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Women Wait Longer for Emergency Angioplasty
Women who presented to Michigan hospitals with acute ST-segment elevation myocardial infarction waited significantly longer than men to undergo emergency angioplasty—and even men waited too long according to Mauro Moscucci, M.D., the lead, investigator in the study.
“We have an ideal target for quality improvement, something we can easily try to correct,” said Dr. Moscucci, who presented the data at the scientific sessions of the American Heart Association and discussed the findings in a later interview. “If we can improve our treatment times, we can substantially reduce the risk of death.”
Dr. Moscucci and his associates analyzed data collected on 1,551 patients who had primary percutaneous coronary intervention for acute ST-segment elevation during a 20-month period ending in June 2004. Patients had the procedure at 1 of the 16 hospitals participating in the regional Blue Cross Blue Shield of Michigan Cardiovascular Consortium.
The investigators found that only 26% of the 442 women who had an emergency angioplasty—and 34% of the 1,069 men—had the procedure within the 90-minute time frame recommended by the American Heart Association and the American College of Cardiology.
On average, women waited more than 118 minutes before treatment began, compared with 106 minutes for men.
Patients of both sexes whose angioplasty began within 90 minutes of arrival at the hospital had a 50% lower risk of dying in the hospital than those who waited longer, said Dr. Moscucci, director of interventional cardiology at the University of Michigan Cardiovascular Center, Ann Arbor.
“Since there's been such a focus on angioplasty recently, we wondered whether the recommended door-to-balloon time of 90 minutes was still significant in terms of survival,” he said. “We found that it's still an important predictor of in-hospital mortality, and that perhaps we're not doing as well as we should.”
Women in the study were more than twice as likely as men to die in the hospital; their mortality rate was about 7%, compared with about 3% in men. When the investigators adjusted for the average older age of women and the higher frequency of comorbidities, they still found higher in-hospital mortality rates for women, Dr. Moscucci said.
The gender-difference findings augment a growing body of research showing that women with heart attacks seek care later, present more often with atypical symptoms and comorbidities such as severe diabetes, and face delays in treatment, he said.
In addition to the greater delays in treatment, the Michigan study showed that it takes longer for women to get to an emergency department in the first place. Women reported that their symptoms started an average of 105 minutes before they got to the emergency department; the average time for men was 85 minutes.
Dr. Moscucci said that hospital procedures for activating cardiac catheterization labs vary significantly. Labs could be activated faster—which, along with faster diagnosis, would help hasten door-to-balloon times—if more ambulances had the capability to automatically read or transmit ECGs and if more hospitals allowed emergency physicians and not just cardiologists to activate the labs directly, he said.
A recent survey of more than 1,000 women older than 35 years showed that only 47% of women who had head, neck, back, and jaw pain—typical heart attack symptoms— would call their doctor, and just 35% would call 911 or visit an emergency department.
“Women and their families still need a great deal of education. Their symptoms can be very atypical—perhaps only weakness, difficulty breathing, or dizziness,” said Michael J. Bresler, M.D., professor of emergency medicine at Stanford (Calif.) University. Women in whom heart attack is diagnosed “should be rushed to the cath lab or quickly given a lytic drug if immediate catheterization isn't available,” he said.
Women who presented to Michigan hospitals with acute ST-segment elevation myocardial infarction waited significantly longer than men to undergo emergency angioplasty—and even men waited too long according to Mauro Moscucci, M.D., the lead, investigator in the study.
“We have an ideal target for quality improvement, something we can easily try to correct,” said Dr. Moscucci, who presented the data at the scientific sessions of the American Heart Association and discussed the findings in a later interview. “If we can improve our treatment times, we can substantially reduce the risk of death.”
Dr. Moscucci and his associates analyzed data collected on 1,551 patients who had primary percutaneous coronary intervention for acute ST-segment elevation during a 20-month period ending in June 2004. Patients had the procedure at 1 of the 16 hospitals participating in the regional Blue Cross Blue Shield of Michigan Cardiovascular Consortium.
The investigators found that only 26% of the 442 women who had an emergency angioplasty—and 34% of the 1,069 men—had the procedure within the 90-minute time frame recommended by the American Heart Association and the American College of Cardiology.
On average, women waited more than 118 minutes before treatment began, compared with 106 minutes for men.
Patients of both sexes whose angioplasty began within 90 minutes of arrival at the hospital had a 50% lower risk of dying in the hospital than those who waited longer, said Dr. Moscucci, director of interventional cardiology at the University of Michigan Cardiovascular Center, Ann Arbor.
“Since there's been such a focus on angioplasty recently, we wondered whether the recommended door-to-balloon time of 90 minutes was still significant in terms of survival,” he said. “We found that it's still an important predictor of in-hospital mortality, and that perhaps we're not doing as well as we should.”
Women in the study were more than twice as likely as men to die in the hospital; their mortality rate was about 7%, compared with about 3% in men. When the investigators adjusted for the average older age of women and the higher frequency of comorbidities, they still found higher in-hospital mortality rates for women, Dr. Moscucci said.
The gender-difference findings augment a growing body of research showing that women with heart attacks seek care later, present more often with atypical symptoms and comorbidities such as severe diabetes, and face delays in treatment, he said.
In addition to the greater delays in treatment, the Michigan study showed that it takes longer for women to get to an emergency department in the first place. Women reported that their symptoms started an average of 105 minutes before they got to the emergency department; the average time for men was 85 minutes.
Dr. Moscucci said that hospital procedures for activating cardiac catheterization labs vary significantly. Labs could be activated faster—which, along with faster diagnosis, would help hasten door-to-balloon times—if more ambulances had the capability to automatically read or transmit ECGs and if more hospitals allowed emergency physicians and not just cardiologists to activate the labs directly, he said.
A recent survey of more than 1,000 women older than 35 years showed that only 47% of women who had head, neck, back, and jaw pain—typical heart attack symptoms— would call their doctor, and just 35% would call 911 or visit an emergency department.
“Women and their families still need a great deal of education. Their symptoms can be very atypical—perhaps only weakness, difficulty breathing, or dizziness,” said Michael J. Bresler, M.D., professor of emergency medicine at Stanford (Calif.) University. Women in whom heart attack is diagnosed “should be rushed to the cath lab or quickly given a lytic drug if immediate catheterization isn't available,” he said.
Women who presented to Michigan hospitals with acute ST-segment elevation myocardial infarction waited significantly longer than men to undergo emergency angioplasty—and even men waited too long according to Mauro Moscucci, M.D., the lead, investigator in the study.
“We have an ideal target for quality improvement, something we can easily try to correct,” said Dr. Moscucci, who presented the data at the scientific sessions of the American Heart Association and discussed the findings in a later interview. “If we can improve our treatment times, we can substantially reduce the risk of death.”
Dr. Moscucci and his associates analyzed data collected on 1,551 patients who had primary percutaneous coronary intervention for acute ST-segment elevation during a 20-month period ending in June 2004. Patients had the procedure at 1 of the 16 hospitals participating in the regional Blue Cross Blue Shield of Michigan Cardiovascular Consortium.
The investigators found that only 26% of the 442 women who had an emergency angioplasty—and 34% of the 1,069 men—had the procedure within the 90-minute time frame recommended by the American Heart Association and the American College of Cardiology.
On average, women waited more than 118 minutes before treatment began, compared with 106 minutes for men.
Patients of both sexes whose angioplasty began within 90 minutes of arrival at the hospital had a 50% lower risk of dying in the hospital than those who waited longer, said Dr. Moscucci, director of interventional cardiology at the University of Michigan Cardiovascular Center, Ann Arbor.
“Since there's been such a focus on angioplasty recently, we wondered whether the recommended door-to-balloon time of 90 minutes was still significant in terms of survival,” he said. “We found that it's still an important predictor of in-hospital mortality, and that perhaps we're not doing as well as we should.”
Women in the study were more than twice as likely as men to die in the hospital; their mortality rate was about 7%, compared with about 3% in men. When the investigators adjusted for the average older age of women and the higher frequency of comorbidities, they still found higher in-hospital mortality rates for women, Dr. Moscucci said.
The gender-difference findings augment a growing body of research showing that women with heart attacks seek care later, present more often with atypical symptoms and comorbidities such as severe diabetes, and face delays in treatment, he said.
In addition to the greater delays in treatment, the Michigan study showed that it takes longer for women to get to an emergency department in the first place. Women reported that their symptoms started an average of 105 minutes before they got to the emergency department; the average time for men was 85 minutes.
Dr. Moscucci said that hospital procedures for activating cardiac catheterization labs vary significantly. Labs could be activated faster—which, along with faster diagnosis, would help hasten door-to-balloon times—if more ambulances had the capability to automatically read or transmit ECGs and if more hospitals allowed emergency physicians and not just cardiologists to activate the labs directly, he said.
A recent survey of more than 1,000 women older than 35 years showed that only 47% of women who had head, neck, back, and jaw pain—typical heart attack symptoms— would call their doctor, and just 35% would call 911 or visit an emergency department.
“Women and their families still need a great deal of education. Their symptoms can be very atypical—perhaps only weakness, difficulty breathing, or dizziness,” said Michael J. Bresler, M.D., professor of emergency medicine at Stanford (Calif.) University. Women in whom heart attack is diagnosed “should be rushed to the cath lab or quickly given a lytic drug if immediate catheterization isn't available,” he said.
Estrogen Used to Suppress Growth in Adolescence Linked to Later Infertility
High-dose estrogen therapy for tall stature in adolescent girls appears to reduce fertility later in life, according to a retrospective cohort study.
Estrogen has been used for years in the United States, Europe, and Australia to limit the adult height of tall girls, but little has been known about its long-term effects, said Alison Venn, Ph.D., of the Menzies Research Institute at the University of Tasmania in Australia, and associates.
Medical record reviews and interviews with women who were assessed for height from 1959 on showed that women who were treated with estrogen as growth-suppressant therapy were significantly more likely to have experienced infertility and were more than twice as likely to have ever taken fertility drugs than were women who were not treated (Lancet 2004;364:1513-8).
The number of girls treated in recent years is lower than in the 1960s to 1980s, the investigators said. However, growth-suppressant therapy is still prescribed. A survey of U.S. pediatric endocrinologists published in 2002 found that 96 (23%) of 411 respondents had treated tall girls in the preceding 5 years. Most said they had treated fewer than five girls.
The practice is based on the knowledge that in healthy pubertal development, estrogen leads to the epiphyseal fusion of the long bones. There have been no randomized controlled trials of treatment effectiveness, but height reductions of 2-10 cm have been reported, the investigators said.
Study participants were identified mainly from the medical records of Australian pediatric endocrinologists who assessed tall girls from 1959 to 1993; other participants self-referred in response to publicity about the study.
A cohort of 1,432 eligible women was identified; 1,243 were located and invited to participate. Of the women who were contacted, 780 completed interviews.
Women who had been treated (371 women, mean age of 40 years) and those who were assessed but not treated (409 women, mean age of 38 years) were similar in terms of socioeconomic status, sexual history, and other characteristics.
The type of estrogen treatment was unknown for 25 women, but in all other cases the treated women had been prescribed diethylstilbestrol (DES) or ethinyl estradiol; DES was in use before 1971.
Women treated with DES and ethinyl estradiol were similar in terms of their age at the start of treatment (approximately 13 years), the estimated mature height predicted before treatment (approximately 182 cm), and the duration of treatment (26 months for DES, 24 months for ethinyl estradiol).
Treated women were 80% more likely to have tried for at least 12 months to become pregnant without success; 36% of treated women and 19% of untreated women reported such difficulties.
Treated women were also 80% more likely to have ever seen a doctor because of trouble becoming pregnant, and they were more than twice as likely to have ever taken fertility drugs; 18% of treated women and 8% of untreated women reported taking the drugs.
An analysis of the reported time to first pregnancy showed that the treated group was 40% less likely to conceive in any given menstrual cycle of unprotected intercourse.
Investigators found the same associations when self-referred women were excluded from the analyses.
High-dose estrogen therapy for tall stature in adolescent girls appears to reduce fertility later in life, according to a retrospective cohort study.
Estrogen has been used for years in the United States, Europe, and Australia to limit the adult height of tall girls, but little has been known about its long-term effects, said Alison Venn, Ph.D., of the Menzies Research Institute at the University of Tasmania in Australia, and associates.
Medical record reviews and interviews with women who were assessed for height from 1959 on showed that women who were treated with estrogen as growth-suppressant therapy were significantly more likely to have experienced infertility and were more than twice as likely to have ever taken fertility drugs than were women who were not treated (Lancet 2004;364:1513-8).
The number of girls treated in recent years is lower than in the 1960s to 1980s, the investigators said. However, growth-suppressant therapy is still prescribed. A survey of U.S. pediatric endocrinologists published in 2002 found that 96 (23%) of 411 respondents had treated tall girls in the preceding 5 years. Most said they had treated fewer than five girls.
The practice is based on the knowledge that in healthy pubertal development, estrogen leads to the epiphyseal fusion of the long bones. There have been no randomized controlled trials of treatment effectiveness, but height reductions of 2-10 cm have been reported, the investigators said.
Study participants were identified mainly from the medical records of Australian pediatric endocrinologists who assessed tall girls from 1959 to 1993; other participants self-referred in response to publicity about the study.
A cohort of 1,432 eligible women was identified; 1,243 were located and invited to participate. Of the women who were contacted, 780 completed interviews.
Women who had been treated (371 women, mean age of 40 years) and those who were assessed but not treated (409 women, mean age of 38 years) were similar in terms of socioeconomic status, sexual history, and other characteristics.
The type of estrogen treatment was unknown for 25 women, but in all other cases the treated women had been prescribed diethylstilbestrol (DES) or ethinyl estradiol; DES was in use before 1971.
Women treated with DES and ethinyl estradiol were similar in terms of their age at the start of treatment (approximately 13 years), the estimated mature height predicted before treatment (approximately 182 cm), and the duration of treatment (26 months for DES, 24 months for ethinyl estradiol).
Treated women were 80% more likely to have tried for at least 12 months to become pregnant without success; 36% of treated women and 19% of untreated women reported such difficulties.
Treated women were also 80% more likely to have ever seen a doctor because of trouble becoming pregnant, and they were more than twice as likely to have ever taken fertility drugs; 18% of treated women and 8% of untreated women reported taking the drugs.
An analysis of the reported time to first pregnancy showed that the treated group was 40% less likely to conceive in any given menstrual cycle of unprotected intercourse.
Investigators found the same associations when self-referred women were excluded from the analyses.
High-dose estrogen therapy for tall stature in adolescent girls appears to reduce fertility later in life, according to a retrospective cohort study.
Estrogen has been used for years in the United States, Europe, and Australia to limit the adult height of tall girls, but little has been known about its long-term effects, said Alison Venn, Ph.D., of the Menzies Research Institute at the University of Tasmania in Australia, and associates.
Medical record reviews and interviews with women who were assessed for height from 1959 on showed that women who were treated with estrogen as growth-suppressant therapy were significantly more likely to have experienced infertility and were more than twice as likely to have ever taken fertility drugs than were women who were not treated (Lancet 2004;364:1513-8).
The number of girls treated in recent years is lower than in the 1960s to 1980s, the investigators said. However, growth-suppressant therapy is still prescribed. A survey of U.S. pediatric endocrinologists published in 2002 found that 96 (23%) of 411 respondents had treated tall girls in the preceding 5 years. Most said they had treated fewer than five girls.
The practice is based on the knowledge that in healthy pubertal development, estrogen leads to the epiphyseal fusion of the long bones. There have been no randomized controlled trials of treatment effectiveness, but height reductions of 2-10 cm have been reported, the investigators said.
Study participants were identified mainly from the medical records of Australian pediatric endocrinologists who assessed tall girls from 1959 to 1993; other participants self-referred in response to publicity about the study.
A cohort of 1,432 eligible women was identified; 1,243 were located and invited to participate. Of the women who were contacted, 780 completed interviews.
Women who had been treated (371 women, mean age of 40 years) and those who were assessed but not treated (409 women, mean age of 38 years) were similar in terms of socioeconomic status, sexual history, and other characteristics.
The type of estrogen treatment was unknown for 25 women, but in all other cases the treated women had been prescribed diethylstilbestrol (DES) or ethinyl estradiol; DES was in use before 1971.
Women treated with DES and ethinyl estradiol were similar in terms of their age at the start of treatment (approximately 13 years), the estimated mature height predicted before treatment (approximately 182 cm), and the duration of treatment (26 months for DES, 24 months for ethinyl estradiol).
Treated women were 80% more likely to have tried for at least 12 months to become pregnant without success; 36% of treated women and 19% of untreated women reported such difficulties.
Treated women were also 80% more likely to have ever seen a doctor because of trouble becoming pregnant, and they were more than twice as likely to have ever taken fertility drugs; 18% of treated women and 8% of untreated women reported taking the drugs.
An analysis of the reported time to first pregnancy showed that the treated group was 40% less likely to conceive in any given menstrual cycle of unprotected intercourse.
Investigators found the same associations when self-referred women were excluded from the analyses.
Propranolol, Other Drugs Eyed to Block PTSD : Idea is that blocking β-adrenergic receptors might tone down consolidation of emotional memories.
Over the next several years, victims of car accidents, crimes, or other traumas who are treated at Boston's Massachusetts General Hospital will be offered a commonly used heart drug–the β-adrenergic blocker propranolol–to potentially help lessen the intensity and future impact of traumatic memories.
Patients who participate in this study will be part of a wave of new drug trials aimed at intervening early to alter memory processes and prevent posttraumatic stress disorder (PTSD). Other studies are planned to aim at intervening later to treat PTSD by effecting memory “reconsolidation,” the process by which memories that have been reactivated are then restored.
As neurobiologists press on with research to better understand the mechanisms and processes involved in acquiring and storing traumatic memories, clinical investigators say they cannot wait to field-test propranolol and other commonly available drugs, some of which appear to target specific mechanisms of action in fear memory.
And some physicians may not even be waiting for study results. According to anecdotal reports, propranolol is already being used off label sporadically in the immediate wake of traumatic experiences.
Possible Clinical Benefits
“There's a real good possibility [we'll soon be using] more specific medications than we have now that will help us deal with the effects of psychological trauma [on the brain],” said Dennis S. Charney, M.D., dean of research at Mount Sinai School of Medicine, New York.
“We'll likely be able to use medication to facilitate fear extinction, to reduce the consolidation of fear memories, and in a rational way, to use medications to augment the effects of psychotherapy,” he said.
The study at Massachusetts General builds on a pilot study, published in 2002, that suggested that posttrauma administration of propranolol in the emergency room may have a “preventive effect” on subsequent PTSD. (See sidebar.)
Harvard/NIMH Study Design
Roger Pitman, M.D., who led the pilot study and has a $2.5 million grant from the National Institutes of Mental Health to conduct the larger double-blind randomized study, hopes to recruit at least 100 patients who have both experienced a traumatic event and present with tachycardia of at least 80 beats/min.
According to Dr. Pitman, most of the published and soon to be published studies addressing the issue of tachycardia as a predictor of PTSD “have been positive.”
Patients in his study will be randomized to receive, within 6 hours of the event, a 10-day course of placebo or propranolol followed by a 9-day taper period, said Dr. Pitman, professor of psychiatry at Harvard Medical School, Boston.
Propranolol is commonly used to treat high blood pressure and for other cardiovascular purposes. It is also prescribed, albeit less frequently, as an antianxiety therapy adjunct for people with public speaking anxieties, fear of flying, and other phobias. It is the only β-blocker that can cross the blood-brain barrier, Dr. Pitman said.
Possible Mechanism of Action
Dr. Pitman latched onto the idea of testing the drug for PTSD prevention 10 years ago, when Larry Cahill, Ph.D., of the Center for the Neurobiology of Learning and Memory at the University of California, Irvine, reported that in a small study of healthy people, the drug significantly impaired memory of an emotionally arousing story but did not affect memory of an emotionally neutral story (Nature 1994;371:702-4).
The findings backed a long-standing hypothesis that enhanced memory associated with emotional experiences results from activation of the β-adrenergic stress hormone systems, particularly in the amygdala. If β-adrenergic receptors are blocked, the theory goes, the consolidation of emotional memories–the formation and storage of long-term emotional memories–can be toned down. As some neurobiologists like to describe it, “overconsolidation”–and overly strong emotional memories–can be prevented.
“The study bridged the gap,” Dr. Cahill said. “It looked like what we were seeing in animals would hold up in humans.”
Studying SSRIs for PTSD Prevention
Other physicians have their eyes on the use of selective serotonin reuptake inhibitors (SSRIs) for PTSD prevention.
At Massachusetts General, Mark Pollack, M.D., is testing the SSRI Lexapro (escitalopram) “at the next potential point of intervention”–in patients who, within a few weeks after trauma, are experiencing acute stress symptoms but do not meet the full criteria for PTSD.
The possible mechanisms of action of the SSRIs in such cases are not all clear, but the hope is that the drugs will help interrupt the cycle of increased arousal and anxiety that may predispose to full-blown PTSD, said Dr. Pollack, director of the hospital's Anxiety and Traumatic Stress Disorders Program. SSRIs are often used (with moderate success) today to treat syndromal PTSD.
Physicians at the Center for the Study of Traumatic Stress at the Uniformed Health Services University of the Health Sciences in Bethesda, Md., have started a similar study, administering an SSRI to car accident victims days to several weeks after the event. Robert Ursano, M.D., who chairs the department of psychiatry at the university, is optimistic enough about these and other studies that he says that “PTSD may be the first psychiatric illness that we'll be able to prevent.”
Therapeutic Window of Opportunity
A major question faced by investigators concerns the timing of the memory consolidation processes. “We don't know what our window of opportunity is,” Dr. Pitman said. “In the most pessimistic estimate, it takes 30 minutes. And it takes at least 30 minutes for propranolol to be absorbed. Some data suggest, though, that the process may take 8 hours.”
Some physicians think that given these uncertainties–as well as lingering questions about who is most at risk for developing PTSD, and limitations in reaching many people early after trauma–it may be more feasible to intervene later and to work on memories that already have formed.
The idea is to reactivate or retrieve the memory and, while it is briefly vulnerable, attempt to weaken it before the memory is restored.
At the October meeting of the Society of Neuroscience, investigators from the Center for Neural Science at New York University presented preliminary findings from animal and human studies that suggested that propranolol at least partly disrupts the “reconsolidation” of fear memories, via the amygdala, making the memories significantly weaker. One of the studies, led by Jacek Debiec, M.D., of New York University, New York, was published in the October issue of Neuroscience (2004;129:267-72).
Other Research Ventures
NYU physicians have begun working with others at the multi-institutional Center for the Neuroscience of Fear and Anxiety on testing whether propranolol helps PTSD patients who take it after recalling traumatic experiences.
Dr. Pitman also is planning a study with Karim Nader, Ph.D., a neuroscientist at McGill University in Montreal, in which they will invoke traumatic memories of PTSD patients and measure the ability of propranolol to reduce the subsequent strength of the memories.
The notion of “reconsolidation” is still controversial among neuroscientists. It's unclear what exactly happens to memories after they're reawakened, and whether attempts to block reconsolidation processes actually block memory restorage or make memories harder to retrieve.
Ethical questions have been raised, but Dr. Nader maintains that the term “therapeutic forgetting”–a phrase that has helped fuel some of the ethical debate–is misleading.
“Memory erasure isn't what we're aiming for. We know that with reactivation of a memory the mechanisms mediating the intensity of the memory will also undergo reconsolidation, and that's what we're targeting,” he said. “We're trying to affect the intensity of the memory … to turn down the volume.”
Current Clinical Use
In the meantime, it is unclear how many physicians have recommended drugs such as propranolol to try to prevent posttrauma suffering.
Physicians contacted by this newspaper said they're unaware of propranolol being used off label for this purpose. Dr. Pitman, however, said that while he does not condone it, “it's happening … I've heard anecdotal reports.”
“I hope we'll hear more about propranolol, especially with the war, with terrorism,” Dr. Debiec said. “We know the drug, we know it's safe.”
Small Pilot Studies Serve as Backdrop
Dr. Pitman's initial study of propranolol is one of two small pilot studies that have looked at treatment with the drug shortly after a traumatic event.
Forty-one patients were randomized in the emergency department at Massachusetts General Hospital to begin–within 6 hours of a traumatic event–a 10-day course of propranolol (40 mg four times daily) or placebo. Eighteen of the 41 received propranolol.
Patients in the double-blind study were instructed to return 1 and 3 months later for assessment with the Clinician-Administered PTSD Scale (CAPS). At the 3-month follow-up, investigators also measured patients' physiologic responses during script-driven imagery of the traumatic event.
At 1 month, the PTSD rate was 30% in the placebo group (6 of 20 patients who returned for follow-up) and 18% (2 of 11 who returned) in the propranolol group.
At 3 months, the CAPS scores did not differ. However, the psychophysiologic testing results suggested that propranolol had an impact. None of the 8 propranolol patients who participated, but 6 of the 14 participating placebo patients, were physiologic responders, reported Dr. Pitman and his associates (Biol. Psychiatry 2002;51:189-92).
The second study was a nonrandomized study of patients who were treated in the emergency departments of two hospitals in France. Eleven patients received propranolol for 7 days (40 mg three times daily), with the first dose administered 2-20 hours after the trauma and with a taper period of 8-12 days. They were compared with 8 patients who refused propranolol but agreed to participate.
PTSD rates, as well as PTSD symptom scores, were higher in the patients who refused the drug (3 of 8) than in patients who took it (1 of 11), reported Guillaume Vaiva, M.D., of the University of Lille (France), and his associates (Biol. Psychiatry 2003;54:947-9).
“The French study showed a significant reduction of PTSD symptoms–we only found a significant trend,” Dr. Pitman said.
Patients in both studies had tachycardia.
Over the next several years, victims of car accidents, crimes, or other traumas who are treated at Boston's Massachusetts General Hospital will be offered a commonly used heart drug–the β-adrenergic blocker propranolol–to potentially help lessen the intensity and future impact of traumatic memories.
Patients who participate in this study will be part of a wave of new drug trials aimed at intervening early to alter memory processes and prevent posttraumatic stress disorder (PTSD). Other studies are planned to aim at intervening later to treat PTSD by effecting memory “reconsolidation,” the process by which memories that have been reactivated are then restored.
As neurobiologists press on with research to better understand the mechanisms and processes involved in acquiring and storing traumatic memories, clinical investigators say they cannot wait to field-test propranolol and other commonly available drugs, some of which appear to target specific mechanisms of action in fear memory.
And some physicians may not even be waiting for study results. According to anecdotal reports, propranolol is already being used off label sporadically in the immediate wake of traumatic experiences.
Possible Clinical Benefits
“There's a real good possibility [we'll soon be using] more specific medications than we have now that will help us deal with the effects of psychological trauma [on the brain],” said Dennis S. Charney, M.D., dean of research at Mount Sinai School of Medicine, New York.
“We'll likely be able to use medication to facilitate fear extinction, to reduce the consolidation of fear memories, and in a rational way, to use medications to augment the effects of psychotherapy,” he said.
The study at Massachusetts General builds on a pilot study, published in 2002, that suggested that posttrauma administration of propranolol in the emergency room may have a “preventive effect” on subsequent PTSD. (See sidebar.)
Harvard/NIMH Study Design
Roger Pitman, M.D., who led the pilot study and has a $2.5 million grant from the National Institutes of Mental Health to conduct the larger double-blind randomized study, hopes to recruit at least 100 patients who have both experienced a traumatic event and present with tachycardia of at least 80 beats/min.
According to Dr. Pitman, most of the published and soon to be published studies addressing the issue of tachycardia as a predictor of PTSD “have been positive.”
Patients in his study will be randomized to receive, within 6 hours of the event, a 10-day course of placebo or propranolol followed by a 9-day taper period, said Dr. Pitman, professor of psychiatry at Harvard Medical School, Boston.
Propranolol is commonly used to treat high blood pressure and for other cardiovascular purposes. It is also prescribed, albeit less frequently, as an antianxiety therapy adjunct for people with public speaking anxieties, fear of flying, and other phobias. It is the only β-blocker that can cross the blood-brain barrier, Dr. Pitman said.
Possible Mechanism of Action
Dr. Pitman latched onto the idea of testing the drug for PTSD prevention 10 years ago, when Larry Cahill, Ph.D., of the Center for the Neurobiology of Learning and Memory at the University of California, Irvine, reported that in a small study of healthy people, the drug significantly impaired memory of an emotionally arousing story but did not affect memory of an emotionally neutral story (Nature 1994;371:702-4).
The findings backed a long-standing hypothesis that enhanced memory associated with emotional experiences results from activation of the β-adrenergic stress hormone systems, particularly in the amygdala. If β-adrenergic receptors are blocked, the theory goes, the consolidation of emotional memories–the formation and storage of long-term emotional memories–can be toned down. As some neurobiologists like to describe it, “overconsolidation”–and overly strong emotional memories–can be prevented.
“The study bridged the gap,” Dr. Cahill said. “It looked like what we were seeing in animals would hold up in humans.”
Studying SSRIs for PTSD Prevention
Other physicians have their eyes on the use of selective serotonin reuptake inhibitors (SSRIs) for PTSD prevention.
At Massachusetts General, Mark Pollack, M.D., is testing the SSRI Lexapro (escitalopram) “at the next potential point of intervention”–in patients who, within a few weeks after trauma, are experiencing acute stress symptoms but do not meet the full criteria for PTSD.
The possible mechanisms of action of the SSRIs in such cases are not all clear, but the hope is that the drugs will help interrupt the cycle of increased arousal and anxiety that may predispose to full-blown PTSD, said Dr. Pollack, director of the hospital's Anxiety and Traumatic Stress Disorders Program. SSRIs are often used (with moderate success) today to treat syndromal PTSD.
Physicians at the Center for the Study of Traumatic Stress at the Uniformed Health Services University of the Health Sciences in Bethesda, Md., have started a similar study, administering an SSRI to car accident victims days to several weeks after the event. Robert Ursano, M.D., who chairs the department of psychiatry at the university, is optimistic enough about these and other studies that he says that “PTSD may be the first psychiatric illness that we'll be able to prevent.”
Therapeutic Window of Opportunity
A major question faced by investigators concerns the timing of the memory consolidation processes. “We don't know what our window of opportunity is,” Dr. Pitman said. “In the most pessimistic estimate, it takes 30 minutes. And it takes at least 30 minutes for propranolol to be absorbed. Some data suggest, though, that the process may take 8 hours.”
Some physicians think that given these uncertainties–as well as lingering questions about who is most at risk for developing PTSD, and limitations in reaching many people early after trauma–it may be more feasible to intervene later and to work on memories that already have formed.
The idea is to reactivate or retrieve the memory and, while it is briefly vulnerable, attempt to weaken it before the memory is restored.
At the October meeting of the Society of Neuroscience, investigators from the Center for Neural Science at New York University presented preliminary findings from animal and human studies that suggested that propranolol at least partly disrupts the “reconsolidation” of fear memories, via the amygdala, making the memories significantly weaker. One of the studies, led by Jacek Debiec, M.D., of New York University, New York, was published in the October issue of Neuroscience (2004;129:267-72).
Other Research Ventures
NYU physicians have begun working with others at the multi-institutional Center for the Neuroscience of Fear and Anxiety on testing whether propranolol helps PTSD patients who take it after recalling traumatic experiences.
Dr. Pitman also is planning a study with Karim Nader, Ph.D., a neuroscientist at McGill University in Montreal, in which they will invoke traumatic memories of PTSD patients and measure the ability of propranolol to reduce the subsequent strength of the memories.
The notion of “reconsolidation” is still controversial among neuroscientists. It's unclear what exactly happens to memories after they're reawakened, and whether attempts to block reconsolidation processes actually block memory restorage or make memories harder to retrieve.
Ethical questions have been raised, but Dr. Nader maintains that the term “therapeutic forgetting”–a phrase that has helped fuel some of the ethical debate–is misleading.
“Memory erasure isn't what we're aiming for. We know that with reactivation of a memory the mechanisms mediating the intensity of the memory will also undergo reconsolidation, and that's what we're targeting,” he said. “We're trying to affect the intensity of the memory … to turn down the volume.”
Current Clinical Use
In the meantime, it is unclear how many physicians have recommended drugs such as propranolol to try to prevent posttrauma suffering.
Physicians contacted by this newspaper said they're unaware of propranolol being used off label for this purpose. Dr. Pitman, however, said that while he does not condone it, “it's happening … I've heard anecdotal reports.”
“I hope we'll hear more about propranolol, especially with the war, with terrorism,” Dr. Debiec said. “We know the drug, we know it's safe.”
Small Pilot Studies Serve as Backdrop
Dr. Pitman's initial study of propranolol is one of two small pilot studies that have looked at treatment with the drug shortly after a traumatic event.
Forty-one patients were randomized in the emergency department at Massachusetts General Hospital to begin–within 6 hours of a traumatic event–a 10-day course of propranolol (40 mg four times daily) or placebo. Eighteen of the 41 received propranolol.
Patients in the double-blind study were instructed to return 1 and 3 months later for assessment with the Clinician-Administered PTSD Scale (CAPS). At the 3-month follow-up, investigators also measured patients' physiologic responses during script-driven imagery of the traumatic event.
At 1 month, the PTSD rate was 30% in the placebo group (6 of 20 patients who returned for follow-up) and 18% (2 of 11 who returned) in the propranolol group.
At 3 months, the CAPS scores did not differ. However, the psychophysiologic testing results suggested that propranolol had an impact. None of the 8 propranolol patients who participated, but 6 of the 14 participating placebo patients, were physiologic responders, reported Dr. Pitman and his associates (Biol. Psychiatry 2002;51:189-92).
The second study was a nonrandomized study of patients who were treated in the emergency departments of two hospitals in France. Eleven patients received propranolol for 7 days (40 mg three times daily), with the first dose administered 2-20 hours after the trauma and with a taper period of 8-12 days. They were compared with 8 patients who refused propranolol but agreed to participate.
PTSD rates, as well as PTSD symptom scores, were higher in the patients who refused the drug (3 of 8) than in patients who took it (1 of 11), reported Guillaume Vaiva, M.D., of the University of Lille (France), and his associates (Biol. Psychiatry 2003;54:947-9).
“The French study showed a significant reduction of PTSD symptoms–we only found a significant trend,” Dr. Pitman said.
Patients in both studies had tachycardia.
Over the next several years, victims of car accidents, crimes, or other traumas who are treated at Boston's Massachusetts General Hospital will be offered a commonly used heart drug–the β-adrenergic blocker propranolol–to potentially help lessen the intensity and future impact of traumatic memories.
Patients who participate in this study will be part of a wave of new drug trials aimed at intervening early to alter memory processes and prevent posttraumatic stress disorder (PTSD). Other studies are planned to aim at intervening later to treat PTSD by effecting memory “reconsolidation,” the process by which memories that have been reactivated are then restored.
As neurobiologists press on with research to better understand the mechanisms and processes involved in acquiring and storing traumatic memories, clinical investigators say they cannot wait to field-test propranolol and other commonly available drugs, some of which appear to target specific mechanisms of action in fear memory.
And some physicians may not even be waiting for study results. According to anecdotal reports, propranolol is already being used off label sporadically in the immediate wake of traumatic experiences.
Possible Clinical Benefits
“There's a real good possibility [we'll soon be using] more specific medications than we have now that will help us deal with the effects of psychological trauma [on the brain],” said Dennis S. Charney, M.D., dean of research at Mount Sinai School of Medicine, New York.
“We'll likely be able to use medication to facilitate fear extinction, to reduce the consolidation of fear memories, and in a rational way, to use medications to augment the effects of psychotherapy,” he said.
The study at Massachusetts General builds on a pilot study, published in 2002, that suggested that posttrauma administration of propranolol in the emergency room may have a “preventive effect” on subsequent PTSD. (See sidebar.)
Harvard/NIMH Study Design
Roger Pitman, M.D., who led the pilot study and has a $2.5 million grant from the National Institutes of Mental Health to conduct the larger double-blind randomized study, hopes to recruit at least 100 patients who have both experienced a traumatic event and present with tachycardia of at least 80 beats/min.
According to Dr. Pitman, most of the published and soon to be published studies addressing the issue of tachycardia as a predictor of PTSD “have been positive.”
Patients in his study will be randomized to receive, within 6 hours of the event, a 10-day course of placebo or propranolol followed by a 9-day taper period, said Dr. Pitman, professor of psychiatry at Harvard Medical School, Boston.
Propranolol is commonly used to treat high blood pressure and for other cardiovascular purposes. It is also prescribed, albeit less frequently, as an antianxiety therapy adjunct for people with public speaking anxieties, fear of flying, and other phobias. It is the only β-blocker that can cross the blood-brain barrier, Dr. Pitman said.
Possible Mechanism of Action
Dr. Pitman latched onto the idea of testing the drug for PTSD prevention 10 years ago, when Larry Cahill, Ph.D., of the Center for the Neurobiology of Learning and Memory at the University of California, Irvine, reported that in a small study of healthy people, the drug significantly impaired memory of an emotionally arousing story but did not affect memory of an emotionally neutral story (Nature 1994;371:702-4).
The findings backed a long-standing hypothesis that enhanced memory associated with emotional experiences results from activation of the β-adrenergic stress hormone systems, particularly in the amygdala. If β-adrenergic receptors are blocked, the theory goes, the consolidation of emotional memories–the formation and storage of long-term emotional memories–can be toned down. As some neurobiologists like to describe it, “overconsolidation”–and overly strong emotional memories–can be prevented.
“The study bridged the gap,” Dr. Cahill said. “It looked like what we were seeing in animals would hold up in humans.”
Studying SSRIs for PTSD Prevention
Other physicians have their eyes on the use of selective serotonin reuptake inhibitors (SSRIs) for PTSD prevention.
At Massachusetts General, Mark Pollack, M.D., is testing the SSRI Lexapro (escitalopram) “at the next potential point of intervention”–in patients who, within a few weeks after trauma, are experiencing acute stress symptoms but do not meet the full criteria for PTSD.
The possible mechanisms of action of the SSRIs in such cases are not all clear, but the hope is that the drugs will help interrupt the cycle of increased arousal and anxiety that may predispose to full-blown PTSD, said Dr. Pollack, director of the hospital's Anxiety and Traumatic Stress Disorders Program. SSRIs are often used (with moderate success) today to treat syndromal PTSD.
Physicians at the Center for the Study of Traumatic Stress at the Uniformed Health Services University of the Health Sciences in Bethesda, Md., have started a similar study, administering an SSRI to car accident victims days to several weeks after the event. Robert Ursano, M.D., who chairs the department of psychiatry at the university, is optimistic enough about these and other studies that he says that “PTSD may be the first psychiatric illness that we'll be able to prevent.”
Therapeutic Window of Opportunity
A major question faced by investigators concerns the timing of the memory consolidation processes. “We don't know what our window of opportunity is,” Dr. Pitman said. “In the most pessimistic estimate, it takes 30 minutes. And it takes at least 30 minutes for propranolol to be absorbed. Some data suggest, though, that the process may take 8 hours.”
Some physicians think that given these uncertainties–as well as lingering questions about who is most at risk for developing PTSD, and limitations in reaching many people early after trauma–it may be more feasible to intervene later and to work on memories that already have formed.
The idea is to reactivate or retrieve the memory and, while it is briefly vulnerable, attempt to weaken it before the memory is restored.
At the October meeting of the Society of Neuroscience, investigators from the Center for Neural Science at New York University presented preliminary findings from animal and human studies that suggested that propranolol at least partly disrupts the “reconsolidation” of fear memories, via the amygdala, making the memories significantly weaker. One of the studies, led by Jacek Debiec, M.D., of New York University, New York, was published in the October issue of Neuroscience (2004;129:267-72).
Other Research Ventures
NYU physicians have begun working with others at the multi-institutional Center for the Neuroscience of Fear and Anxiety on testing whether propranolol helps PTSD patients who take it after recalling traumatic experiences.
Dr. Pitman also is planning a study with Karim Nader, Ph.D., a neuroscientist at McGill University in Montreal, in which they will invoke traumatic memories of PTSD patients and measure the ability of propranolol to reduce the subsequent strength of the memories.
The notion of “reconsolidation” is still controversial among neuroscientists. It's unclear what exactly happens to memories after they're reawakened, and whether attempts to block reconsolidation processes actually block memory restorage or make memories harder to retrieve.
Ethical questions have been raised, but Dr. Nader maintains that the term “therapeutic forgetting”–a phrase that has helped fuel some of the ethical debate–is misleading.
“Memory erasure isn't what we're aiming for. We know that with reactivation of a memory the mechanisms mediating the intensity of the memory will also undergo reconsolidation, and that's what we're targeting,” he said. “We're trying to affect the intensity of the memory … to turn down the volume.”
Current Clinical Use
In the meantime, it is unclear how many physicians have recommended drugs such as propranolol to try to prevent posttrauma suffering.
Physicians contacted by this newspaper said they're unaware of propranolol being used off label for this purpose. Dr. Pitman, however, said that while he does not condone it, “it's happening … I've heard anecdotal reports.”
“I hope we'll hear more about propranolol, especially with the war, with terrorism,” Dr. Debiec said. “We know the drug, we know it's safe.”
Small Pilot Studies Serve as Backdrop
Dr. Pitman's initial study of propranolol is one of two small pilot studies that have looked at treatment with the drug shortly after a traumatic event.
Forty-one patients were randomized in the emergency department at Massachusetts General Hospital to begin–within 6 hours of a traumatic event–a 10-day course of propranolol (40 mg four times daily) or placebo. Eighteen of the 41 received propranolol.
Patients in the double-blind study were instructed to return 1 and 3 months later for assessment with the Clinician-Administered PTSD Scale (CAPS). At the 3-month follow-up, investigators also measured patients' physiologic responses during script-driven imagery of the traumatic event.
At 1 month, the PTSD rate was 30% in the placebo group (6 of 20 patients who returned for follow-up) and 18% (2 of 11 who returned) in the propranolol group.
At 3 months, the CAPS scores did not differ. However, the psychophysiologic testing results suggested that propranolol had an impact. None of the 8 propranolol patients who participated, but 6 of the 14 participating placebo patients, were physiologic responders, reported Dr. Pitman and his associates (Biol. Psychiatry 2002;51:189-92).
The second study was a nonrandomized study of patients who were treated in the emergency departments of two hospitals in France. Eleven patients received propranolol for 7 days (40 mg three times daily), with the first dose administered 2-20 hours after the trauma and with a taper period of 8-12 days. They were compared with 8 patients who refused propranolol but agreed to participate.
PTSD rates, as well as PTSD symptom scores, were higher in the patients who refused the drug (3 of 8) than in patients who took it (1 of 11), reported Guillaume Vaiva, M.D., of the University of Lille (France), and his associates (Biol. Psychiatry 2003;54:947-9).
“The French study showed a significant reduction of PTSD symptoms–we only found a significant trend,” Dr. Pitman said.
Patients in both studies had tachycardia.