Robert Finn

Patients suffering from acute ischemic stroke are significantly more likely to achieve recanalization and/or early or dramatic clinical recovery if thrombolytic therapy is combined with continuous transcranial Doppler sonography, according to a study by Andrei V. Alexandrov, M.D., of the University of Texas, Houston, and colleagues.

Of 63 patients receiving ultrasound combined with tissue plasminogen activator (t-PA), 31 (49%) achieved recanalization and/or clinical recovery within 2 hours, compared with 19 of 63 patients (30%) who received t-PA combined with sham sonography. Within 2 hours, 16 (25%) of the patients in the treatment group experienced both recanalization and clinical recovery, compared with 5 (8%) of the control group. Both differences were statistically significant (N. Engl. J. Med. 2004;351:2170–8).

All patients had occlusions of the middle cerebral artery, and all were treated within 3 hours of the onset of symptoms. The patients were randomly assigned to the treatment or the control group.

Known as the Combined Lysis of Thrombus in Brain Ischemia Using Transcranial Ultrasound and Systemic t-PA (CLOTBUST) trial, the study was funded in part by the National Institute of Neurological Disorders and Stroke, a unit of the National Institutes of Health.

This phase II study, although not designed to look at clinical outcomes 3 months after treatment, showed that of the 53 patients eligible for follow-up, 22 (42%) had achieved a modified Rankin score of 0 or 1, compared with 4 of the 15 eligible patients (27%) in the control group. Investigators calculated that a phase III study would need just 274 patients in each group to replicate the results with statistical significance.

“At our center, it's the standard of care right now,” he said. “Both [t-PA and transcranial Doppler sonography] are FDA-approved technologies, and the trial was exempt from investigational new drug status by FDA because these results would not change the labels. Right now in our institution, when we give systemic t-PA within 3 hours [after a stroke], we always put a transcranial Doppler probe on the scalp to help the patient pass the clot faster.”

Nevertheless, “I will not stand here and recommend that everybody else should do the same,” Dr. Alexandrov said. “The reason is that to do it right, you have to pass through a very lengthy and labor-intense training that is not a routine part of any neurology residency. To do the protocol, you need 1–6 months of daily practicing of this technique under supervision, and that's something that very few programs can do in the United States.”

Dr. Alexandrov is involved in an effort to design an operator-independent device that would obviate the need for an experienced operator. With such a device, “an emergency department physician could do it, a neurologist could do it, and a nurse could mount the ultrasound machine on the head,” he said.

The mechanism by which transcranial Doppler sonography improves thrombolysis is still unclear. In a commentary accompanying Dr. Alexandrov's paper, Joseph F. Polak, M.D., of Tufts University, Boston, weighs a number of the possibilities (N. Engl. J. Med. 2004;351:2154–5).

It's clear that the mechanism does not involve cavitation, which ultrasound at high energies can cause. It's also unlikely that the relatively low energies used in transcranial Doppler ultrasound could accelerate thrombolysis by producing heat.

Dr. Alexandrov believes that the combined treatment works because ultrasound is causing a gentle mechanical pressure wave, which delivers more t-PA molecules to and through the clot.

The study was sparked by a observation, Dr. Alexandrov said. “Patients who were wearing these transducers for diagnostic purposes started to move their paralyzed arms and legs and to talk to us much faster than we ever expected otherwise.

Patients suffering from acute ischemic stroke are significantly more likely to achieve recanalization and/or early or dramatic clinical recovery if thrombolytic therapy is combined with continuous transcranial Doppler sonography, according to a study by Andrei V. Alexandrov, M.D., of the University of Texas, Houston, and colleagues.

Of 63 patients receiving ultrasound combined with tissue plasminogen activator (t-PA), 31 (49%) achieved recanalization and/or clinical recovery within 2 hours, compared with 19 of 63 patients (30%) who received t-PA combined with sham sonography. Within 2 hours, 16 (25%) of the patients in the treatment group experienced both recanalization and clinical recovery, compared with 5 (8%) of the control group. Both differences were statistically significant (N. Engl. J. Med. 2004;351:2170–8).

All patients had occlusions of the middle cerebral artery, and all were treated within 3 hours of the onset of symptoms. The patients were randomly assigned to the treatment or the control group.

Known as the Combined Lysis of Thrombus in Brain Ischemia Using Transcranial Ultrasound and Systemic t-PA (CLOTBUST) trial, the study was funded in part by the National Institute of Neurological Disorders and Stroke, a unit of the National Institutes of Health.

This phase II study, although not designed to look at clinical outcomes 3 months after treatment, showed that of the 53 patients eligible for follow-up, 22 (42%) had achieved a modified Rankin score of 0 or 1, compared with 4 of the 15 eligible patients (27%) in the control group. Investigators calculated that a phase III study would need just 274 patients in each group to replicate the results with statistical significance.

“At our center, it's the standard of care right now,” he said. “Both [t-PA and transcranial Doppler sonography] are FDA-approved technologies, and the trial was exempt from investigational new drug status by FDA because these results would not change the labels. Right now in our institution, when we give systemic t-PA within 3 hours [after a stroke], we always put a transcranial Doppler probe on the scalp to help the patient pass the clot faster.”

Nevertheless, “I will not stand here and recommend that everybody else should do the same,” Dr. Alexandrov said. “The reason is that to do it right, you have to pass through a very lengthy and labor-intense training that is not a routine part of any neurology residency. To do the protocol, you need 1–6 months of daily practicing of this technique under supervision, and that's something that very few programs can do in the United States.”

Dr. Alexandrov is involved in an effort to design an operator-independent device that would obviate the need for an experienced operator. With such a device, “an emergency department physician could do it, a neurologist could do it, and a nurse could mount the ultrasound machine on the head,” he said.

The mechanism by which transcranial Doppler sonography improves thrombolysis is still unclear. In a commentary accompanying Dr. Alexandrov's paper, Joseph F. Polak, M.D., of Tufts University, Boston, weighs a number of the possibilities (N. Engl. J. Med. 2004;351:2154–5).

It's clear that the mechanism does not involve cavitation, which ultrasound at high energies can cause. It's also unlikely that the relatively low energies used in transcranial Doppler ultrasound could accelerate thrombolysis by producing heat.

Dr. Alexandrov believes that the combined treatment works because ultrasound is causing a gentle mechanical pressure wave, which delivers more t-PA molecules to and through the clot.

The study was sparked by a observation, Dr. Alexandrov said. “Patients who were wearing these transducers for diagnostic purposes started to move their paralyzed arms and legs and to talk to us much faster than we ever expected otherwise.

Patients suffering from acute ischemic stroke are significantly more likely to achieve recanalization and/or early or dramatic clinical recovery if thrombolytic therapy is combined with continuous transcranial Doppler sonography, according to a study by Andrei V. Alexandrov, M.D., of the University of Texas, Houston, and colleagues.

Of 63 patients receiving ultrasound combined with tissue plasminogen activator (t-PA), 31 (49%) achieved recanalization and/or clinical recovery within 2 hours, compared with 19 of 63 patients (30%) who received t-PA combined with sham sonography. Within 2 hours, 16 (25%) of the patients in the treatment group experienced both recanalization and clinical recovery, compared with 5 (8%) of the control group. Both differences were statistically significant (N. Engl. J. Med. 2004;351:2170–8).

All patients had occlusions of the middle cerebral artery, and all were treated within 3 hours of the onset of symptoms. The patients were randomly assigned to the treatment or the control group.

Known as the Combined Lysis of Thrombus in Brain Ischemia Using Transcranial Ultrasound and Systemic t-PA (CLOTBUST) trial, the study was funded in part by the National Institute of Neurological Disorders and Stroke, a unit of the National Institutes of Health.

This phase II study, although not designed to look at clinical outcomes 3 months after treatment, showed that of the 53 patients eligible for follow-up, 22 (42%) had achieved a modified Rankin score of 0 or 1, compared with 4 of the 15 eligible patients (27%) in the control group. Investigators calculated that a phase III study would need just 274 patients in each group to replicate the results with statistical significance.

“At our center, it's the standard of care right now,” he said. “Both [t-PA and transcranial Doppler sonography] are FDA-approved technologies, and the trial was exempt from investigational new drug status by FDA because these results would not change the labels. Right now in our institution, when we give systemic t-PA within 3 hours [after a stroke], we always put a transcranial Doppler probe on the scalp to help the patient pass the clot faster.”

Nevertheless, “I will not stand here and recommend that everybody else should do the same,” Dr. Alexandrov said. “The reason is that to do it right, you have to pass through a very lengthy and labor-intense training that is not a routine part of any neurology residency. To do the protocol, you need 1–6 months of daily practicing of this technique under supervision, and that's something that very few programs can do in the United States.”

Dr. Alexandrov is involved in an effort to design an operator-independent device that would obviate the need for an experienced operator. With such a device, “an emergency department physician could do it, a neurologist could do it, and a nurse could mount the ultrasound machine on the head,” he said.

The mechanism by which transcranial Doppler sonography improves thrombolysis is still unclear. In a commentary accompanying Dr. Alexandrov's paper, Joseph F. Polak, M.D., of Tufts University, Boston, weighs a number of the possibilities (N. Engl. J. Med. 2004;351:2154–5).

It's clear that the mechanism does not involve cavitation, which ultrasound at high energies can cause. It's also unlikely that the relatively low energies used in transcranial Doppler ultrasound could accelerate thrombolysis by producing heat.

Dr. Alexandrov believes that the combined treatment works because ultrasound is causing a gentle mechanical pressure wave, which delivers more t-PA molecules to and through the clot.

The study was sparked by a observation, Dr. Alexandrov said. “Patients who were wearing these transducers for diagnostic purposes started to move their paralyzed arms and legs and to talk to us much faster than we ever expected otherwise.

SANTA FE, N.M. – Atypical antipsychotics remain the treatment of choice for the agitation and psychosis that often accompany dementia, but these agents have only modest effects, Murray A. Raskind, M.D., said at a psychiatric symposium sponsored by the University of Arizona.

A systematic approach to identifying and quantifying target symptoms–followed by an evaluation of the medical, psychiatric, and environmental contributors to the behavior–is essential, said Dr. Raskind, director of the Alzheimer's Disease Research Center at the University of Washington, Seattle.

The first step should be to gradually reduce or eliminate medications that may be exacerbating the patient's agitation or psychosis. These include theophylline and other bronchodilators, thyroid hormones, caffeine, and anticholinergics, such as antispasmodics. Withdrawal from short-half-life benzodiazepines can also result in similar symptoms.

The antipsychotics are the only drugs that have substantial evidence for efficacy in this population, and among the antipsychotics, the atypicals would be preferred because of their more favorable side-effect profiles, Dr. Raskind said at the symposium, which was also sponsored by the University of Texas, Dallas, and the University of New Mexico.

Many patients have inadequate responses to antipsychotics, however. At least two classes of drugs–anticonvulsants and antiadrenergic agents–are currently under investigation in this population and seem to show some promise.

Use of the anticonvulsant carbamazepine at a dosage of 300 mg/day, for example, was shown to be more effective than placebo in a study of 51 nursing home patients with Alzheimer's disease (Am. J. Psychiatry 1998;155:54–61). Divalproex at 800 mg/day, on the other hand, was no more effective than placebo in another study, although the investigators noted a trend in the direction of effectiveness (Am. J. Geriatr. Psychiatry 2001;9:58–66).

Dr. Raskind and his colleagues have been investigating noradrenergic function in Alzheimer's disease. Adrenergic stimulation appears to increase agitation in these patients, and propranolol–a β-adrenergic receptor antagonist–appears to be effective as an adjunct in antipsychotic nonresponders, according to an as-yet-unpublished study.

In an open-label study, prazosin, which blocks alpha1 receptors, appeared to be especially effective, Dr. Raskind said. He and his colleagues tried 1–5 mg/day of prazosin on 11 nursing-home residents with Alzheimer's disease, all of whom had severe or very severe treatment-resistant disruptive agitation. After 8 weeks, the patients were judged to be moderately to markedly improved on the Clinical Global Impression scale.

Dr. Raskind has a placebo-controlled trial of prazosin under way. Meanwhile, “if you're up against the wall and you want to try something, it's helpful,” he said. He cautioned that the patient should always be started at a dosage of 1 mg/day. With a higher initial dosage, there's a dramatic incidence of hypotension, which can cause a fall. This side effect disappears after several days, he said, after which the dosage may be increased gradually.

KEVIN FOLEY, RESEARCH

SANTA FE, N.M. – Atypical antipsychotics remain the treatment of choice for the agitation and psychosis that often accompany dementia, but these agents have only modest effects, Murray A. Raskind, M.D., said at a psychiatric symposium sponsored by the University of Arizona.

A systematic approach to identifying and quantifying target symptoms–followed by an evaluation of the medical, psychiatric, and environmental contributors to the behavior–is essential, said Dr. Raskind, director of the Alzheimer's Disease Research Center at the University of Washington, Seattle.

The first step should be to gradually reduce or eliminate medications that may be exacerbating the patient's agitation or psychosis. These include theophylline and other bronchodilators, thyroid hormones, caffeine, and anticholinergics, such as antispasmodics. Withdrawal from short-half-life benzodiazepines can also result in similar symptoms.

The antipsychotics are the only drugs that have substantial evidence for efficacy in this population, and among the antipsychotics, the atypicals would be preferred because of their more favorable side-effect profiles, Dr. Raskind said at the symposium, which was also sponsored by the University of Texas, Dallas, and the University of New Mexico.

Many patients have inadequate responses to antipsychotics, however. At least two classes of drugs–anticonvulsants and antiadrenergic agents–are currently under investigation in this population and seem to show some promise.

Use of the anticonvulsant carbamazepine at a dosage of 300 mg/day, for example, was shown to be more effective than placebo in a study of 51 nursing home patients with Alzheimer's disease (Am. J. Psychiatry 1998;155:54–61). Divalproex at 800 mg/day, on the other hand, was no more effective than placebo in another study, although the investigators noted a trend in the direction of effectiveness (Am. J. Geriatr. Psychiatry 2001;9:58–66).

Dr. Raskind and his colleagues have been investigating noradrenergic function in Alzheimer's disease. Adrenergic stimulation appears to increase agitation in these patients, and propranolol–a β-adrenergic receptor antagonist–appears to be effective as an adjunct in antipsychotic nonresponders, according to an as-yet-unpublished study.

In an open-label study, prazosin, which blocks alpha1 receptors, appeared to be especially effective, Dr. Raskind said. He and his colleagues tried 1–5 mg/day of prazosin on 11 nursing-home residents with Alzheimer's disease, all of whom had severe or very severe treatment-resistant disruptive agitation. After 8 weeks, the patients were judged to be moderately to markedly improved on the Clinical Global Impression scale.

Dr. Raskind has a placebo-controlled trial of prazosin under way. Meanwhile, “if you're up against the wall and you want to try something, it's helpful,” he said. He cautioned that the patient should always be started at a dosage of 1 mg/day. With a higher initial dosage, there's a dramatic incidence of hypotension, which can cause a fall. This side effect disappears after several days, he said, after which the dosage may be increased gradually.

KEVIN FOLEY, RESEARCH

SANTA FE, N.M. – Atypical antipsychotics remain the treatment of choice for the agitation and psychosis that often accompany dementia, but these agents have only modest effects, Murray A. Raskind, M.D., said at a psychiatric symposium sponsored by the University of Arizona.

A systematic approach to identifying and quantifying target symptoms–followed by an evaluation of the medical, psychiatric, and environmental contributors to the behavior–is essential, said Dr. Raskind, director of the Alzheimer's Disease Research Center at the University of Washington, Seattle.

The first step should be to gradually reduce or eliminate medications that may be exacerbating the patient's agitation or psychosis. These include theophylline and other bronchodilators, thyroid hormones, caffeine, and anticholinergics, such as antispasmodics. Withdrawal from short-half-life benzodiazepines can also result in similar symptoms.

The antipsychotics are the only drugs that have substantial evidence for efficacy in this population, and among the antipsychotics, the atypicals would be preferred because of their more favorable side-effect profiles, Dr. Raskind said at the symposium, which was also sponsored by the University of Texas, Dallas, and the University of New Mexico.

Many patients have inadequate responses to antipsychotics, however. At least two classes of drugs–anticonvulsants and antiadrenergic agents–are currently under investigation in this population and seem to show some promise.

Use of the anticonvulsant carbamazepine at a dosage of 300 mg/day, for example, was shown to be more effective than placebo in a study of 51 nursing home patients with Alzheimer's disease (Am. J. Psychiatry 1998;155:54–61). Divalproex at 800 mg/day, on the other hand, was no more effective than placebo in another study, although the investigators noted a trend in the direction of effectiveness (Am. J. Geriatr. Psychiatry 2001;9:58–66).

Dr. Raskind and his colleagues have been investigating noradrenergic function in Alzheimer's disease. Adrenergic stimulation appears to increase agitation in these patients, and propranolol–a β-adrenergic receptor antagonist–appears to be effective as an adjunct in antipsychotic nonresponders, according to an as-yet-unpublished study.

In an open-label study, prazosin, which blocks alpha1 receptors, appeared to be especially effective, Dr. Raskind said. He and his colleagues tried 1–5 mg/day of prazosin on 11 nursing-home residents with Alzheimer's disease, all of whom had severe or very severe treatment-resistant disruptive agitation. After 8 weeks, the patients were judged to be moderately to markedly improved on the Clinical Global Impression scale.

Dr. Raskind has a placebo-controlled trial of prazosin under way. Meanwhile, “if you're up against the wall and you want to try something, it's helpful,” he said. He cautioned that the patient should always be started at a dosage of 1 mg/day. With a higher initial dosage, there's a dramatic incidence of hypotension, which can cause a fall. This side effect disappears after several days, he said, after which the dosage may be increased gradually.

KEVIN FOLEY, RESEARCH

SAN FRANCISCO — People infected with HIV are diagnosed with acute coronary syndromes an average of 11 years earlier than are their HIV-negative counterparts, Priscilla Hsue, M.D., reported at a meeting on HIV management sponsored by the University of California, San Francisco.

Moreover, atherosclerosis, as measured by carotid intima-media thickness, progresses much faster in patients who are HIV-positive, and restenosis rates after percutaneous coronary intervention are significantly higher in HIV patients than in control subjects.

Although protease inhibitors and other components of highly active antiretroviral therapy may contribute to acute coronary syndromes in patients with HIV, this can't account for all of the differences between patients with HIV and noninfected controls. HIV may be an independent coronary risk factor, said Dr. Hsue, assistant professor of medicine at the university.

She reported on the results of two studies. One was a retrospective chart review of 68 acute coronary syndrome patients with HIV who were compared with 68 uninfected acute coronary syndrome patients. Acute coronary syndrome was defined by a diagnosis of acute myocardial infarction or unstable angina. The other was a prospective study of 148 HIV-infected patients and 63 age- and sex-matched controls.

The chart review showed that the average age of HIV-infected acute coronary syndrome patients was 50 years, compared with 61 years for the noninfected patients. HIV patients with acute coronary syndrome were significantly more likely to be male (90% vs. 62%), to be current cigarette smokers (68% vs. 41%), and to have low HDL cholesterol levels (35 mg/dL vs. 41 mg/dL). Results of this study were published last year (Circulation 2004;109:316–9).

HIV patients were significantly less likely to have diabetes (13% vs. 41%), and they had significantly less extensive coronary disease at angiography. An average of 1.3 vessels were involved in patients with HIV, compared with 1.9 vessels in controls.

Percutaneous coronary intervention was performed on 29 HIV patients and 21 controls. Restenosis occurred in 15 of the HIV patients (52%) and in 3 controls (14%), a significant difference.

In the prospective study, the HIV-infected patients had significantly higher carotid intima-media thickness (as measured by B-mode ultrasound) than did controls (0.91 mm vs. 0.74 mm). Investigators detected carotid plaques in 45% of the HIV patients and 24% of the control patients, a significant difference (Circulation 2004;109:1603–8).

In a multivariate analysis combining infected and uninfected patients, HIV infection proved to be an independent predictor of greater intima-media thickness, even after controlling for other classic coronary risk factors, including age, sex, smoking, hypertension, lipid abnormalities, and diabetes. Other independent predictors were age, LDL cholesterol, cigarette pack-years, and Hispanic race.

Investigators were able to obtain follow-up measurements at 1 year in 121 HIV patients and 27 controls. Among HIV patients, intima-media thickness increased a mean of 0.074 mm, while among control subjects intima-media thickness decreased by 0.006 mm, a significant difference.

Previous studies of noninfected patients suggest carotid intima-media thickness tends to increase at about 0.01 mm/year, a rate about sevenfold lower than that observed among HIV patients in this study.

These studies suggest that clinicians should engage in aggressive control of risk factors in patients with HIV. Smoking may be of particular importance because of its high prevalence in this population. Hypertension should be treated, LDL cholesterol should be reduced to low levels, and hypertriglyceridemia should be controlled, Dr. Hsue said.

SAN FRANCISCO — People infected with HIV are diagnosed with acute coronary syndromes an average of 11 years earlier than are their HIV-negative counterparts, Priscilla Hsue, M.D., reported at a meeting on HIV management sponsored by the University of California, San Francisco.

Moreover, atherosclerosis, as measured by carotid intima-media thickness, progresses much faster in patients who are HIV-positive, and restenosis rates after percutaneous coronary intervention are significantly higher in HIV patients than in control subjects.

Although protease inhibitors and other components of highly active antiretroviral therapy may contribute to acute coronary syndromes in patients with HIV, this can't account for all of the differences between patients with HIV and noninfected controls. HIV may be an independent coronary risk factor, said Dr. Hsue, assistant professor of medicine at the university.

She reported on the results of two studies. One was a retrospective chart review of 68 acute coronary syndrome patients with HIV who were compared with 68 uninfected acute coronary syndrome patients. Acute coronary syndrome was defined by a diagnosis of acute myocardial infarction or unstable angina. The other was a prospective study of 148 HIV-infected patients and 63 age- and sex-matched controls.

The chart review showed that the average age of HIV-infected acute coronary syndrome patients was 50 years, compared with 61 years for the noninfected patients. HIV patients with acute coronary syndrome were significantly more likely to be male (90% vs. 62%), to be current cigarette smokers (68% vs. 41%), and to have low HDL cholesterol levels (35 mg/dL vs. 41 mg/dL). Results of this study were published last year (Circulation 2004;109:316–9).

HIV patients were significantly less likely to have diabetes (13% vs. 41%), and they had significantly less extensive coronary disease at angiography. An average of 1.3 vessels were involved in patients with HIV, compared with 1.9 vessels in controls.

Percutaneous coronary intervention was performed on 29 HIV patients and 21 controls. Restenosis occurred in 15 of the HIV patients (52%) and in 3 controls (14%), a significant difference.

In the prospective study, the HIV-infected patients had significantly higher carotid intima-media thickness (as measured by B-mode ultrasound) than did controls (0.91 mm vs. 0.74 mm). Investigators detected carotid plaques in 45% of the HIV patients and 24% of the control patients, a significant difference (Circulation 2004;109:1603–8).

In a multivariate analysis combining infected and uninfected patients, HIV infection proved to be an independent predictor of greater intima-media thickness, even after controlling for other classic coronary risk factors, including age, sex, smoking, hypertension, lipid abnormalities, and diabetes. Other independent predictors were age, LDL cholesterol, cigarette pack-years, and Hispanic race.

Investigators were able to obtain follow-up measurements at 1 year in 121 HIV patients and 27 controls. Among HIV patients, intima-media thickness increased a mean of 0.074 mm, while among control subjects intima-media thickness decreased by 0.006 mm, a significant difference.

Previous studies of noninfected patients suggest carotid intima-media thickness tends to increase at about 0.01 mm/year, a rate about sevenfold lower than that observed among HIV patients in this study.

These studies suggest that clinicians should engage in aggressive control of risk factors in patients with HIV. Smoking may be of particular importance because of its high prevalence in this population. Hypertension should be treated, LDL cholesterol should be reduced to low levels, and hypertriglyceridemia should be controlled, Dr. Hsue said.

SAN FRANCISCO — People infected with HIV are diagnosed with acute coronary syndromes an average of 11 years earlier than are their HIV-negative counterparts, Priscilla Hsue, M.D., reported at a meeting on HIV management sponsored by the University of California, San Francisco.

Moreover, atherosclerosis, as measured by carotid intima-media thickness, progresses much faster in patients who are HIV-positive, and restenosis rates after percutaneous coronary intervention are significantly higher in HIV patients than in control subjects.

Although protease inhibitors and other components of highly active antiretroviral therapy may contribute to acute coronary syndromes in patients with HIV, this can't account for all of the differences between patients with HIV and noninfected controls. HIV may be an independent coronary risk factor, said Dr. Hsue, assistant professor of medicine at the university.

She reported on the results of two studies. One was a retrospective chart review of 68 acute coronary syndrome patients with HIV who were compared with 68 uninfected acute coronary syndrome patients. Acute coronary syndrome was defined by a diagnosis of acute myocardial infarction or unstable angina. The other was a prospective study of 148 HIV-infected patients and 63 age- and sex-matched controls.

The chart review showed that the average age of HIV-infected acute coronary syndrome patients was 50 years, compared with 61 years for the noninfected patients. HIV patients with acute coronary syndrome were significantly more likely to be male (90% vs. 62%), to be current cigarette smokers (68% vs. 41%), and to have low HDL cholesterol levels (35 mg/dL vs. 41 mg/dL). Results of this study were published last year (Circulation 2004;109:316–9).

HIV patients were significantly less likely to have diabetes (13% vs. 41%), and they had significantly less extensive coronary disease at angiography. An average of 1.3 vessels were involved in patients with HIV, compared with 1.9 vessels in controls.

Percutaneous coronary intervention was performed on 29 HIV patients and 21 controls. Restenosis occurred in 15 of the HIV patients (52%) and in 3 controls (14%), a significant difference.

In the prospective study, the HIV-infected patients had significantly higher carotid intima-media thickness (as measured by B-mode ultrasound) than did controls (0.91 mm vs. 0.74 mm). Investigators detected carotid plaques in 45% of the HIV patients and 24% of the control patients, a significant difference (Circulation 2004;109:1603–8).

In a multivariate analysis combining infected and uninfected patients, HIV infection proved to be an independent predictor of greater intima-media thickness, even after controlling for other classic coronary risk factors, including age, sex, smoking, hypertension, lipid abnormalities, and diabetes. Other independent predictors were age, LDL cholesterol, cigarette pack-years, and Hispanic race.

Investigators were able to obtain follow-up measurements at 1 year in 121 HIV patients and 27 controls. Among HIV patients, intima-media thickness increased a mean of 0.074 mm, while among control subjects intima-media thickness decreased by 0.006 mm, a significant difference.

Previous studies of noninfected patients suggest carotid intima-media thickness tends to increase at about 0.01 mm/year, a rate about sevenfold lower than that observed among HIV patients in this study.

These studies suggest that clinicians should engage in aggressive control of risk factors in patients with HIV. Smoking may be of particular importance because of its high prevalence in this population. Hypertension should be treated, LDL cholesterol should be reduced to low levels, and hypertriglyceridemia should be controlled, Dr. Hsue said.

SAN FRANCISCO — The debate continues to rage on when to initiate highly active antiretroviral therapy in HIV disease.

At a meeting on HIV management sponsored by the University of California, San Francisco, Paul A. Volberding, M.D., joked that the answer is obvious: before it's too late, but after it's too early.

But whatever the clinician decides, there is a series of steps that must be taken before antiretroviral therapy begins, said Dr. Volberding of the Veterans Affairs Medical Center in San Francisco:

▸ Confirm the HIV results. “We [recently] had in the Bay Area yet another case of a person who had been followed for HIV infection without anyone noticing that his HIV test was negative,” he said.

▸ Take a history and conduct a thorough physical exam.

▸ Get a CBC and a chemistry profile.

▸ Order a CD4 cell count and a plasma HIV RNA measurement.

▸ Consider resistance testing. “I think we're at the point where baseline resistance testing should be recommended in all cases,” Dr. Volberding said, but this is not yet part of official practice guidelines.

▸ Assess the patient's readiness for treatment and the likelihood that he or she will be adherent.

▸ Refer the patient for an ophthalmology exam if the CD4 count is below 100 cells/μL.

▸ Make sure female patients get a gynecologic exam with a Pap smear.

▸ Test for syphilis with a rapid plasma reagin test or a Venereal Disease Research Laboratory test.

▸ Test for tuberculin with a purified protein derivative test.

▸ Order a chest x-ray.

▸ Order hepatitis A, B, and C serology.

▸ Order a toxoplasma IgG test.

▸ Order a fasting glucose and a lipid panel.

SAN FRANCISCO — The debate continues to rage on when to initiate highly active antiretroviral therapy in HIV disease.

At a meeting on HIV management sponsored by the University of California, San Francisco, Paul A. Volberding, M.D., joked that the answer is obvious: before it's too late, but after it's too early.

But whatever the clinician decides, there is a series of steps that must be taken before antiretroviral therapy begins, said Dr. Volberding of the Veterans Affairs Medical Center in San Francisco:

▸ Confirm the HIV results. “We [recently] had in the Bay Area yet another case of a person who had been followed for HIV infection without anyone noticing that his HIV test was negative,” he said.

▸ Take a history and conduct a thorough physical exam.

▸ Get a CBC and a chemistry profile.

▸ Order a CD4 cell count and a plasma HIV RNA measurement.

▸ Consider resistance testing. “I think we're at the point where baseline resistance testing should be recommended in all cases,” Dr. Volberding said, but this is not yet part of official practice guidelines.

▸ Assess the patient's readiness for treatment and the likelihood that he or she will be adherent.

▸ Refer the patient for an ophthalmology exam if the CD4 count is below 100 cells/μL.

▸ Make sure female patients get a gynecologic exam with a Pap smear.

▸ Test for syphilis with a rapid plasma reagin test or a Venereal Disease Research Laboratory test.

▸ Test for tuberculin with a purified protein derivative test.

▸ Order a chest x-ray.

▸ Order hepatitis A, B, and C serology.

▸ Order a toxoplasma IgG test.

▸ Order a fasting glucose and a lipid panel.

SAN FRANCISCO — The debate continues to rage on when to initiate highly active antiretroviral therapy in HIV disease.

At a meeting on HIV management sponsored by the University of California, San Francisco, Paul A. Volberding, M.D., joked that the answer is obvious: before it's too late, but after it's too early.

But whatever the clinician decides, there is a series of steps that must be taken before antiretroviral therapy begins, said Dr. Volberding of the Veterans Affairs Medical Center in San Francisco:

▸ Confirm the HIV results. “We [recently] had in the Bay Area yet another case of a person who had been followed for HIV infection without anyone noticing that his HIV test was negative,” he said.

▸ Take a history and conduct a thorough physical exam.

▸ Get a CBC and a chemistry profile.

▸ Order a CD4 cell count and a plasma HIV RNA measurement.

▸ Consider resistance testing. “I think we're at the point where baseline resistance testing should be recommended in all cases,” Dr. Volberding said, but this is not yet part of official practice guidelines.

▸ Assess the patient's readiness for treatment and the likelihood that he or she will be adherent.

▸ Refer the patient for an ophthalmology exam if the CD4 count is below 100 cells/μL.

▸ Make sure female patients get a gynecologic exam with a Pap smear.

▸ Test for syphilis with a rapid plasma reagin test or a Venereal Disease Research Laboratory test.

▸ Test for tuberculin with a purified protein derivative test.

▸ Order a chest x-ray.

▸ Order hepatitis A, B, and C serology.

▸ Order a toxoplasma IgG test.

▸ Order a fasting glucose and a lipid panel.

SAN FRANCISCO — A feasibility study among 891 individuals in San Francisco has identified issues that must be considered in offering nonoccupational postexposure prophylaxis, Michelle Rowland, M.D., said at a meeting on HIV management sponsored by the University of California, San Francisco.

Postexposure prophylaxis (PEP) has been shown to reduce the risk of HIV transmission by 81% in health care workers, but no information is available about the efficacy of prophylaxis after nonoccupational HIV exposure. A placebo-controlled study would be difficult to conduct because of ethical considerations, said Dr. Rowland of UCSF.

At press time, the Centers for Disease Control and Prevention was preparing to issue national guidelines on the use of PEP to reduce the risk of HIV infection.

Of the 891 people in the study, all of whom were given PEP within 72 hours after exposure, 700 could be evaluated 12 weeks after PEP was initiated, and 7 (1%) seroconverted. All seven reported having unprotected receptive anal intercourse, four of them with a partner known to be infected with HIV. In contrast, only 50% of the nonseroconverters presented after receptive anal intercourse, a significantly lower percentage.

Individuals in the study reported one or more episodes of unprotected receptive or insertive anal or vaginal intercourse, receptive oral sex with ejaculation, or shared injection drug equipment. The potential sources of infection had to be known HIV-infected persons, men who has sex with men of unknown HIV status, a past or present injection drug user, a commercial sex worker, or an anonymous contact.

Adherence was fairly good. During week 1, 84% of patients reported no missed doses during the prior 4 days; that figure was 78% during both week 2 and week 4.

Previous studies have yielded estimates that the risk of infection from a single encounter is 0.8% to 5.0% for receptive anal intercourse and substantially lower for other types of exposure. The investigators therefore queried the seroconverters about additional risk behavior. Six of the seven reported other high-risk encounters in the 6 months before PEP, and three of the seven reported ongoing high-risk behavior even after starting PEP, suggesting that the failure of PEP in these patients may not have been entirely due to medication failure.

“PEP is not just medication,” Dr. Rowland said. “It's also adherence counseling, risk-reduction counseling, and referral, because the whole point of this is to help people stay HIV negative. The per-contact transmission rate is virtually almost nothing. So people are not at risk for HIV just at that particular moment; they're particularly at risk for the rest of their lives.”

There's a tendency to want to divide people presenting for PEP into three groups: those who should be advised to use PEP, those who should be offered PEP, and those who should not be offered PEP. In practice, she said, “It's hard for me to recommend PEP to anybody, and it's easy for me to agree to offer it to a fair number of people. The bottom line for me is that it's my job to help that individual person make an individual risk-benefit assessment.”

Animal studies and experience with health care workers suggest it's important to begin antiretroviral therapy at most 72 hours after exposure. But many people who are exposed misinterpret that as meaning that they can wait 72 hours before deciding on PEP. “The message we're trying to get across is, 'You want to start this as soon as possible, and we're not going to initiate it after 72 hours,'” she said.

Investigators generally agree that the antiretroviral component of PEP should be continued for 28 days, but there's a great deal of controversy about what antiretrovirals to use and whether two nucleosides are enough or whether a three-drug regimen is better. The practice at UCSF is to use two drugs, but Dr. Rowland would consider using three in certain circumstances. For example, a three-drug regimen might be indicated if a patient reports multiple exposures over 5 days, including several within the required 72-hour period.

She recommended that clinicians be aggressive in getting information about the source of the exposure, to determine whether that person is truly HIV-positive, and to conduct viral resistance testing. This is critical in choosing which antiretrovirals to use.

SAN FRANCISCO — A feasibility study among 891 individuals in San Francisco has identified issues that must be considered in offering nonoccupational postexposure prophylaxis, Michelle Rowland, M.D., said at a meeting on HIV management sponsored by the University of California, San Francisco.

Postexposure prophylaxis (PEP) has been shown to reduce the risk of HIV transmission by 81% in health care workers, but no information is available about the efficacy of prophylaxis after nonoccupational HIV exposure. A placebo-controlled study would be difficult to conduct because of ethical considerations, said Dr. Rowland of UCSF.

At press time, the Centers for Disease Control and Prevention was preparing to issue national guidelines on the use of PEP to reduce the risk of HIV infection.

Of the 891 people in the study, all of whom were given PEP within 72 hours after exposure, 700 could be evaluated 12 weeks after PEP was initiated, and 7 (1%) seroconverted. All seven reported having unprotected receptive anal intercourse, four of them with a partner known to be infected with HIV. In contrast, only 50% of the nonseroconverters presented after receptive anal intercourse, a significantly lower percentage.

Individuals in the study reported one or more episodes of unprotected receptive or insertive anal or vaginal intercourse, receptive oral sex with ejaculation, or shared injection drug equipment. The potential sources of infection had to be known HIV-infected persons, men who has sex with men of unknown HIV status, a past or present injection drug user, a commercial sex worker, or an anonymous contact.

Adherence was fairly good. During week 1, 84% of patients reported no missed doses during the prior 4 days; that figure was 78% during both week 2 and week 4.

Previous studies have yielded estimates that the risk of infection from a single encounter is 0.8% to 5.0% for receptive anal intercourse and substantially lower for other types of exposure. The investigators therefore queried the seroconverters about additional risk behavior. Six of the seven reported other high-risk encounters in the 6 months before PEP, and three of the seven reported ongoing high-risk behavior even after starting PEP, suggesting that the failure of PEP in these patients may not have been entirely due to medication failure.

“PEP is not just medication,” Dr. Rowland said. “It's also adherence counseling, risk-reduction counseling, and referral, because the whole point of this is to help people stay HIV negative. The per-contact transmission rate is virtually almost nothing. So people are not at risk for HIV just at that particular moment; they're particularly at risk for the rest of their lives.”

There's a tendency to want to divide people presenting for PEP into three groups: those who should be advised to use PEP, those who should be offered PEP, and those who should not be offered PEP. In practice, she said, “It's hard for me to recommend PEP to anybody, and it's easy for me to agree to offer it to a fair number of people. The bottom line for me is that it's my job to help that individual person make an individual risk-benefit assessment.”

Animal studies and experience with health care workers suggest it's important to begin antiretroviral therapy at most 72 hours after exposure. But many people who are exposed misinterpret that as meaning that they can wait 72 hours before deciding on PEP. “The message we're trying to get across is, 'You want to start this as soon as possible, and we're not going to initiate it after 72 hours,'” she said.

Investigators generally agree that the antiretroviral component of PEP should be continued for 28 days, but there's a great deal of controversy about what antiretrovirals to use and whether two nucleosides are enough or whether a three-drug regimen is better. The practice at UCSF is to use two drugs, but Dr. Rowland would consider using three in certain circumstances. For example, a three-drug regimen might be indicated if a patient reports multiple exposures over 5 days, including several within the required 72-hour period.

She recommended that clinicians be aggressive in getting information about the source of the exposure, to determine whether that person is truly HIV-positive, and to conduct viral resistance testing. This is critical in choosing which antiretrovirals to use.

SAN FRANCISCO — A feasibility study among 891 individuals in San Francisco has identified issues that must be considered in offering nonoccupational postexposure prophylaxis, Michelle Rowland, M.D., said at a meeting on HIV management sponsored by the University of California, San Francisco.

Postexposure prophylaxis (PEP) has been shown to reduce the risk of HIV transmission by 81% in health care workers, but no information is available about the efficacy of prophylaxis after nonoccupational HIV exposure. A placebo-controlled study would be difficult to conduct because of ethical considerations, said Dr. Rowland of UCSF.

At press time, the Centers for Disease Control and Prevention was preparing to issue national guidelines on the use of PEP to reduce the risk of HIV infection.

Of the 891 people in the study, all of whom were given PEP within 72 hours after exposure, 700 could be evaluated 12 weeks after PEP was initiated, and 7 (1%) seroconverted. All seven reported having unprotected receptive anal intercourse, four of them with a partner known to be infected with HIV. In contrast, only 50% of the nonseroconverters presented after receptive anal intercourse, a significantly lower percentage.

Individuals in the study reported one or more episodes of unprotected receptive or insertive anal or vaginal intercourse, receptive oral sex with ejaculation, or shared injection drug equipment. The potential sources of infection had to be known HIV-infected persons, men who has sex with men of unknown HIV status, a past or present injection drug user, a commercial sex worker, or an anonymous contact.

Adherence was fairly good. During week 1, 84% of patients reported no missed doses during the prior 4 days; that figure was 78% during both week 2 and week 4.

Previous studies have yielded estimates that the risk of infection from a single encounter is 0.8% to 5.0% for receptive anal intercourse and substantially lower for other types of exposure. The investigators therefore queried the seroconverters about additional risk behavior. Six of the seven reported other high-risk encounters in the 6 months before PEP, and three of the seven reported ongoing high-risk behavior even after starting PEP, suggesting that the failure of PEP in these patients may not have been entirely due to medication failure.

“PEP is not just medication,” Dr. Rowland said. “It's also adherence counseling, risk-reduction counseling, and referral, because the whole point of this is to help people stay HIV negative. The per-contact transmission rate is virtually almost nothing. So people are not at risk for HIV just at that particular moment; they're particularly at risk for the rest of their lives.”

There's a tendency to want to divide people presenting for PEP into three groups: those who should be advised to use PEP, those who should be offered PEP, and those who should not be offered PEP. In practice, she said, “It's hard for me to recommend PEP to anybody, and it's easy for me to agree to offer it to a fair number of people. The bottom line for me is that it's my job to help that individual person make an individual risk-benefit assessment.”

Animal studies and experience with health care workers suggest it's important to begin antiretroviral therapy at most 72 hours after exposure. But many people who are exposed misinterpret that as meaning that they can wait 72 hours before deciding on PEP. “The message we're trying to get across is, 'You want to start this as soon as possible, and we're not going to initiate it after 72 hours,'” she said.

Investigators generally agree that the antiretroviral component of PEP should be continued for 28 days, but there's a great deal of controversy about what antiretrovirals to use and whether two nucleosides are enough or whether a three-drug regimen is better. The practice at UCSF is to use two drugs, but Dr. Rowland would consider using three in certain circumstances. For example, a three-drug regimen might be indicated if a patient reports multiple exposures over 5 days, including several within the required 72-hour period.

She recommended that clinicians be aggressive in getting information about the source of the exposure, to determine whether that person is truly HIV-positive, and to conduct viral resistance testing. This is critical in choosing which antiretrovirals to use.

SANTA FE, N.M. — Botox is an effective treatment for hyperhidrosis, but the large number of units required is painful unless the clinician uses nerve blocks, George J. Hruza, M.D., said at a conference sponsored by the Skin Disease Education Foundation. However, topical anesthesia is sufficient for the axilla, said Dr. Hruza of the Laser and Dermatologic Surgery Center in Town and Country, Mo.

Treating palmar surfaces with Botox (botulinum toxin type A) requires blocks of the median and ulnar nerves. A radial nerve block is unnecessary, since that nerve innervates the dorsal surface of the hand.

The median nerve is right under the palmaris longus tendon and is best reached in the carpal tunnel. Have the patient touch his or her thumb and little fingers; the nerve will be found at the most proximal crease. One can approach from either side, angling the needle to go under the tendon. If an approach from one side proves unsuccessful, try from the opposite side.

"You can feel it pop in when you get to the carpal tunnel," Dr. Hruza said. "Then inject your anesthetic right in there. There's no big vein or artery there to worry about."

While the ulnar nerve can be reached in the wrist, he prefers to block this nerve by injecting at the elbow between the medial epicondyle and the olecranon process. It's important to avoid injections directly into the nerve, so if the patient shows any sign of paresthesia when the needle goes in, one should back away a bit before injecting. Dr. Hruza recalled one patient who suffered from paresthesia for 4 months as a result of an anesthetic injection into the ulnar nerve.

Treating plantar surfaces requires blocks of the posterior tibial, sural, and superficial peroneal nerves, and, optionally, the deep peroneal nerve.

The posterior tibial nerve is next to the tibial artery, which is easy to find if you can feel the pulse. If you can't feel the pulse, you may want to use Doppler ultrasound to localize the artery. Dr. Hruza has one patient whose tibial artery and nerve are 2 cm out of place. For the first few treatments, Dr. Hruza used Doppler ultrasound; after that, he was able to locate the artery without assistance.

After localizing the artery, insert the needle posterior to anterior, anteromedial to the bone, retract a few millimeters, and inject several milliliters of anesthetic.

The sural nerve is at about the same location on the other side of the ankle. However, there's no artery to guide the injection, which should be placed between the lateral malleolus and the Achilles tendon.

Anesthetize the superficial peroneal nerve by laying down a row of anesthetic in the subcutaneous plane on the front of the foot, extending from the medial to the lateral malleolus.

One may also choose to anesthetize the deep peroneal nerve with a deep injection lateral to the extensor hallucis longus tendon. Dr. Hruza chooses not to block this nerve, because it only innervates the web space between the first and second toes, and only one or two botulinum toxin injections will be made in that location.

The SDEF and this newspaper are wholly owned subsidiaries of Elsevier.

SANTA FE, N.M. — Botox is an effective treatment for hyperhidrosis, but the large number of units required is painful unless the clinician uses nerve blocks, George J. Hruza, M.D., said at a conference sponsored by the Skin Disease Education Foundation. However, topical anesthesia is sufficient for the axilla, said Dr. Hruza of the Laser and Dermatologic Surgery Center in Town and Country, Mo.

Treating palmar surfaces with Botox (botulinum toxin type A) requires blocks of the median and ulnar nerves. A radial nerve block is unnecessary, since that nerve innervates the dorsal surface of the hand.

The median nerve is right under the palmaris longus tendon and is best reached in the carpal tunnel. Have the patient touch his or her thumb and little fingers; the nerve will be found at the most proximal crease. One can approach from either side, angling the needle to go under the tendon. If an approach from one side proves unsuccessful, try from the opposite side.

"You can feel it pop in when you get to the carpal tunnel," Dr. Hruza said. "Then inject your anesthetic right in there. There's no big vein or artery there to worry about."

While the ulnar nerve can be reached in the wrist, he prefers to block this nerve by injecting at the elbow between the medial epicondyle and the olecranon process. It's important to avoid injections directly into the nerve, so if the patient shows any sign of paresthesia when the needle goes in, one should back away a bit before injecting. Dr. Hruza recalled one patient who suffered from paresthesia for 4 months as a result of an anesthetic injection into the ulnar nerve.

Treating plantar surfaces requires blocks of the posterior tibial, sural, and superficial peroneal nerves, and, optionally, the deep peroneal nerve.

The posterior tibial nerve is next to the tibial artery, which is easy to find if you can feel the pulse. If you can't feel the pulse, you may want to use Doppler ultrasound to localize the artery. Dr. Hruza has one patient whose tibial artery and nerve are 2 cm out of place. For the first few treatments, Dr. Hruza used Doppler ultrasound; after that, he was able to locate the artery without assistance.

After localizing the artery, insert the needle posterior to anterior, anteromedial to the bone, retract a few millimeters, and inject several milliliters of anesthetic.

The sural nerve is at about the same location on the other side of the ankle. However, there's no artery to guide the injection, which should be placed between the lateral malleolus and the Achilles tendon.

Anesthetize the superficial peroneal nerve by laying down a row of anesthetic in the subcutaneous plane on the front of the foot, extending from the medial to the lateral malleolus.

One may also choose to anesthetize the deep peroneal nerve with a deep injection lateral to the extensor hallucis longus tendon. Dr. Hruza chooses not to block this nerve, because it only innervates the web space between the first and second toes, and only one or two botulinum toxin injections will be made in that location.

The SDEF and this newspaper are wholly owned subsidiaries of Elsevier.

SANTA FE, N.M. — Botox is an effective treatment for hyperhidrosis, but the large number of units required is painful unless the clinician uses nerve blocks, George J. Hruza, M.D., said at a conference sponsored by the Skin Disease Education Foundation. However, topical anesthesia is sufficient for the axilla, said Dr. Hruza of the Laser and Dermatologic Surgery Center in Town and Country, Mo.

Treating palmar surfaces with Botox (botulinum toxin type A) requires blocks of the median and ulnar nerves. A radial nerve block is unnecessary, since that nerve innervates the dorsal surface of the hand.

The median nerve is right under the palmaris longus tendon and is best reached in the carpal tunnel. Have the patient touch his or her thumb and little fingers; the nerve will be found at the most proximal crease. One can approach from either side, angling the needle to go under the tendon. If an approach from one side proves unsuccessful, try from the opposite side.

"You can feel it pop in when you get to the carpal tunnel," Dr. Hruza said. "Then inject your anesthetic right in there. There's no big vein or artery there to worry about."

While the ulnar nerve can be reached in the wrist, he prefers to block this nerve by injecting at the elbow between the medial epicondyle and the olecranon process. It's important to avoid injections directly into the nerve, so if the patient shows any sign of paresthesia when the needle goes in, one should back away a bit before injecting. Dr. Hruza recalled one patient who suffered from paresthesia for 4 months as a result of an anesthetic injection into the ulnar nerve.

Treating plantar surfaces requires blocks of the posterior tibial, sural, and superficial peroneal nerves, and, optionally, the deep peroneal nerve.

The posterior tibial nerve is next to the tibial artery, which is easy to find if you can feel the pulse. If you can't feel the pulse, you may want to use Doppler ultrasound to localize the artery. Dr. Hruza has one patient whose tibial artery and nerve are 2 cm out of place. For the first few treatments, Dr. Hruza used Doppler ultrasound; after that, he was able to locate the artery without assistance.

After localizing the artery, insert the needle posterior to anterior, anteromedial to the bone, retract a few millimeters, and inject several milliliters of anesthetic.

The sural nerve is at about the same location on the other side of the ankle. However, there's no artery to guide the injection, which should be placed between the lateral malleolus and the Achilles tendon.

Anesthetize the superficial peroneal nerve by laying down a row of anesthetic in the subcutaneous plane on the front of the foot, extending from the medial to the lateral malleolus.

One may also choose to anesthetize the deep peroneal nerve with a deep injection lateral to the extensor hallucis longus tendon. Dr. Hruza chooses not to block this nerve, because it only innervates the web space between the first and second toes, and only one or two botulinum toxin injections will be made in that location.

The SDEF and this newspaper are wholly owned subsidiaries of Elsevier.

SAN FRANCISCO — An investigational form of depot medroxy-progesterone acetate is as effective as leuprolide for the treatment of endometriosis-associated pelvic pain, but it's significantly safer and better tolerated, Anthony A. Luciano, M.D., said at the annual meeting of the American Association of Gynecologic Laparoscopists.

The new formulation, called DMPA-SC (depot medroxyprogesterone acetate-subcutaneous), resulted in significantly smaller losses in bone mineral density (BMD) and significantly fewer menopausal symptoms than did leuprolide in the prospective, randomized, investigator-blinded study, said Dr. Luciano of the University of Connecticut in Farmington.

DMPA-SC has not been approved by the Food and Drug Administration. The study was funded by its manufacturer, Pharmacia Upjohn, a company that has become part of Pfizer Inc. Dr. Luciano acknowledged receiving consulting and honorarium support from Pfizer.

During the study, 274 women aged 18-49 years who had diagnoses of endometriosis-associated pelvic pain received 6 months of treatment with either DMPA-SC (104 mg every 3 months) or leuprolide (11.25 mg IM every 3 months). They were followed for an additional 12 months after completing treatment.

Patients rated their pain in five categories: dysmenorrhea, dyspareunia, pelvic pain, pelvic tenderness, and induration. Investigators used the Kupperman Index—a composite score involving 11 menopausal symptoms—to assess hypoestrogenemia.

Both groups experienced substantial improvements in their pelvic pain, both at the end of treatment and continuing 12 months later, with no significant differences between the two groups.

Both groups showed some BMD declines at the end of treatment, but the mean losses were significantly less for women taking DMPA-SC than for women taking leuprolide in both the femur (0.3% vs. 1.65%) and the spine (1.1% vs. 3.95%).

Those who'd been taking DMPA-SC saw their BMD return to pretreatment levels 12 months after discontinuing treatment, whereas those who had been taking leuprolide showed continued BMD losses: 1.3% in the femur and 1.7% in the spine.

Women taking leuprolide had significant increases in Kupperman Index scores; those taking DMPA-SC showed no increase. Between the second and sixth month of treatment, women taking leuprolide experienced an average of two to three hot flashes per day. Women on DMPA-SC had almost no hot flashes. A significantly higher percentage of leuprolide patients had estradiol levels lower than 41 pg/mL (77% vs. 33%).

Adverse events seen more often in the DMPA-SC group were injection-site reactions (6.9% vs. 0%) and intermenstrual bleeding (5.4% vs 0.7%).

SAN FRANCISCO — An investigational form of depot medroxy-progesterone acetate is as effective as leuprolide for the treatment of endometriosis-associated pelvic pain, but it's significantly safer and better tolerated, Anthony A. Luciano, M.D., said at the annual meeting of the American Association of Gynecologic Laparoscopists.

The new formulation, called DMPA-SC (depot medroxyprogesterone acetate-subcutaneous), resulted in significantly smaller losses in bone mineral density (BMD) and significantly fewer menopausal symptoms than did leuprolide in the prospective, randomized, investigator-blinded study, said Dr. Luciano of the University of Connecticut in Farmington.

DMPA-SC has not been approved by the Food and Drug Administration. The study was funded by its manufacturer, Pharmacia Upjohn, a company that has become part of Pfizer Inc. Dr. Luciano acknowledged receiving consulting and honorarium support from Pfizer.

During the study, 274 women aged 18-49 years who had diagnoses of endometriosis-associated pelvic pain received 6 months of treatment with either DMPA-SC (104 mg every 3 months) or leuprolide (11.25 mg IM every 3 months). They were followed for an additional 12 months after completing treatment.

Patients rated their pain in five categories: dysmenorrhea, dyspareunia, pelvic pain, pelvic tenderness, and induration. Investigators used the Kupperman Index—a composite score involving 11 menopausal symptoms—to assess hypoestrogenemia.

Both groups experienced substantial improvements in their pelvic pain, both at the end of treatment and continuing 12 months later, with no significant differences between the two groups.

Both groups showed some BMD declines at the end of treatment, but the mean losses were significantly less for women taking DMPA-SC than for women taking leuprolide in both the femur (0.3% vs. 1.65%) and the spine (1.1% vs. 3.95%).

Those who'd been taking DMPA-SC saw their BMD return to pretreatment levels 12 months after discontinuing treatment, whereas those who had been taking leuprolide showed continued BMD losses: 1.3% in the femur and 1.7% in the spine.

Women taking leuprolide had significant increases in Kupperman Index scores; those taking DMPA-SC showed no increase. Between the second and sixth month of treatment, women taking leuprolide experienced an average of two to three hot flashes per day. Women on DMPA-SC had almost no hot flashes. A significantly higher percentage of leuprolide patients had estradiol levels lower than 41 pg/mL (77% vs. 33%).

Adverse events seen more often in the DMPA-SC group were injection-site reactions (6.9% vs. 0%) and intermenstrual bleeding (5.4% vs 0.7%).

SAN FRANCISCO — An investigational form of depot medroxy-progesterone acetate is as effective as leuprolide for the treatment of endometriosis-associated pelvic pain, but it's significantly safer and better tolerated, Anthony A. Luciano, M.D., said at the annual meeting of the American Association of Gynecologic Laparoscopists.

The new formulation, called DMPA-SC (depot medroxyprogesterone acetate-subcutaneous), resulted in significantly smaller losses in bone mineral density (BMD) and significantly fewer menopausal symptoms than did leuprolide in the prospective, randomized, investigator-blinded study, said Dr. Luciano of the University of Connecticut in Farmington.

DMPA-SC has not been approved by the Food and Drug Administration. The study was funded by its manufacturer, Pharmacia Upjohn, a company that has become part of Pfizer Inc. Dr. Luciano acknowledged receiving consulting and honorarium support from Pfizer.

During the study, 274 women aged 18-49 years who had diagnoses of endometriosis-associated pelvic pain received 6 months of treatment with either DMPA-SC (104 mg every 3 months) or leuprolide (11.25 mg IM every 3 months). They were followed for an additional 12 months after completing treatment.

Patients rated their pain in five categories: dysmenorrhea, dyspareunia, pelvic pain, pelvic tenderness, and induration. Investigators used the Kupperman Index—a composite score involving 11 menopausal symptoms—to assess hypoestrogenemia.

Both groups experienced substantial improvements in their pelvic pain, both at the end of treatment and continuing 12 months later, with no significant differences between the two groups.

Both groups showed some BMD declines at the end of treatment, but the mean losses were significantly less for women taking DMPA-SC than for women taking leuprolide in both the femur (0.3% vs. 1.65%) and the spine (1.1% vs. 3.95%).

Those who'd been taking DMPA-SC saw their BMD return to pretreatment levels 12 months after discontinuing treatment, whereas those who had been taking leuprolide showed continued BMD losses: 1.3% in the femur and 1.7% in the spine.

Women taking leuprolide had significant increases in Kupperman Index scores; those taking DMPA-SC showed no increase. Between the second and sixth month of treatment, women taking leuprolide experienced an average of two to three hot flashes per day. Women on DMPA-SC had almost no hot flashes. A significantly higher percentage of leuprolide patients had estradiol levels lower than 41 pg/mL (77% vs. 33%).

Adverse events seen more often in the DMPA-SC group were injection-site reactions (6.9% vs. 0%) and intermenstrual bleeding (5.4% vs 0.7%).

SAN FRANCISCO — A feasibility study among 891 individuals in San Francisco has identified some of the issues that must be considered in offering nonoccupational postexposure prophylaxis, Michelle Rowland, M.D., said at a meeting on HIV management sponsored by the University of California, San Francisco.

Postexposure prophylaxis (PEP) has been shown to reduce the risk of HIV transmission by 81% in health care workers, but no information is available about the efficacy of prophylaxis after nonoccupational HIV exposure. A placebo-controlled study would be difficult to conduct because of ethical considerations.

Of the 891 people in the study, all of whom were given PEP within 72 hours after exposure, 700 could be evaluated 12 weeks after PEP was initiated, and 7 individuals (1%) seroconverted, said Dr. Rowland of UCSF. All seven reported having unprotected receptive anal intercourse, four of them with a partner known to be infected with HIV. In contrast, only 50% of the nonseroconverters presented after receptive anal intercourse, a significantly lower percentage.

Individuals in the study reported one or more episodes of unprotected receptive or insertive anal or vaginal intercourse, receptive oral sex with ejaculation, or shared injection drug equipment. The potential sources of infection had to be known HIV-infected persons, men who have sex with men of unknown HIV status, a past or present injection drug user, a commercial sex worker, or an anonymous contact.

Previous studies have yielded estimates that the risk of infection from a single encounter is 0.8%-5.0% for receptive anal intercourse and substantially lower for other types of exposure. The investigators therefore queried the seroconverters about additional risk behavior. Six of the seven reported other high-risk encounters in the 6 months before PEP, and three of the seven reported ongoing high-risk behavior even after starting PEP, suggesting that the failure of PEP in these patients may not have been entirely due to medication failure.

“PEP is not just medication,” Dr. Rowland said. “It's also adherence counseling, risk-reduction counseling, and referral, because the whole point of this is to help people stay HIV negative. The per-contact transmission rate is virtually almost nothing. So people are not at risk for HIV just at that particular moment; they're particularly at risk for the rest of their lives.”

There's a tendency to want to divide people presenting for PEP into three groups: those who should be advised to use PEP, those who should be offered PEP, and those who should not be offered PEP. In practice, she said, “The bottom line for me is that it's my job to help that individual person make an individual risk-benefit assessment.”

Animal studies and experience with health care workers suggest it's important to begin antiretroviral therapy at most 72 hours after exposure. But many people who are exposed misinterpret that as meaning that they can wait 72 hours before deciding on PEP. “The message we're trying to get across is, 'You want to start this as soon as possible, and we're not going to initiate it after 72 hours,' ” she said.

Investigators generally agree that the antiretroviral component of PEP should be continued for 28 days, but there's a great deal of controversy about what antiretrovirals to use and whether two nucleosides are enough or whether a three-drug regimen is better. The practice at UCSF is to use two drugs, but Dr. Rowland would consider using three in certain circumstances. For example, a three-drug regimen might be indicated if a patient reports multiple exposures over 5 days, including several within the required 72-hour period.

She recommended that clinicians be aggressive in getting information about the source of the exposure, to determine whether that person is truly HIV positive, and to conduct viral resistance testing. This is critical in choosing which antiretrovirals to use.

SAN FRANCISCO — A feasibility study among 891 individuals in San Francisco has identified some of the issues that must be considered in offering nonoccupational postexposure prophylaxis, Michelle Rowland, M.D., said at a meeting on HIV management sponsored by the University of California, San Francisco.

Postexposure prophylaxis (PEP) has been shown to reduce the risk of HIV transmission by 81% in health care workers, but no information is available about the efficacy of prophylaxis after nonoccupational HIV exposure. A placebo-controlled study would be difficult to conduct because of ethical considerations.

Of the 891 people in the study, all of whom were given PEP within 72 hours after exposure, 700 could be evaluated 12 weeks after PEP was initiated, and 7 individuals (1%) seroconverted, said Dr. Rowland of UCSF. All seven reported having unprotected receptive anal intercourse, four of them with a partner known to be infected with HIV. In contrast, only 50% of the nonseroconverters presented after receptive anal intercourse, a significantly lower percentage.

Individuals in the study reported one or more episodes of unprotected receptive or insertive anal or vaginal intercourse, receptive oral sex with ejaculation, or shared injection drug equipment. The potential sources of infection had to be known HIV-infected persons, men who have sex with men of unknown HIV status, a past or present injection drug user, a commercial sex worker, or an anonymous contact.

Previous studies have yielded estimates that the risk of infection from a single encounter is 0.8%-5.0% for receptive anal intercourse and substantially lower for other types of exposure. The investigators therefore queried the seroconverters about additional risk behavior. Six of the seven reported other high-risk encounters in the 6 months before PEP, and three of the seven reported ongoing high-risk behavior even after starting PEP, suggesting that the failure of PEP in these patients may not have been entirely due to medication failure.

“PEP is not just medication,” Dr. Rowland said. “It's also adherence counseling, risk-reduction counseling, and referral, because the whole point of this is to help people stay HIV negative. The per-contact transmission rate is virtually almost nothing. So people are not at risk for HIV just at that particular moment; they're particularly at risk for the rest of their lives.”

There's a tendency to want to divide people presenting for PEP into three groups: those who should be advised to use PEP, those who should be offered PEP, and those who should not be offered PEP. In practice, she said, “The bottom line for me is that it's my job to help that individual person make an individual risk-benefit assessment.”

Animal studies and experience with health care workers suggest it's important to begin antiretroviral therapy at most 72 hours after exposure. But many people who are exposed misinterpret that as meaning that they can wait 72 hours before deciding on PEP. “The message we're trying to get across is, 'You want to start this as soon as possible, and we're not going to initiate it after 72 hours,' ” she said.

Investigators generally agree that the antiretroviral component of PEP should be continued for 28 days, but there's a great deal of controversy about what antiretrovirals to use and whether two nucleosides are enough or whether a three-drug regimen is better. The practice at UCSF is to use two drugs, but Dr. Rowland would consider using three in certain circumstances. For example, a three-drug regimen might be indicated if a patient reports multiple exposures over 5 days, including several within the required 72-hour period.

She recommended that clinicians be aggressive in getting information about the source of the exposure, to determine whether that person is truly HIV positive, and to conduct viral resistance testing. This is critical in choosing which antiretrovirals to use.

SAN FRANCISCO — A feasibility study among 891 individuals in San Francisco has identified some of the issues that must be considered in offering nonoccupational postexposure prophylaxis, Michelle Rowland, M.D., said at a meeting on HIV management sponsored by the University of California, San Francisco.

Postexposure prophylaxis (PEP) has been shown to reduce the risk of HIV transmission by 81% in health care workers, but no information is available about the efficacy of prophylaxis after nonoccupational HIV exposure. A placebo-controlled study would be difficult to conduct because of ethical considerations.

Of the 891 people in the study, all of whom were given PEP within 72 hours after exposure, 700 could be evaluated 12 weeks after PEP was initiated, and 7 individuals (1%) seroconverted, said Dr. Rowland of UCSF. All seven reported having unprotected receptive anal intercourse, four of them with a partner known to be infected with HIV. In contrast, only 50% of the nonseroconverters presented after receptive anal intercourse, a significantly lower percentage.

Individuals in the study reported one or more episodes of unprotected receptive or insertive anal or vaginal intercourse, receptive oral sex with ejaculation, or shared injection drug equipment. The potential sources of infection had to be known HIV-infected persons, men who have sex with men of unknown HIV status, a past or present injection drug user, a commercial sex worker, or an anonymous contact.

Previous studies have yielded estimates that the risk of infection from a single encounter is 0.8%-5.0% for receptive anal intercourse and substantially lower for other types of exposure. The investigators therefore queried the seroconverters about additional risk behavior. Six of the seven reported other high-risk encounters in the 6 months before PEP, and three of the seven reported ongoing high-risk behavior even after starting PEP, suggesting that the failure of PEP in these patients may not have been entirely due to medication failure.

“PEP is not just medication,” Dr. Rowland said. “It's also adherence counseling, risk-reduction counseling, and referral, because the whole point of this is to help people stay HIV negative. The per-contact transmission rate is virtually almost nothing. So people are not at risk for HIV just at that particular moment; they're particularly at risk for the rest of their lives.”

There's a tendency to want to divide people presenting for PEP into three groups: those who should be advised to use PEP, those who should be offered PEP, and those who should not be offered PEP. In practice, she said, “The bottom line for me is that it's my job to help that individual person make an individual risk-benefit assessment.”

Animal studies and experience with health care workers suggest it's important to begin antiretroviral therapy at most 72 hours after exposure. But many people who are exposed misinterpret that as meaning that they can wait 72 hours before deciding on PEP. “The message we're trying to get across is, 'You want to start this as soon as possible, and we're not going to initiate it after 72 hours,' ” she said.

Investigators generally agree that the antiretroviral component of PEP should be continued for 28 days, but there's a great deal of controversy about what antiretrovirals to use and whether two nucleosides are enough or whether a three-drug regimen is better. The practice at UCSF is to use two drugs, but Dr. Rowland would consider using three in certain circumstances. For example, a three-drug regimen might be indicated if a patient reports multiple exposures over 5 days, including several within the required 72-hour period.

She recommended that clinicians be aggressive in getting information about the source of the exposure, to determine whether that person is truly HIV positive, and to conduct viral resistance testing. This is critical in choosing which antiretrovirals to use.

Patients suffering from acute ischemic stroke are significantly more likely to achieve recanalization and/or early or dramatic clinical recovery if thrombolytic therapy is combined with continuous transcranial Doppler sonography, according to a study by Andrei V. Alexandrov, M.D., of the University of Texas, Houston, and colleagues.

Of 63 patients receiving ultrasound combined with tissue plasminogen activator (t-PA), 31 (49%) achieved recanalization and/or clinical recovery within 2 hours, compared with 19 of 63 patients (30%) who received t-PA that was combined with sham sonography.

Within 2 hours, 16 (25%) of the patients in the treatment group experienced both recanalization and clinical recovery, compared with 5 (8%) of those in control group. Both of the differences were statistically significant (N. Engl. J. Med. 2004; 351:2170-8).

All patients had occlusions of the middle cerebral artery, and all were treated within 3 hours of the onset of symptoms. The patients were randomly assigned to the treatment or the control group, he said.

Known as the Combined Lysis of Thrombus in Brain Ischemia Using Transcranial Ultrasound and Systemic t-PA (CLOTBUST) trial, the study was funded in part by the National Institute of Neurological Disorders and Stroke, a unit of the National Institutes of Health.

This phase II study was not sufficiently powered to detect a difference in clinical outcome 3 months after the treatment, but there was a statistical trend in that direction.

Of the 53 patients from the treatment group eligible for follow-up, 22 (42%) had achieved a modified Rankin score of 0 or 1, compared with 4 of the 15 eligible patients (27%) in the control group. Given those rates of recovery, the investigators calculated that a phase III study would need to include just 274 patients in each group to replicate the results with statistical significance.

“If you look at the trials being done in cardiology right now, they enroll thousands and tens of thousands of patients to show a difference of a very few percentage points,” Dr. Alexandrov said in an interview. “Cardiologists would love to have an absolute difference of 10% or more between the groups, and that's what we can shoot for. We can shoot for easily up to a 13% difference between the groups.”

But Dr. Alexandrov is not waiting for the results of that trial, which will likely take 2-3 years, to put the combined treatment into practice.

“At our center, it's the standard of care right now,” he said. “Both [t-PA and transcranial Doppler sonography] are Food and Drug Administration-approved technologies, and the trial was exempt from investigational new drug status by FDA because these results would not change the labels. Right now in our institution, when we give systemic t-PA within 3 hours [after a stroke], we always put a transcranial Doppler probe on the scalp to help the patient pass the clot faster.”

Nevertheless, “I will not stand here and recommend that everybody else should do the same,” Dr. Alexandrov said. “The reason is that to do it right, you have to pass through a very lengthy and labor-intense training that is not a routine part of any neurology residency. To do the protocol, you need 1-6 months of daily practicing of this technique under supervision, and that's something that very few programs can do in the United States.”

Dr. Alexandrov is involved in an effort to design an operator-independent device that would obviate the need for an experienced operator.

With such a device, “an emergency department physician could do it, a neurologist could do it, and a nurse could mount the ultrasound machine on the head,” he said.

The mechanism by which transcranial Doppler sonography improves thrombolysis is still unclear. In a commentary accompanying Dr. Alexandrov's paper, Joseph F. Polak, M.D., of Tufts University, Boston, weighs a number of the possibilities (N. Engl. J. Med. 2004;351:2154-5).

It's clear that the mechanism does not involve cavitation, which ultrasound at high energies can cause. In a cavitational mechanism, the ultrasound energy causes partially dissolved gases to form small bubbles in the blood vessels, which literally explode.

It's also unlikely that the relatively low energies used in transcranial Doppler ultrasound could accelerate thrombolysis by producing heat.

Dr. Alexandrov believes that the combined treatment works because ultrasound is causing a gentle mechanical pressure wave, which delivers more t-PA molecules to and through the clot.

The study was sparked by a clinical observation, Dr. Alexandrov explained. “Patients who were wearing these transducers for diagnostic purposes started to move their paralyzed arms and legs and to talk to us much faster than we ever [would have] expected otherwise.”

Patients suffering from acute ischemic stroke are significantly more likely to achieve recanalization and/or early or dramatic clinical recovery if thrombolytic therapy is combined with continuous transcranial Doppler sonography, according to a study by Andrei V. Alexandrov, M.D., of the University of Texas, Houston, and colleagues.

Of 63 patients receiving ultrasound combined with tissue plasminogen activator (t-PA), 31 (49%) achieved recanalization and/or clinical recovery within 2 hours, compared with 19 of 63 patients (30%) who received t-PA that was combined with sham sonography.

Within 2 hours, 16 (25%) of the patients in the treatment group experienced both recanalization and clinical recovery, compared with 5 (8%) of those in control group. Both of the differences were statistically significant (N. Engl. J. Med. 2004; 351:2170-8).

All patients had occlusions of the middle cerebral artery, and all were treated within 3 hours of the onset of symptoms. The patients were randomly assigned to the treatment or the control group, he said.

Known as the Combined Lysis of Thrombus in Brain Ischemia Using Transcranial Ultrasound and Systemic t-PA (CLOTBUST) trial, the study was funded in part by the National Institute of Neurological Disorders and Stroke, a unit of the National Institutes of Health.

This phase II study was not sufficiently powered to detect a difference in clinical outcome 3 months after the treatment, but there was a statistical trend in that direction.

Of the 53 patients from the treatment group eligible for follow-up, 22 (42%) had achieved a modified Rankin score of 0 or 1, compared with 4 of the 15 eligible patients (27%) in the control group. Given those rates of recovery, the investigators calculated that a phase III study would need to include just 274 patients in each group to replicate the results with statistical significance.

“If you look at the trials being done in cardiology right now, they enroll thousands and tens of thousands of patients to show a difference of a very few percentage points,” Dr. Alexandrov said in an interview. “Cardiologists would love to have an absolute difference of 10% or more between the groups, and that's what we can shoot for. We can shoot for easily up to a 13% difference between the groups.”

But Dr. Alexandrov is not waiting for the results of that trial, which will likely take 2-3 years, to put the combined treatment into practice.

“At our center, it's the standard of care right now,” he said. “Both [t-PA and transcranial Doppler sonography] are Food and Drug Administration-approved technologies, and the trial was exempt from investigational new drug status by FDA because these results would not change the labels. Right now in our institution, when we give systemic t-PA within 3 hours [after a stroke], we always put a transcranial Doppler probe on the scalp to help the patient pass the clot faster.”

Nevertheless, “I will not stand here and recommend that everybody else should do the same,” Dr. Alexandrov said. “The reason is that to do it right, you have to pass through a very lengthy and labor-intense training that is not a routine part of any neurology residency. To do the protocol, you need 1-6 months of daily practicing of this technique under supervision, and that's something that very few programs can do in the United States.”

Dr. Alexandrov is involved in an effort to design an operator-independent device that would obviate the need for an experienced operator.

With such a device, “an emergency department physician could do it, a neurologist could do it, and a nurse could mount the ultrasound machine on the head,” he said.

The mechanism by which transcranial Doppler sonography improves thrombolysis is still unclear. In a commentary accompanying Dr. Alexandrov's paper, Joseph F. Polak, M.D., of Tufts University, Boston, weighs a number of the possibilities (N. Engl. J. Med. 2004;351:2154-5).

It's clear that the mechanism does not involve cavitation, which ultrasound at high energies can cause. In a cavitational mechanism, the ultrasound energy causes partially dissolved gases to form small bubbles in the blood vessels, which literally explode.

It's also unlikely that the relatively low energies used in transcranial Doppler ultrasound could accelerate thrombolysis by producing heat.

Dr. Alexandrov believes that the combined treatment works because ultrasound is causing a gentle mechanical pressure wave, which delivers more t-PA molecules to and through the clot.

The study was sparked by a clinical observation, Dr. Alexandrov explained. “Patients who were wearing these transducers for diagnostic purposes started to move their paralyzed arms and legs and to talk to us much faster than we ever [would have] expected otherwise.”

Patients suffering from acute ischemic stroke are significantly more likely to achieve recanalization and/or early or dramatic clinical recovery if thrombolytic therapy is combined with continuous transcranial Doppler sonography, according to a study by Andrei V. Alexandrov, M.D., of the University of Texas, Houston, and colleagues.

Of 63 patients receiving ultrasound combined with tissue plasminogen activator (t-PA), 31 (49%) achieved recanalization and/or clinical recovery within 2 hours, compared with 19 of 63 patients (30%) who received t-PA that was combined with sham sonography.

Within 2 hours, 16 (25%) of the patients in the treatment group experienced both recanalization and clinical recovery, compared with 5 (8%) of those in control group. Both of the differences were statistically significant (N. Engl. J. Med. 2004; 351:2170-8).

All patients had occlusions of the middle cerebral artery, and all were treated within 3 hours of the onset of symptoms. The patients were randomly assigned to the treatment or the control group, he said.

Known as the Combined Lysis of Thrombus in Brain Ischemia Using Transcranial Ultrasound and Systemic t-PA (CLOTBUST) trial, the study was funded in part by the National Institute of Neurological Disorders and Stroke, a unit of the National Institutes of Health.

This phase II study was not sufficiently powered to detect a difference in clinical outcome 3 months after the treatment, but there was a statistical trend in that direction.

Of the 53 patients from the treatment group eligible for follow-up, 22 (42%) had achieved a modified Rankin score of 0 or 1, compared with 4 of the 15 eligible patients (27%) in the control group. Given those rates of recovery, the investigators calculated that a phase III study would need to include just 274 patients in each group to replicate the results with statistical significance.

“If you look at the trials being done in cardiology right now, they enroll thousands and tens of thousands of patients to show a difference of a very few percentage points,” Dr. Alexandrov said in an interview. “Cardiologists would love to have an absolute difference of 10% or more between the groups, and that's what we can shoot for. We can shoot for easily up to a 13% difference between the groups.”

But Dr. Alexandrov is not waiting for the results of that trial, which will likely take 2-3 years, to put the combined treatment into practice.

“At our center, it's the standard of care right now,” he said. “Both [t-PA and transcranial Doppler sonography] are Food and Drug Administration-approved technologies, and the trial was exempt from investigational new drug status by FDA because these results would not change the labels. Right now in our institution, when we give systemic t-PA within 3 hours [after a stroke], we always put a transcranial Doppler probe on the scalp to help the patient pass the clot faster.”

Nevertheless, “I will not stand here and recommend that everybody else should do the same,” Dr. Alexandrov said. “The reason is that to do it right, you have to pass through a very lengthy and labor-intense training that is not a routine part of any neurology residency. To do the protocol, you need 1-6 months of daily practicing of this technique under supervision, and that's something that very few programs can do in the United States.”

Dr. Alexandrov is involved in an effort to design an operator-independent device that would obviate the need for an experienced operator.

With such a device, “an emergency department physician could do it, a neurologist could do it, and a nurse could mount the ultrasound machine on the head,” he said.

The mechanism by which transcranial Doppler sonography improves thrombolysis is still unclear. In a commentary accompanying Dr. Alexandrov's paper, Joseph F. Polak, M.D., of Tufts University, Boston, weighs a number of the possibilities (N. Engl. J. Med. 2004;351:2154-5).

It's clear that the mechanism does not involve cavitation, which ultrasound at high energies can cause. In a cavitational mechanism, the ultrasound energy causes partially dissolved gases to form small bubbles in the blood vessels, which literally explode.

It's also unlikely that the relatively low energies used in transcranial Doppler ultrasound could accelerate thrombolysis by producing heat.

Dr. Alexandrov believes that the combined treatment works because ultrasound is causing a gentle mechanical pressure wave, which delivers more t-PA molecules to and through the clot.

The study was sparked by a clinical observation, Dr. Alexandrov explained. “Patients who were wearing these transducers for diagnostic purposes started to move their paralyzed arms and legs and to talk to us much faster than we ever [would have] expected otherwise.”

SAN FRANCISCO — Only five pregnancies have been reported in the first year of worldwide commercial experience with the Essure hysteroscopic sterilization device, and none resulted from devices that were placed properly, Andrew I. Brill, M.D., reported at the annual meeting of the American Association for Gynecologic Laparoscopists.

After the device was approved by the Food and Drug Adminsitration in 2002, Conceptus Inc. of San Carlos, Calif., shipped 9,000 units of Essure in the first year of commercial availability, said Dr. Brill, who is professor of ob.gyn., and director of gynecologic endoscopy at the University of Illinois, Chicago.

“Essure and other hysteroscopic sterilization methodologies are quickly becoming a standard option for patients seeking permanent sterilization and probably will become the norm, by my prediction, in 2 or 3 years,” Dr. Brill said. “The effectiveness rate remains high in the commercial marketplace.”

The rates of various adverse events reported in that first year were lower than those reported during the pivotal premarket clinical trials, but Dr. Brill acknowledged that the actual number of adverse events—and pregnancies—may be higher than the number voluntarily reported to the company by clinicians.

For example, the rate of expulsion of the Essure microinserts was 0.16% in commercial experience, compared with 2.9% in the clinical trials.

Tubal perforation was 0.31% in commercial experience and 1.1% in clinical trials.

Clinicians also reported that 0.97% of the insertion devices had bent tips, resulting in deployment difficulties.

Dr. Brill discussed the five pregnancies in detail.

The first case was a of woman who appeared to have had an adequate bilateral placement, but she failed the hysterosalpingogram (HSG) 3 months later. When she had a subsequent laparoscopic tubal ligation, it was discovered that one of the microinserts had been expelled.

The second case involved a unilateral placement, because the physician mistakenly believed the woman had a unicornuate uterus and placed only one insert. In fact, she had a normal bicornuate uterus and had an intact fallopian tube remaining. This woman, too, failed a 3-month HSG.

In the third case, the inserts were placed bilaterally in a patient who had a conceptus in situ and a documented luteal pregnancy.

In the fourth and fifth cases, placement of the devices was bilateral, but on review, it turned out there was subsequent misreading of radiographic criteria. In one case, the clinician apparently misread the HSG, which other reviewers later determined did indeed document a cornual perforation.

In the other case, the problem was a misread three-dimensional ultrasound, which on review documented a misplaced device. Although physicians in the United States don't use 3D ultrasound to document proper placement of the microinserts, in Europe the technology is used for this purpose.

Although Dr. Brill did acknowledge receiving consulting and grant support from several companies, including TAP Pharmaceuticals, Gynecare, SurgRx, Gyrus Medical, and ACMI, this list did not include Conceptus, which distributes Essure.

SAN FRANCISCO — Only five pregnancies have been reported in the first year of worldwide commercial experience with the Essure hysteroscopic sterilization device, and none resulted from devices that were placed properly, Andrew I. Brill, M.D., reported at the annual meeting of the American Association for Gynecologic Laparoscopists.

After the device was approved by the Food and Drug Adminsitration in 2002, Conceptus Inc. of San Carlos, Calif., shipped 9,000 units of Essure in the first year of commercial availability, said Dr. Brill, who is professor of ob.gyn., and director of gynecologic endoscopy at the University of Illinois, Chicago.

“Essure and other hysteroscopic sterilization methodologies are quickly becoming a standard option for patients seeking permanent sterilization and probably will become the norm, by my prediction, in 2 or 3 years,” Dr. Brill said. “The effectiveness rate remains high in the commercial marketplace.”

The rates of various adverse events reported in that first year were lower than those reported during the pivotal premarket clinical trials, but Dr. Brill acknowledged that the actual number of adverse events—and pregnancies—may be higher than the number voluntarily reported to the company by clinicians.

For example, the rate of expulsion of the Essure microinserts was 0.16% in commercial experience, compared with 2.9% in the clinical trials.

Tubal perforation was 0.31% in commercial experience and 1.1% in clinical trials.

Clinicians also reported that 0.97% of the insertion devices had bent tips, resulting in deployment difficulties.

Dr. Brill discussed the five pregnancies in detail.

The first case was a of woman who appeared to have had an adequate bilateral placement, but she failed the hysterosalpingogram (HSG) 3 months later. When she had a subsequent laparoscopic tubal ligation, it was discovered that one of the microinserts had been expelled.

The second case involved a unilateral placement, because the physician mistakenly believed the woman had a unicornuate uterus and placed only one insert. In fact, she had a normal bicornuate uterus and had an intact fallopian tube remaining. This woman, too, failed a 3-month HSG.

In the third case, the inserts were placed bilaterally in a patient who had a conceptus in situ and a documented luteal pregnancy.

In the fourth and fifth cases, placement of the devices was bilateral, but on review, it turned out there was subsequent misreading of radiographic criteria. In one case, the clinician apparently misread the HSG, which other reviewers later determined did indeed document a cornual perforation.

In the other case, the problem was a misread three-dimensional ultrasound, which on review documented a misplaced device. Although physicians in the United States don't use 3D ultrasound to document proper placement of the microinserts, in Europe the technology is used for this purpose.

Although Dr. Brill did acknowledge receiving consulting and grant support from several companies, including TAP Pharmaceuticals, Gynecare, SurgRx, Gyrus Medical, and ACMI, this list did not include Conceptus, which distributes Essure.

SAN FRANCISCO — Only five pregnancies have been reported in the first year of worldwide commercial experience with the Essure hysteroscopic sterilization device, and none resulted from devices that were placed properly, Andrew I. Brill, M.D., reported at the annual meeting of the American Association for Gynecologic Laparoscopists.

After the device was approved by the Food and Drug Adminsitration in 2002, Conceptus Inc. of San Carlos, Calif., shipped 9,000 units of Essure in the first year of commercial availability, said Dr. Brill, who is professor of ob.gyn., and director of gynecologic endoscopy at the University of Illinois, Chicago.

“Essure and other hysteroscopic sterilization methodologies are quickly becoming a standard option for patients seeking permanent sterilization and probably will become the norm, by my prediction, in 2 or 3 years,” Dr. Brill said. “The effectiveness rate remains high in the commercial marketplace.”

The rates of various adverse events reported in that first year were lower than those reported during the pivotal premarket clinical trials, but Dr. Brill acknowledged that the actual number of adverse events—and pregnancies—may be higher than the number voluntarily reported to the company by clinicians.

For example, the rate of expulsion of the Essure microinserts was 0.16% in commercial experience, compared with 2.9% in the clinical trials.

Tubal perforation was 0.31% in commercial experience and 1.1% in clinical trials.

Clinicians also reported that 0.97% of the insertion devices had bent tips, resulting in deployment difficulties.

Dr. Brill discussed the five pregnancies in detail.

The first case was a of woman who appeared to have had an adequate bilateral placement, but she failed the hysterosalpingogram (HSG) 3 months later. When she had a subsequent laparoscopic tubal ligation, it was discovered that one of the microinserts had been expelled.

The second case involved a unilateral placement, because the physician mistakenly believed the woman had a unicornuate uterus and placed only one insert. In fact, she had a normal bicornuate uterus and had an intact fallopian tube remaining. This woman, too, failed a 3-month HSG.

In the third case, the inserts were placed bilaterally in a patient who had a conceptus in situ and a documented luteal pregnancy.

In the fourth and fifth cases, placement of the devices was bilateral, but on review, it turned out there was subsequent misreading of radiographic criteria. In one case, the clinician apparently misread the HSG, which other reviewers later determined did indeed document a cornual perforation.

In the other case, the problem was a misread three-dimensional ultrasound, which on review documented a misplaced device. Although physicians in the United States don't use 3D ultrasound to document proper placement of the microinserts, in Europe the technology is used for this purpose.

Although Dr. Brill did acknowledge receiving consulting and grant support from several companies, including TAP Pharmaceuticals, Gynecare, SurgRx, Gyrus Medical, and ACMI, this list did not include Conceptus, which distributes Essure.