subscales for activity and perceived sexual life. IIEF scores improved by an average of 7.5 with vardenafil and 1.5 with placebo (P=0.0001).
The third study, a post hoc analysis of 156 men with erectile dysfunction and concomitant lower urinary tract symptoms showed that tadalafil (Cialis) significantly improved erectile function compared to placebo after 12 weeks of randomized therapy, reported Marc C. Gittelman, M.D., of South Florida Medical Research in Aventura, and colleagues.
Patients randomized to tadalafil started treatment at 5 mg/day for six weeks, followed by dose escalation to 20 mg/day over an additional six weeks.
Baseline IIEF scores averaged 13 to 14 in the placebo and tadalafil groups. The data were stratified by baseline urinary symptom severity.
Among patients with moderate symptoms, the erectile function score had improved by 6.8 points with tadalafil at six weeks versus 0.8 with placebo. At 12 weeks the tadalafil patients had a mean improvement of 8.3 compared with 1.7 in the placebo group.
In patients with severe symptoms, the EF domain score improved by 4.5 with tadalafil after six weeks compared to no change in the placebo group. At 12 weeks tadalafil patients had a mean improvement of 6.7 in the EF score compared with 0.7 in the placebo patients.
For all comparisons, tadalafil demonstrated a significant advantage over placebo (P<0.001). The magnitude of the tadalafil benefit did not differ between patients with moderate or severe lower urinary tract symptoms.
Multiple lines of evidence suggest a common pathophysiology for erectile dysfunction and BPH/lower urinary tract symptoms, said Dr. Kaplan. Such findings point toward the attractive possibility of treating the conditions with a single agent.
Studies involving all three of the currently available type 5 phosphodiesterase (PDE5) inhibitors showed improvement in BPH and urinary symptoms, regardless of whether the patients had concomitant erectile dysfunction. The three studies, two from the U.S. and one from Germany, were reported at the American Urological Association meeting.
The data reinforce an emerging theoretical and scientific framework that posits a common pathway for development of erectile dysfunction, benign prostatic hyperplasia, and lower urinary tract symptoms, and, the research suggests, possibly overactive bladder, researchers said.
The larger of the two prospective, randomized trials was conducted by Kevin McVary, M.D., of Northwestern University, and colleagues. It involved 369 men who had erectile dysfunction and concomitant lower urinary tract symptoms.
The patients, whose mean age was 60, had about a six-year history of erectile dysfunction and a five-year history of BPH and lower urinary tract symptoms. They were randomized to placebo or to 50 mg of sildenafil (Viagra) taken nightly before bedtime or 1 hour before sexual activity.
Treatment continued for 12 weeks. The primary endpoints were change in the erectile function (EF) domain score of the International Index of Erectile Function, change in the International Prostate Symptom Score (IPSS), and change in maximum urinary flow (Qmax).
Overall, patients treated with sildenafil had a 6.32-point improvement in the IPSS compared to 1.93 for the placebo group (P<0.001). EF domain scores improved by an average of 9.17 in the sildenafil group and 1.86 in the placebo group (P<0.001). Qmax did not differ between groups at baseline or at the end of the study.
Stratification of the data by baseline severity showed that patients with severe (IPSS ≥20) lower urinary tract symptoms improved substantially more compared with placebo than did those with moderate (IPSS 8-19) symptoms (P=0.0619). Among men with severe symptoms at baseline (54% of the cohort), substantially more had mild (16% vs. 4%) or moderate (57% vs. 36%) symptoms compared with placebo at the end of the study, the researchers found.
"The improvement in IPSS correlated with the IIEF changes," said Dr. McVary said. "Patients with more severe symptoms had more improvement, in a sense because they have more room for change."
He noted, however, that the researchers were surprised to find that the improvement did not correspond with the flow rate. "Although we didn't have an active comparator, the improvement looks to be comparable to what we might expect when giving alpha-blockers or a five-alpha reductase inhibitor," he said.
Asked to speculate about the lack of correlation between symptom improvement and flow rate, Dr. McVary said he and his colleagues initially suspected a predominance of urgency symptoms as opposed to obstruction. However, the data showed that both types of symptoms improved to a similar degree.
With respect to potential mechanisms involved in the co-existence of lower urinary tract symptoms and erectile dysfunction and the lack of flow improvement, Dr. McVary said that a pelvic deficiency in nitric oxide remains a viable explanation.
Other possibilities, he said, include an effect on bladder compliance, modulation of potential PDE5 effects on sensory innervation, and perhaps a change in pelvic flow affecting ischemia.
German investigators prospectively evaluated vardenafil (Levitra) as treatment for BPH in a randomized placebo-controlled study involving 222 men with moderate or severe symptoms.
The patients were randomized to placebo or vardenafil 10 mg BID for eight weeks, and the primary endpoints were change in IPSS, UROLIFE (a BPH quality-of-life questionnaire), and the EF domain of the IIEF.
The mean baseline IPSS was 16.8 in both groups. At the end of the study, vardenafil patients had a mean improvement of 5.9 compared with 3.6 for the placebo group (P=0.0013), reported Christian Stief, M.D., of Ludwig-Maximilians University in Munich.
Vardenafil also led to significantly greater improvement in the IPSS subscales for obstructive symptoms (3.2 vs. 1.9, P=0.0081) and irritative symptoms (2.6 vs. 1.7, P=0.0017).
The vardenafil group had significantly greater improvement on the UROLIFE questionnaire (P<0.0001 compared to placebo) and in the subscales for activity and perceived sexual life. IIEF scores improved by an average of 7.5 with vardenafil and 1.5 with placebo (P=0.0001).
The third study, a post hoc analysis of 156 men with erectile dysfunction and concomitant lower urinary tract symptoms showed that tadalafil (Cialis) significantly improved erectile function compared to placebo after 12 weeks of randomized therapy, reported Marc C. Gittelman, M.D., of South Florida Medical Research in Aventura, and colleagues.
Patients randomized to tadalafil started treatment at 5 mg/day for six weeks, followed by dose escalation to 20 mg/day over an additional six weeks.
Baseline IIEF scores averaged 13 to 14 in the placebo and tadalafil groups. The data were stratified by baseline urinary symptom severity.
Among patients with moderate symptoms, the erectile function score had improved by 6.8 points with tadalafil at six weeks versus 0.8 with placebo. At 12 weeks the tadalafil patients had a mean improvement of 8.3 compared with 1.7 in the placebo group.
In patients with severe symptoms, the EF domain score improved by 4.5 with tadalafil after six weeks compared to no change in the placebo group. At 12 weeks tadalafil patients had a mean improvement of 6.7 in the EF score compared with 0.7 in the placebo patients.
For all comparisons, tadalafil demonstrated a significant advantage over placebo (P<0.001). The magnitude of the tadalafil benefit did not differ between patients with moderate or severe lower urinary tract symptoms.
Multiple lines of evidence suggest a common pathophysiology for erectile dysfunction and BPH/lower urinary tract symptoms, said Dr. Kaplan. Such findings point toward the attractive possibility of treating the conditions with a single agent.
APA: Simple Screen Improves Suicide Risk Assessment
SAN DIEGO, May 25 -- Emergency department patients who may be suicidal can be identified with a simple tool designed for use by health professionals without a mental health background.
The risk-assessment tool, which goes by the tortuous acronym SAD PERSONS, assigns one point to each of 10 items on a risk-factor scale, reported Brian P. Miller, M.D. and Roseann Giordano, R.N., M.S., both of Grossmont Hospital in Costa Mesa, Calif. A score on the scale from seven to 10 indicates that the patient is at high risk for attempting suicide.
"We use this in a community-based hospital," said Dr. Miller, clinical director of Grossmont Hospital, at the American Psychiatric Association meeting here.
"It's designed for non-mental health professionals to use, so in our setting, the triage nurse in the emergency department uses this scale," he continued. "When people come into the emergency department and they've got a psychiatric complaint, or known substance abuse history, we give them the scale and it gives the triage nurse the ability to direct the patient at that point."
The test could also be administered by a social worker or other health care professional, he noted.
Dr. Miller and colleagues adopted and tested the scale in response to a mandate from the Joint Commission of Accreditation of Healthcare Organizations, which requires that hospitals provide a "documented suicide-risk assessment of patients in a psychiatric hospital and patients being treated for emotional or behavioral disorders in general hospitals."
After a literature review to determine existing knowledge on suicide risk assessment instruments, they settled on the modified SAD PERSONS scale.
The scale, which has items that spell out the acronym, assigns one point to each of 10 items identified as risk factors for suicide:
Sex (male)
Age less than 19 or greater than 45 years
Depression (patient admits to depression or decreased concentration, sleep, appetite and/or libido
Previous suicide attempt or psychiatric care
Excessive alcohol or drug use
Rational thinking loss: psychosis, organic brain syndrome
Separated, divorced, or widowed
Organized plan or serious attempt
No social support
Sickness, chronic disease
A score of one or two points indicates low risk, three to five points indicates moderate risk, and seven to 10 signals high risk.
Dr. Miller said that the cumulative score can tell the triage nurse whether the patient "is just someone who can just go into the waiting room, as most patients do, or is going to need a sitter or security, and how soon is going to need a psychiatric consultation."
Before the hospital implemented the SAD PERSONS, emergency department nurses were tested on their suicide risk assessment skills and knowledge of risk factors, as well as what they should do when a patient is identified as a high suicide risk,
The nurses were tested again after the computerized risk-assessment tool was put in place. The authors found that their knowledge of suicide risk factors and how to use the information provided by the screening tool improved significantly.
"The idea is that someone without a whole lot of psychiatric sophistication can use it and have an idea of where to direct the patient so they can have a more thorough evaluation," Dr, Miller said.
The risk-assessment tool, which goes by the tortuous acronym SAD PERSONS, assigns one point to each of 10 items on a risk-factor scale, reported Brian P. Miller, M.D. and Roseann Giordano, R.N., M.S., both of Grossmont Hospital in Costa Mesa, Calif. A score on the scale from seven to 10 indicates that the patient is at high risk for attempting suicide.
"We use this in a community-based hospital," said Dr. Miller, clinical director of Grossmont Hospital, at the American Psychiatric Association meeting here.
"It's designed for non-mental health professionals to use, so in our setting, the triage nurse in the emergency department uses this scale," he continued. "When people come into the emergency department and they've got a psychiatric complaint, or known substance abuse history, we give them the scale and it gives the triage nurse the ability to direct the patient at that point."
The test could also be administered by a social worker or other health care professional, he noted.
Dr. Miller and colleagues adopted and tested the scale in response to a mandate from the Joint Commission of Accreditation of Healthcare Organizations, which requires that hospitals provide a "documented suicide-risk assessment of patients in a psychiatric hospital and patients being treated for emotional or behavioral disorders in general hospitals."
After a literature review to determine existing knowledge on suicide risk assessment instruments, they settled on the modified SAD PERSONS scale.
The scale, which has items that spell out the acronym, assigns one point to each of 10 items identified as risk factors for suicide:
Sex (male)
Age less than 19 or greater than 45 years
Depression (patient admits to depression or decreased concentration, sleep, appetite and/or libido
Previous suicide attempt or psychiatric care
Excessive alcohol or drug use
Rational thinking loss: psychosis, organic brain syndrome
Separated, divorced, or widowed
Organized plan or serious attempt
No social support
Sickness, chronic disease
A score of one or two points indicates low risk, three to five points indicates moderate risk, and seven to 10 signals high risk.
Dr. Miller said that the cumulative score can tell the triage nurse whether the patient "is just someone who can just go into the waiting room, as most patients do, or is going to need a sitter or security, and how soon is going to need a psychiatric consultation."
Before the hospital implemented the SAD PERSONS, emergency department nurses were tested on their suicide risk assessment skills and knowledge of risk factors, as well as what they should do when a patient is identified as a high suicide risk,
The nurses were tested again after the computerized risk-assessment tool was put in place. The authors found that their knowledge of suicide risk factors and how to use the information provided by the screening tool improved significantly.
"The idea is that someone without a whole lot of psychiatric sophistication can use it and have an idea of where to direct the patient so they can have a more thorough evaluation," Dr, Miller said.
Friday, May 25, 2007
The Rosiglitazone Aftermath: Legitimate Concerns or Hype?
May 24, 2007 (Cleveland, OH) - The publication earlier this week in the New England Journal of Medicine (NEJM) of a meta-analysis suggesting an increased risk of MI and cardiovascular death with the diabetes drug rosiglitazone (Avandia, GlaxoSmithKline [GSK]) [1] led to a media furor, with headlines telling of deaths and articles describing irresponsible behavior of regulatory agencies. This has inevitably led to widespread patient panic. Was this justified given that the authors of the meta-analysis themselves admit that their study had severe limitations? Many experts think not.
Rosiglitazone is taken by about seven million people worldwide and brings in sales of more than $3 billion for GlaxoSmithKline. Analysts have warned that these new safety concerns could cut sales by 50%, and shares in GlaxoSmithKline have plummeted
Was the NEJM right to publish?
Several opinion leaders contacted by heartwire expressed concern that the meta-analysis, which was led by Dr Steve Nissen (Cleveland Clinic), was published in such a high-profile journal, with an editorial that fueled the flames [2], when the data were so far from perfect.
Dr Steven Haffner (University of Texas Health Science Center, San Antonio), who was involved in the ADOPT study of rosiglitazone, said the paper needed to be published, but it should have undergone a more extensive review, and there should have been a different editorial with more emphasis on the flaws of the study. “The NEJM was irresponsible to go to [Drs Bruce] Psaty and [Curt] Furberg for the editorial--they were always going to emphasize concerns about drug safety; that’s what they do," he commented. “But I’m not surprised this paper was published like this. The three major medical journals are becoming more like British tabloid newspapers--all they lack is a bare-chested woman on page 3," he jibed.
Dr Brian Strom (University of Pennsylvania, Philadelphia) agrees. “Drugs are given because they have benefits. Where there’s a scare, people stop taking them. So you can do more harm than good if the scare is not based on correct information. I do believe this meta-analysis should have been published, but a less sensational editorial would have been better," he told heartwire.
Dr Robert Califf (Duke University, Durham, NC) made the point that news reporting should follow scientific discussion on drug-safety issues, not precede it. “It would be better if we had a system of postmarketing signal detection in which signals were vetted scientifically rather than splashed over TV and newspapers. I can't help but wonder if the NEJM is functioning more like the mainstream press than a scientific journal at this point, since many potential peer reviewers seem to feel that Dr Nissen's analyses are missing key elements that could have been added."
Other doctors highlighted the stress caused to patients by all the media coverage of the study. Dr Darren McGuire (University of Texas Southwestern, Dallas) commented to heartwire: “All the sensationalism surrounding this observation has created unnecessary chaos and confusion at the patient level." Dr Jim Meade, a family doctor from Watertown, WI, was more outspoken on this issue: “To say that rosiglitazone might be causing heart attacks and CV deaths is above what this study is powered to do. Now that media attention is drawn to this, though, I have to go through the statistical problems with this study just to reassure all the patients who have called me. This type of hype is making life for doctors harder. It confuses patients, erodes trust, and in the end erodes trust even in the research we rely on."
No need for Molotov cocktails
Haffner said the results of Nissen’s analysis were not a surprise, as the two large studies conducted recently with rosiglitazone (ADOPT and DREAM) suggested some increased cardiovascular risk. “The FDA was well aware of the cardiovascular data with rosiglitazone. The cardiorenal advisory board has a calm and sedate head, unlike Steve Nissen. They would have come to the right decision to put a black-box warning on the label, which is what they will still do, in my view. They are not going to pull it from the market. So, the data would have come out anyway, but without so many fireworks. I don’t think throwing Molotov cocktails is the way to go about these things.”
Don’t panic
An editorial published online May 23, 2007 in the Lancet weighs in on the debate, urging calm [3]. It points out that the two most reliable studies to inform decision-making are ADOPT and DREAM. The DREAM study showed MI rates of 0.6% for rosiglitazone group vs 0.3% for controls, and the MI/stroke/cardiovascular composite occurred in 1.2% of rosiglitazone vs 0.9% of control patients, with neither result reaching statistical significance. The only significantly relevant finding in the ADOPT trial was an excess of congestive heart failure episodes for rosiglitazone-treated patients compared with glyburide (22 vs 9 events), the editorial adds.
“Taken together, these results, although based on very small numbers of events, certainly raise a signal of concern and indicate the need for more reliable information about rosiglitazone’s safety. But the FDA, physicians, and patients can reasonably await the results of RECORD, a phase 3 trial designed specifically to study cardiovascular outcomes. Until the results of RECORD are in, it would be premature to overinterpret a meta-analysis that the authors and NEJM editorialists all acknowledge contains important weaknesses. To avoid unnecessary panic among patients, a calmer and more considered approach to the safety of rosiglitazone is needed. Alarmist headlines and confident declarations help nobody," the Lancet editorial concludes.
Inaccurate estimate of risk
On the limitations of Nissen’s analysis, Haffner explained that one of the main concerns he has is the fact that it used a statistical technique that weighted the studies by the number of subjects included. “This would be acceptable if the studies were of a similar length, but the analysis included two large-scale studies with long-term follow-up and 40 smaller studies with much shorter follow-up. Under these circumstances, the smaller studies have been overweighted," he said.
Haffner added that if the 43% increase in risk shown in the analysis had occurred in the ongoing RECORD study with rosiglitazone, it would have been stopped a year ago. “I think if a proper meta-analysis were done with rosiglitazone, it would probably show some increased risk, but this would not be significant. The hazard ratio would not be 43%--but it may be 30%. That doesn’t mean it has a clean bill of health, but it doesn’t justify pulling it off the market, either. It’s ludicrous to suggest taking a drug off the market based on flawed data showing p values of 0.03 and 0.06.”
Strom also feels there has been an overreaction to these data. “Nissen did a good job with the data he had, but this meta-analysis is very far from being definitive. If this is all the evidence they have for harm, then people are overreacting. Yes, this meta-analysis is important--but it should be viewed as raising questions, not providing answers."
Strom makes the point that a meta-analysis cannot deal with studies in which no outcomes were seen, which is why such studies were excluded, but from a safety point of view, these studies give important information. He also highlighted the lack of individual data as a huge drawback. “They recognized this and stated it as a limitation in their paper, but you can’t do the correct analysis without the individual data, and maybe they shouldn’t have tried. They ended up doing the wrong analysis. These are very borderline findings--p values of 0.03 for MI and 0.06 for CV death, and doing a different analysis could easily have generated a different answer. Their findings are therefore only suggestive at most.
“I’m not panicking about this. I think these drugs are overused, but I do have some patients on rosiglitazone, and I will not take them off it just because of this study. It is an interesting hypothesis but far from conclusive," Strom added.
What is the absolute increase in risk?
McGuire believes a cardiovascular safety signal does exist within the rosiglitazone data set, but he adds that “to present the data as point estimates of risk without the clear context of the absolute signal is irresponsible and alarmist." He explains that the worst-case scenario from these data is that rosiglitazone would elevate risk for MI from 1.4% to 2%. “So, a safety signal--yes. An emergency call to remove the drug from the market and cause global chaos among patients taking the drug? No. At least three large-scale trials currently under way will have much more robust power to evaluate these effects. With this small safety signal, we can afford to wait for the additional data being accumulated."
“These are the data we have--they shouldn’t be ignored”
One unlikely source of support for Nissen’s paper came from GlaxoSmithKline’s CEO, Jean-Pierre Garnier, who told journalists that the controversy was “an overreaction to a publication that was actually quite sensibly written."
But Dr David Nathan (Harvard Medical School, Boston, MA), who was one of the reviewers of the NEJM paper, is not so sure that people have overreacted. “Yes, this was an imperfect analysis. It can’t be looked at as definitive, but at the same time the findings shouldn’t be ignored," he told heartwire. “GlaxoSmithKline had the opportunity to collaborate, and they chose not to. They say they have more data, but why have they not published it? If they can produce convincing data, we can become more relaxed about this drug. But for the moment all we have is Nissen’s analysis," he added.
“I’m advising patients to discuss this with their doctors--there are other choices for the treatment of diabetes. It certainly doesn’t make much sense to me to use a drug that is potentially cardiotoxic in a condition that causes heart disease. Given the choice of all the drugs available I would be very cautious about using this medicine," Nathan said.
What about pioglitazone?
And what effect will all this have on the other thiazolidinedione (TZD)--pioglitazone (Actos, Takeda)? Opinions on this also seem to vary. Nathan believes pioglitazone is a better bet than rosiglitazone, as it does not have the same adverse lipid profile. “I don’t use a lot of these drugs, but if I do use one it would be pioglitazone. PROACTIVE in my opinion was a terribly done study, but even with its flaws, the data appear to show that, if anything, there may be a protective effect of pioglitazone against heart disease."
Haffner takes a slightly different view on this: “While the PROACTIVE trial with pioglitazone did not suggest harm, it did not show benefit either. All the talk of cardiovascular benefit in this trial has been manufactured. I don’t think there is much to choose from between the two drugs. The studies overall have eliminated any idea that TZDs would protect against cardiovascular disease. It’s plain now that they don’t. I would say that it is not clear if they actually increase risk, as the rosiglitazone data are very thin, but we can definitely now say that they do not protect," he commented to heartwire.
“It’s my guess that the TZDs will now start a long decline. These drugs are overused, but we don’t have many options, and they do have a place in the treatment of diabetes. Not as first or second line--more like third line. In my view the fracture data will be more damaging to these drugs than the cardiovascular risks. They double the risk of fractures and this is a big fear factor, particularly for older women," Haffner added.
Implications for regulatory process
All the controversy generated on rosiglitazone this week has again focused attention on the process regulating drug approvals and postmarketing surveillance.
On this, Califf says: “Dr Nissen has done us a favor by pressing the issue that we have an inadequate postmarketing system that is falling further behind." And Dr Salim Yusuf (McMaster University, Hamilton, ON) also praises Nissen for demanding new standards in approving drugs. “We need data on both-long term efficacy and safety before these drugs are used widely," he commented.
McGuire points out that while the cardiovascular effects of rosiglitazone remain uncertain, so do those of every drug ever approved for the treatment of diabetes, due to the complete reliance on HbA1c as a registration end point. “We must demand more rigorous appraisal of existing and emerging therapies for diabetes with regard to CV efficacy and safety," he said.
But Strom highlights the difficulties of requiring outcome studies before approval. “The problem is that these studies take a long time to conduct, and we have to ask whether we should deny patients access to the drug while these studies are under way. My view is that these studies should be done, and the drugs should be available while they are being done, but only selectively to patients that really need them. The situation we have now is that new drugs are grossly overused too early.”
Congress now involved
The Wall Street Journal (WSJ) reports that the rosiglitazone affair is now moving to Capitol Hill [4]. It says that Sen Charles Grassley (R-IA) has written to the FDA expressing concern that "tens of thousands of excess heart attacks may have occurred" since the FDA began reviewing data from Glaxo's meta-analysis, and he has also sent a letter to Glaxo mentioning "reports that GSK employees silenced one or more medical professionals who attempted to speak out about the potential for cardiovascular problems with Avandia." The company has called the suggestion "absolutely false." Democratic Rep Henry Waxman of California said he will hold a hearing on the matter in early June and summon the FDA commissioner, GSK's Garnier, and Nissen.
Meanwhile Europe's main medical regulator, EMEA, said it has already assessed the majority of the studies included in the NEJM paper, and the European Union product information was updated in September 2006 with information about the risk of cardiac events.
Nissen: A public safety net?
Other media coverage surrounding the rosiglitazone saga has focused on Nissen himself. The WSJ chronicled the background to the current study, noting that Nissen first became interested in rosiglitazone after finding that cardiovascular side effects were an issue with a related drug, muraglitazar. After publishing these findings, he received an email from a diabetes expert suggesting that rosiglitazone may have similar issues. Then last year, after seeing signs of cardiovascular problems in the DREAM and ADOPT studies, he started searching for more data, which he found on the FDA and GlaxoSmithKline websites. Cleveland Clinic statistician Kathy Wolski, who helped Nissen with the analysis, describes him in the WSJ article as “a dog with a bone" in his determination to investigate this issue.
As Nissen was also involved in the downfall of Vioxx (rofecoxib, Merck), he is gaining somewhat of a reputation as a drug watchdog. An Associated Press report describes Nissen as a “public safety net," adding: "As criticism of the FDA mounts, Nissen, aided by powerful medical journals and government officials, has become a de facto drug regulator." But one blogger on the WSJ site has a less charitable take on Nissen’s actions, noting that his unfavorable studies are focused on drugs and companies that are not supporting large trials with the Cleveland Clinic [5]. “Wake up pharmaceutical companies. . . . If you don’t hire the Cleveland Clinic for your big trials then you face the firing squad from Nissen and company," he jests.
Rosiglitazone is taken by about seven million people worldwide and brings in sales of more than $3 billion for GlaxoSmithKline. Analysts have warned that these new safety concerns could cut sales by 50%, and shares in GlaxoSmithKline have plummeted
Was the NEJM right to publish?
Several opinion leaders contacted by heartwire expressed concern that the meta-analysis, which was led by Dr Steve Nissen (Cleveland Clinic), was published in such a high-profile journal, with an editorial that fueled the flames [2], when the data were so far from perfect.
Dr Steven Haffner (University of Texas Health Science Center, San Antonio), who was involved in the ADOPT study of rosiglitazone, said the paper needed to be published, but it should have undergone a more extensive review, and there should have been a different editorial with more emphasis on the flaws of the study. “The NEJM was irresponsible to go to [Drs Bruce] Psaty and [Curt] Furberg for the editorial--they were always going to emphasize concerns about drug safety; that’s what they do," he commented. “But I’m not surprised this paper was published like this. The three major medical journals are becoming more like British tabloid newspapers--all they lack is a bare-chested woman on page 3," he jibed.
Dr Brian Strom (University of Pennsylvania, Philadelphia) agrees. “Drugs are given because they have benefits. Where there’s a scare, people stop taking them. So you can do more harm than good if the scare is not based on correct information. I do believe this meta-analysis should have been published, but a less sensational editorial would have been better," he told heartwire.
Dr Robert Califf (Duke University, Durham, NC) made the point that news reporting should follow scientific discussion on drug-safety issues, not precede it. “It would be better if we had a system of postmarketing signal detection in which signals were vetted scientifically rather than splashed over TV and newspapers. I can't help but wonder if the NEJM is functioning more like the mainstream press than a scientific journal at this point, since many potential peer reviewers seem to feel that Dr Nissen's analyses are missing key elements that could have been added."
Other doctors highlighted the stress caused to patients by all the media coverage of the study. Dr Darren McGuire (University of Texas Southwestern, Dallas) commented to heartwire: “All the sensationalism surrounding this observation has created unnecessary chaos and confusion at the patient level." Dr Jim Meade, a family doctor from Watertown, WI, was more outspoken on this issue: “To say that rosiglitazone might be causing heart attacks and CV deaths is above what this study is powered to do. Now that media attention is drawn to this, though, I have to go through the statistical problems with this study just to reassure all the patients who have called me. This type of hype is making life for doctors harder. It confuses patients, erodes trust, and in the end erodes trust even in the research we rely on."
No need for Molotov cocktails
Haffner said the results of Nissen’s analysis were not a surprise, as the two large studies conducted recently with rosiglitazone (ADOPT and DREAM) suggested some increased cardiovascular risk. “The FDA was well aware of the cardiovascular data with rosiglitazone. The cardiorenal advisory board has a calm and sedate head, unlike Steve Nissen. They would have come to the right decision to put a black-box warning on the label, which is what they will still do, in my view. They are not going to pull it from the market. So, the data would have come out anyway, but without so many fireworks. I don’t think throwing Molotov cocktails is the way to go about these things.”
Don’t panic
An editorial published online May 23, 2007 in the Lancet weighs in on the debate, urging calm [3]. It points out that the two most reliable studies to inform decision-making are ADOPT and DREAM. The DREAM study showed MI rates of 0.6% for rosiglitazone group vs 0.3% for controls, and the MI/stroke/cardiovascular composite occurred in 1.2% of rosiglitazone vs 0.9% of control patients, with neither result reaching statistical significance. The only significantly relevant finding in the ADOPT trial was an excess of congestive heart failure episodes for rosiglitazone-treated patients compared with glyburide (22 vs 9 events), the editorial adds.
“Taken together, these results, although based on very small numbers of events, certainly raise a signal of concern and indicate the need for more reliable information about rosiglitazone’s safety. But the FDA, physicians, and patients can reasonably await the results of RECORD, a phase 3 trial designed specifically to study cardiovascular outcomes. Until the results of RECORD are in, it would be premature to overinterpret a meta-analysis that the authors and NEJM editorialists all acknowledge contains important weaknesses. To avoid unnecessary panic among patients, a calmer and more considered approach to the safety of rosiglitazone is needed. Alarmist headlines and confident declarations help nobody," the Lancet editorial concludes.
Inaccurate estimate of risk
On the limitations of Nissen’s analysis, Haffner explained that one of the main concerns he has is the fact that it used a statistical technique that weighted the studies by the number of subjects included. “This would be acceptable if the studies were of a similar length, but the analysis included two large-scale studies with long-term follow-up and 40 smaller studies with much shorter follow-up. Under these circumstances, the smaller studies have been overweighted," he said.
Haffner added that if the 43% increase in risk shown in the analysis had occurred in the ongoing RECORD study with rosiglitazone, it would have been stopped a year ago. “I think if a proper meta-analysis were done with rosiglitazone, it would probably show some increased risk, but this would not be significant. The hazard ratio would not be 43%--but it may be 30%. That doesn’t mean it has a clean bill of health, but it doesn’t justify pulling it off the market, either. It’s ludicrous to suggest taking a drug off the market based on flawed data showing p values of 0.03 and 0.06.”
Strom also feels there has been an overreaction to these data. “Nissen did a good job with the data he had, but this meta-analysis is very far from being definitive. If this is all the evidence they have for harm, then people are overreacting. Yes, this meta-analysis is important--but it should be viewed as raising questions, not providing answers."
Strom makes the point that a meta-analysis cannot deal with studies in which no outcomes were seen, which is why such studies were excluded, but from a safety point of view, these studies give important information. He also highlighted the lack of individual data as a huge drawback. “They recognized this and stated it as a limitation in their paper, but you can’t do the correct analysis without the individual data, and maybe they shouldn’t have tried. They ended up doing the wrong analysis. These are very borderline findings--p values of 0.03 for MI and 0.06 for CV death, and doing a different analysis could easily have generated a different answer. Their findings are therefore only suggestive at most.
“I’m not panicking about this. I think these drugs are overused, but I do have some patients on rosiglitazone, and I will not take them off it just because of this study. It is an interesting hypothesis but far from conclusive," Strom added.
What is the absolute increase in risk?
McGuire believes a cardiovascular safety signal does exist within the rosiglitazone data set, but he adds that “to present the data as point estimates of risk without the clear context of the absolute signal is irresponsible and alarmist." He explains that the worst-case scenario from these data is that rosiglitazone would elevate risk for MI from 1.4% to 2%. “So, a safety signal--yes. An emergency call to remove the drug from the market and cause global chaos among patients taking the drug? No. At least three large-scale trials currently under way will have much more robust power to evaluate these effects. With this small safety signal, we can afford to wait for the additional data being accumulated."
“These are the data we have--they shouldn’t be ignored”
One unlikely source of support for Nissen’s paper came from GlaxoSmithKline’s CEO, Jean-Pierre Garnier, who told journalists that the controversy was “an overreaction to a publication that was actually quite sensibly written."
But Dr David Nathan (Harvard Medical School, Boston, MA), who was one of the reviewers of the NEJM paper, is not so sure that people have overreacted. “Yes, this was an imperfect analysis. It can’t be looked at as definitive, but at the same time the findings shouldn’t be ignored," he told heartwire. “GlaxoSmithKline had the opportunity to collaborate, and they chose not to. They say they have more data, but why have they not published it? If they can produce convincing data, we can become more relaxed about this drug. But for the moment all we have is Nissen’s analysis," he added.
“I’m advising patients to discuss this with their doctors--there are other choices for the treatment of diabetes. It certainly doesn’t make much sense to me to use a drug that is potentially cardiotoxic in a condition that causes heart disease. Given the choice of all the drugs available I would be very cautious about using this medicine," Nathan said.
What about pioglitazone?
And what effect will all this have on the other thiazolidinedione (TZD)--pioglitazone (Actos, Takeda)? Opinions on this also seem to vary. Nathan believes pioglitazone is a better bet than rosiglitazone, as it does not have the same adverse lipid profile. “I don’t use a lot of these drugs, but if I do use one it would be pioglitazone. PROACTIVE in my opinion was a terribly done study, but even with its flaws, the data appear to show that, if anything, there may be a protective effect of pioglitazone against heart disease."
Haffner takes a slightly different view on this: “While the PROACTIVE trial with pioglitazone did not suggest harm, it did not show benefit either. All the talk of cardiovascular benefit in this trial has been manufactured. I don’t think there is much to choose from between the two drugs. The studies overall have eliminated any idea that TZDs would protect against cardiovascular disease. It’s plain now that they don’t. I would say that it is not clear if they actually increase risk, as the rosiglitazone data are very thin, but we can definitely now say that they do not protect," he commented to heartwire.
“It’s my guess that the TZDs will now start a long decline. These drugs are overused, but we don’t have many options, and they do have a place in the treatment of diabetes. Not as first or second line--more like third line. In my view the fracture data will be more damaging to these drugs than the cardiovascular risks. They double the risk of fractures and this is a big fear factor, particularly for older women," Haffner added.
Implications for regulatory process
All the controversy generated on rosiglitazone this week has again focused attention on the process regulating drug approvals and postmarketing surveillance.
On this, Califf says: “Dr Nissen has done us a favor by pressing the issue that we have an inadequate postmarketing system that is falling further behind." And Dr Salim Yusuf (McMaster University, Hamilton, ON) also praises Nissen for demanding new standards in approving drugs. “We need data on both-long term efficacy and safety before these drugs are used widely," he commented.
McGuire points out that while the cardiovascular effects of rosiglitazone remain uncertain, so do those of every drug ever approved for the treatment of diabetes, due to the complete reliance on HbA1c as a registration end point. “We must demand more rigorous appraisal of existing and emerging therapies for diabetes with regard to CV efficacy and safety," he said.
But Strom highlights the difficulties of requiring outcome studies before approval. “The problem is that these studies take a long time to conduct, and we have to ask whether we should deny patients access to the drug while these studies are under way. My view is that these studies should be done, and the drugs should be available while they are being done, but only selectively to patients that really need them. The situation we have now is that new drugs are grossly overused too early.”
Congress now involved
The Wall Street Journal (WSJ) reports that the rosiglitazone affair is now moving to Capitol Hill [4]. It says that Sen Charles Grassley (R-IA) has written to the FDA expressing concern that "tens of thousands of excess heart attacks may have occurred" since the FDA began reviewing data from Glaxo's meta-analysis, and he has also sent a letter to Glaxo mentioning "reports that GSK employees silenced one or more medical professionals who attempted to speak out about the potential for cardiovascular problems with Avandia." The company has called the suggestion "absolutely false." Democratic Rep Henry Waxman of California said he will hold a hearing on the matter in early June and summon the FDA commissioner, GSK's Garnier, and Nissen.
Meanwhile Europe's main medical regulator, EMEA, said it has already assessed the majority of the studies included in the NEJM paper, and the European Union product information was updated in September 2006 with information about the risk of cardiac events.
Nissen: A public safety net?
Other media coverage surrounding the rosiglitazone saga has focused on Nissen himself. The WSJ chronicled the background to the current study, noting that Nissen first became interested in rosiglitazone after finding that cardiovascular side effects were an issue with a related drug, muraglitazar. After publishing these findings, he received an email from a diabetes expert suggesting that rosiglitazone may have similar issues. Then last year, after seeing signs of cardiovascular problems in the DREAM and ADOPT studies, he started searching for more data, which he found on the FDA and GlaxoSmithKline websites. Cleveland Clinic statistician Kathy Wolski, who helped Nissen with the analysis, describes him in the WSJ article as “a dog with a bone" in his determination to investigate this issue.
As Nissen was also involved in the downfall of Vioxx (rofecoxib, Merck), he is gaining somewhat of a reputation as a drug watchdog. An Associated Press report describes Nissen as a “public safety net," adding: "As criticism of the FDA mounts, Nissen, aided by powerful medical journals and government officials, has become a de facto drug regulator." But one blogger on the WSJ site has a less charitable take on Nissen’s actions, noting that his unfavorable studies are focused on drugs and companies that are not supporting large trials with the Cleveland Clinic [5]. “Wake up pharmaceutical companies. . . . If you don’t hire the Cleveland Clinic for your big trials then you face the firing squad from Nissen and company," he jests.
Journal Advises Calm in Rosiglitazone (Avandia) Uproar
LONDON, May 24 -- The editors of The Lancet have cautioned against a rush to judgment in the face of a meta-analysis released Monday that linked the diabetes drug rosiglitazone (Avandia) to a 43% increase in relative risk of myocardial infarction.
In an unsigned editorial posted online Wednesday, The Lancet agreed that results of a meta-analysis published by the New England Journal of Medicine "certainly raise a signal of concern" that should be pursued, but it urged a wait-and-see approach.
Charactering the tone of the NEJM paper as "one of urgency," the British journal asserted, "To avoid unnecessary panic among patients, a calmer and more considered approach to the safety of rosiglitazone is needed. Alarmist headlines and confident declarations help nobody."
The FDA, physicians, and patients "can reasonably await the results of RECORD, a phase III trial designed specifically to study cardiovascular outcomes," said the editorial.
Until those data are available, "it would be premature to over-interpret a meta-analysis that the authors and NEJM editorialists all acknowledge contains important weaknesses," said The Lancet.
The odds ratio for MI was 1.43 (95% confidence interval 1.03-1.98, P=0.03), said Steven E. Nissen, M.D., of the Cleveland Clinic, lead author of the meta-analysis.
But the absolute number of rosiglitazone-associated events was small -- 86 MIs in the rosiglitazone patients versus 72 in the controls and 39 cardiovascular deaths versus 22 cardiovascular deaths in the control arm -- so even a slight change could tip the balance toward a null finding.
Nonetheless, Dr. Nissen said in an interview that he was confident that the cardiovascular risk was real and that the signal was lurking from the very beginning. There were, he said, an excess number of cardiovascular events in the registry data given to the FDA during the initial approval process. "Although those events did not reach statistical significance, the data were all going the wrong way."
Dr. Nissen concluded, "If I had been a member of the FDA advisory panel that reviewed this drug in 1999, I would have voted against approval and would have asked for more studies to assess cardiovascular risk."
According to a report in today's New York Times at least one other physician identified a risk early on -- John R. Buse, M.D., of the University of North Carolina. He wrote to the FDA in 2000 to inform the agency of "a worrisome trend in cardiovascular deaths and adverse events."
Dr. Buse, who is president-elect of the American Diabetes Association, told the newspaper that his opinion of rosiglitazone has not changed since 2000.
Rep. Henry Waxman (D-Calif.) will conduct a hearing into the FDA's oversight of the safety of rosiglitazone. Dr. Buse, along with Dr. Nissen, are expected to be star witnesses at that hearing, which is scheduled for June 6.
The weaknesses in the meta-analysis involve the data, which were obtained from the FDA, a clinical trials registry website maintained by GlaxoSmithKline, which markets rosiglitazone, and published trials. There were no patient-level data and no time-to-event studies.
At a press conference on Monday, Robert J. Meyer, M.D., of the FDA's Center for Drug Evaluation and Research, said the agency had reviewed data that contradicted the findings of the Dr. Nissen's analysis. Yet he conceded that early findings from the FDA's own meta-analysis also found an increased cardiovascular risk.
GlaxoSmithKline was also critical of the Nissen findings. Nonetheless, it acknowledged that a meta-analysis conducted by its own researchers had identified an increased cardiovascular risk, although not as great as the risk reported in the NEJM.
In an unsigned editorial posted online Wednesday, The Lancet agreed that results of a meta-analysis published by the New England Journal of Medicine "certainly raise a signal of concern" that should be pursued, but it urged a wait-and-see approach.
Charactering the tone of the NEJM paper as "one of urgency," the British journal asserted, "To avoid unnecessary panic among patients, a calmer and more considered approach to the safety of rosiglitazone is needed. Alarmist headlines and confident declarations help nobody."
The FDA, physicians, and patients "can reasonably await the results of RECORD, a phase III trial designed specifically to study cardiovascular outcomes," said the editorial.
Until those data are available, "it would be premature to over-interpret a meta-analysis that the authors and NEJM editorialists all acknowledge contains important weaknesses," said The Lancet.
The odds ratio for MI was 1.43 (95% confidence interval 1.03-1.98, P=0.03), said Steven E. Nissen, M.D., of the Cleveland Clinic, lead author of the meta-analysis.
But the absolute number of rosiglitazone-associated events was small -- 86 MIs in the rosiglitazone patients versus 72 in the controls and 39 cardiovascular deaths versus 22 cardiovascular deaths in the control arm -- so even a slight change could tip the balance toward a null finding.
Nonetheless, Dr. Nissen said in an interview that he was confident that the cardiovascular risk was real and that the signal was lurking from the very beginning. There were, he said, an excess number of cardiovascular events in the registry data given to the FDA during the initial approval process. "Although those events did not reach statistical significance, the data were all going the wrong way."
Dr. Nissen concluded, "If I had been a member of the FDA advisory panel that reviewed this drug in 1999, I would have voted against approval and would have asked for more studies to assess cardiovascular risk."
According to a report in today's New York Times at least one other physician identified a risk early on -- John R. Buse, M.D., of the University of North Carolina. He wrote to the FDA in 2000 to inform the agency of "a worrisome trend in cardiovascular deaths and adverse events."
Dr. Buse, who is president-elect of the American Diabetes Association, told the newspaper that his opinion of rosiglitazone has not changed since 2000.
Rep. Henry Waxman (D-Calif.) will conduct a hearing into the FDA's oversight of the safety of rosiglitazone. Dr. Buse, along with Dr. Nissen, are expected to be star witnesses at that hearing, which is scheduled for June 6.
The weaknesses in the meta-analysis involve the data, which were obtained from the FDA, a clinical trials registry website maintained by GlaxoSmithKline, which markets rosiglitazone, and published trials. There were no patient-level data and no time-to-event studies.
At a press conference on Monday, Robert J. Meyer, M.D., of the FDA's Center for Drug Evaluation and Research, said the agency had reviewed data that contradicted the findings of the Dr. Nissen's analysis. Yet he conceded that early findings from the FDA's own meta-analysis also found an increased cardiovascular risk.
GlaxoSmithKline was also critical of the Nissen findings. Nonetheless, it acknowledged that a meta-analysis conducted by its own researchers had identified an increased cardiovascular risk, although not as great as the risk reported in the NEJM.
AUA: ED Drug May Boost Psyche and Functional Performance
ANAHEIM, Calif., May 24 -- An investigational centrally active melanocortin agonist gives men with erectile dysfunction a psychological boost as well as a physical one, researchers reported here.
Men who used bremelanotide in an intranasal formulation reported improvement in sexual relationships, sexual satisfaction, confidence, and self-esteem. The synthetic peptide also led to significant improvement in erectile function during 12 weeks of on-demand therapy.
"These results indicate that bremelanotide improves sexual confidence and has the potential to be an important treatment option for patients with erectile dysfunction," said psychologist Stanley Althof, Ph.D., of Case Western Reserve in Cleveland, at the American Urological Association meeting.
Bremelanotide is the first of a new class of erectile dysfunction drugs known as melanocortin receptor agonists. Unlike PDE-5 inhibitors, which have a vascular mechanism of action, bremelanotide exerts its effects through the central nervous system. According to the manufacturer, Palatin Technologies of Cranbury, N.J., the agent binds primarily to melanocortin receptor 4 in the hypothalamus, triggering descending neural signals to the penis.
In a multicenter, randomized, placebo-controlled trial, 726 nondiabetic men with erectile dysfunction were randomized to placebo or to one of five intranasal bremelanotide doses ranging between 5 mg and 15 mg, said Dr. Althof. Patients self-administered therapy as needed, 45 minutes before sexual activity.
The study participants had a mean age of 55 years and a six-year history of erectile dysfunction. The population comprised similar numbers of men with mild, moderate, and severe erectile dysfunction, and most of the men had experience with PDE5 inhibitors.
Sexual function was assessed by means of the International Index of Erectile Function (IIEF) at baseline and at the end of the study. Patients assigned to placebo averaged a one-point improvement in IIEF score over the course of the trial. In contrast, patients assigned to bremelanotide doses of 7.5 mg to 15 mg had four- to five-point improvements in IIEF score (P≤0.05 compared with placebo).
As part of the study protocol, participants completed the Self Esteem and Relationship (SEAR) Questionnaire, a 14-item survey instrument that assesses change in two major domains: sexual relationship and confidence, said Dr. Althof. The confidence domain has two sub-domains of self-esteem and overall relationship.
Patients randomized to all but the lowest (5 mg) bremelanotide doses improved by about 15 to 17 points on the sexual relationship domain of SEAR, compared to about a five-point improvement in the placebo group (p≤0.01) In general, the bremelanotide groups had greater improvement in the remaining major and minor domains compared to placebo, but the differences were not statistically significant.
Dr. Althof said that SEAR scores improved across all categories of erectile dysfunction severity, although patients with mild or severe ED tended to derive the greatest overall benefit. In addition, IIEF and SEAR domains exhibited statistically significant correlations.
Another bremelanotide study reported here involved 294 men with diabetes and erectile dysfunction. The patients were randomized to placebo or one of three doses of bremelanotide (10, 12.5, or 15 mg) and self-administered treatment as needed for 12 weeks.
Patients assigned to the two highest bremelanotide doses had significantly greater improvement in the erectile function domain of the IIEF compared to placebo (P<0.05), said urologist Christopher Steidle, M.D., of Indiana University in Indianapolis.
In both studies, bremelanotide-treated patients had higher rates of adverse effects compared to placebo, but the effects tended to be mild or moderate in severity. More common adverse events reported by bremelanotide patients included nausea, emesis, flushing, transient increases in blood pressure, headache, spontaneous erection, skin darkening, and nasal symptoms.
Bremelanotide is not a new drug, commented Ira Sharlip, M.D., of the University of California San Francisco, and a spokesperson for the AUA. The agent originally was developed as a skin-tanning product. Thus far, clinical results with the intranasal formulation developed for management of erectile dysfunction have been promising, he said.
"It has a different mechanism of action, so that creates the potential for combination therapy with a PDE5 inhibitor," said Dr. Sharlip. "Right now the manufacturer is evaluating it as monotherapy, but I wouldn't be surprised to see bremelanotide and a PDE5 inhibitor used in combination."
Men who used bremelanotide in an intranasal formulation reported improvement in sexual relationships, sexual satisfaction, confidence, and self-esteem. The synthetic peptide also led to significant improvement in erectile function during 12 weeks of on-demand therapy.
"These results indicate that bremelanotide improves sexual confidence and has the potential to be an important treatment option for patients with erectile dysfunction," said psychologist Stanley Althof, Ph.D., of Case Western Reserve in Cleveland, at the American Urological Association meeting.
Bremelanotide is the first of a new class of erectile dysfunction drugs known as melanocortin receptor agonists. Unlike PDE-5 inhibitors, which have a vascular mechanism of action, bremelanotide exerts its effects through the central nervous system. According to the manufacturer, Palatin Technologies of Cranbury, N.J., the agent binds primarily to melanocortin receptor 4 in the hypothalamus, triggering descending neural signals to the penis.
In a multicenter, randomized, placebo-controlled trial, 726 nondiabetic men with erectile dysfunction were randomized to placebo or to one of five intranasal bremelanotide doses ranging between 5 mg and 15 mg, said Dr. Althof. Patients self-administered therapy as needed, 45 minutes before sexual activity.
The study participants had a mean age of 55 years and a six-year history of erectile dysfunction. The population comprised similar numbers of men with mild, moderate, and severe erectile dysfunction, and most of the men had experience with PDE5 inhibitors.
Sexual function was assessed by means of the International Index of Erectile Function (IIEF) at baseline and at the end of the study. Patients assigned to placebo averaged a one-point improvement in IIEF score over the course of the trial. In contrast, patients assigned to bremelanotide doses of 7.5 mg to 15 mg had four- to five-point improvements in IIEF score (P≤0.05 compared with placebo).
As part of the study protocol, participants completed the Self Esteem and Relationship (SEAR) Questionnaire, a 14-item survey instrument that assesses change in two major domains: sexual relationship and confidence, said Dr. Althof. The confidence domain has two sub-domains of self-esteem and overall relationship.
Patients randomized to all but the lowest (5 mg) bremelanotide doses improved by about 15 to 17 points on the sexual relationship domain of SEAR, compared to about a five-point improvement in the placebo group (p≤0.01) In general, the bremelanotide groups had greater improvement in the remaining major and minor domains compared to placebo, but the differences were not statistically significant.
Dr. Althof said that SEAR scores improved across all categories of erectile dysfunction severity, although patients with mild or severe ED tended to derive the greatest overall benefit. In addition, IIEF and SEAR domains exhibited statistically significant correlations.
Another bremelanotide study reported here involved 294 men with diabetes and erectile dysfunction. The patients were randomized to placebo or one of three doses of bremelanotide (10, 12.5, or 15 mg) and self-administered treatment as needed for 12 weeks.
Patients assigned to the two highest bremelanotide doses had significantly greater improvement in the erectile function domain of the IIEF compared to placebo (P<0.05), said urologist Christopher Steidle, M.D., of Indiana University in Indianapolis.
In both studies, bremelanotide-treated patients had higher rates of adverse effects compared to placebo, but the effects tended to be mild or moderate in severity. More common adverse events reported by bremelanotide patients included nausea, emesis, flushing, transient increases in blood pressure, headache, spontaneous erection, skin darkening, and nasal symptoms.
Bremelanotide is not a new drug, commented Ira Sharlip, M.D., of the University of California San Francisco, and a spokesperson for the AUA. The agent originally was developed as a skin-tanning product. Thus far, clinical results with the intranasal formulation developed for management of erectile dysfunction have been promising, he said.
"It has a different mechanism of action, so that creates the potential for combination therapy with a PDE5 inhibitor," said Dr. Sharlip. "Right now the manufacturer is evaluating it as monotherapy, but I wouldn't be surprised to see bremelanotide and a PDE5 inhibitor used in combination."
Subscribe to:
Posts (Atom)