Mary Ann Moon

Major Finding: Both venlafaxine and clonidine reduced the frequency and severity of hot flashes by approximately 45%, compared with placebo.

Data Source: A prospective, randomized, double-blind, multicenter clinical trial comparing 12 weeks of venlafaxine, clonidine, or placebo for control of hot flashes in 102 Dutch women with breast cancer.

Disclosures: No financial conflicts of interest were reported.

Venlafaxine and clonidine both outperformed placebo in controlling hot flashes among women with breast cancer in a randomized, placebo-controlled trial.

Effective treatments for hot flashes may improve these patients' ability to continue their anticancer therapies, said Dr. Annelies H. Boekhout of The Netherlands Cancer Institute, Amsterdam, and her associates.

The selective serotonin reuptake inhibitor venlafaxine (Effexor) and the antihypertensive clonidine “both are often prescribed treatments and are recommended in clinical guidelines in the management of hot flashes. However, a three-arm trial comparing clonidine, venlafaxine, and placebo in patients with breast cancer has not been conducted” until now, they noted.

In their double-blind study at three Dutch hospitals, 102 women with breast cancer who experienced at least two hot flashes per day were stratified by age, duration of symptoms, concurrent endocrine therapy, and previous chemotherapy, and randomly assigned to receive 75 mg of venlafaxine (41 patients), 0.1 mg of clonidine (41 patients), or matching placebo (20 patients) daily for 12 weeks.

The study participants completed daily diaries recording the frequency and severity of hot flashes. They also reported every week on adverse events such as reduced appetite, nausea, sleepiness, dizziness, fatigue, dry mouth, and constipation. In addition, they recorded their sleep quality, anxiety, depression, and sexual function at 4 weeks and at the conclusion of treatment.

A total of 22 subjects (22%) either dropped out of the study or were lost to follow-up. Two patients (5%) in the venlafaxine group and six (15%) in the clonidine group cited adverse effects such as somnolence, dizziness, and dry mouth as their reason for discontinuing. Another 9% of the study participants discontinued because of noncompliance, which “had some effect on the observed differences between treatments in this study.”

Among the 35 women assigned to venlafaxine who completed the trial, there was a 42% decline in hot flashes during weeks 1–4, compared with the placebo group. Over the entire study period, the reduction in hot flashes was 41% with venlafaxine, compared with placebo, according to Dr. Boekhout and her colleagues.

Among the 28 women assigned to clonidine who completed the trial, hot flashes declined by only 26% during weeks 1–4 but then declined another 22% during the remainder of the study, for an overall reduction of approximately 45%.

Thus, both active agents decreased the frequency and severity of hot flashes compared with placebo, with no discernible difference between the two by week 12.

“A more rapid reduction of hot flashes suggests that venlafaxine is to be preferred over clonidine,” Dr. Boekhout and her co-investigators said (J. Clin. Oncol. 2011 Sept. 12 [doi:10.1200/JCO.2010.33.1298]).

It is “advisable to treat patients to manage hot flashes with venlafaxine 37.5 mg daily in the first week and increase the venlafaxine dose to 75 mg if greater efficacy is desired.”

A total of 14 patients (34%) in the clonidine group, 23 (56%) in the venlafaxine group, and 4 (20%) in the placebo group said that they wished to continue the study treatment at the end of the trial.

Women taking clonidine reported more symptoms of anxiety and women taking venlafaxine reported more symptoms of depression.

Sexual function and sleep quality did not differ between the two groups. However, the duration of this study may have been too short to permit adequate assessment of these adverse effects, according to the researchers.

View on the News

Small Numbers Mar Findings

The main weakness of this study was that “the patient numbers were too small to reliably identify suspected differences between the two active study arms,” said Dr. Charles L. Loprinzi, Dr. Debra L. Barton, and Dr. Rui Qin.

The unbalanced randomization scheme and the unequal dropout rates, which likely were due to perceived toxicities, meant that only 35 patients were available for analysis in the venlafaxine group, 28 in the clonidine group, and 17 in the placebo group. To detect a10% difference between the two active drugs, 156 subjects would have been needed per study arm, and to detect a 5% difference, 620 would have been needed.

“With the currently reported sample size … the power of detecting a 10% difference is only 29%,” they noted.

For clinicians, they added, available data suggest that multiple nonestrogenic options are available for treating hot flashes. “Our suggestion is that these nonhormonal options be tried in the order in which they are listed (an antidepressant, then an antiseizure medication, then clonidine), unless there are contraindications to particular drugs in individual patients,” they wrote.

DR. LOPRINZI, DR. BARTON, and DR. QIN are at the Mayo Clinic in Rochester, Minn. Dr. Loprinzi reported ties to Pfizer. These remarks were taken from their editorial accompanying Dr. Boekhout's report (J. Clin. Oncol. 2011 Sept. 12 [doi:10.120o/JCO.2011.37.5865]).

Major Finding: Both venlafaxine and clonidine reduced the frequency and severity of hot flashes by approximately 45%, compared with placebo.

Data Source: A prospective, randomized, double-blind, multicenter clinical trial comparing 12 weeks of venlafaxine, clonidine, or placebo for control of hot flashes in 102 Dutch women with breast cancer.

Disclosures: No financial conflicts of interest were reported.

Venlafaxine and clonidine both outperformed placebo in controlling hot flashes among women with breast cancer in a randomized, placebo-controlled trial.

Effective treatments for hot flashes may improve these patients' ability to continue their anticancer therapies, said Dr. Annelies H. Boekhout of The Netherlands Cancer Institute, Amsterdam, and her associates.

The selective serotonin reuptake inhibitor venlafaxine (Effexor) and the antihypertensive clonidine “both are often prescribed treatments and are recommended in clinical guidelines in the management of hot flashes. However, a three-arm trial comparing clonidine, venlafaxine, and placebo in patients with breast cancer has not been conducted” until now, they noted.

In their double-blind study at three Dutch hospitals, 102 women with breast cancer who experienced at least two hot flashes per day were stratified by age, duration of symptoms, concurrent endocrine therapy, and previous chemotherapy, and randomly assigned to receive 75 mg of venlafaxine (41 patients), 0.1 mg of clonidine (41 patients), or matching placebo (20 patients) daily for 12 weeks.

The study participants completed daily diaries recording the frequency and severity of hot flashes. They also reported every week on adverse events such as reduced appetite, nausea, sleepiness, dizziness, fatigue, dry mouth, and constipation. In addition, they recorded their sleep quality, anxiety, depression, and sexual function at 4 weeks and at the conclusion of treatment.

A total of 22 subjects (22%) either dropped out of the study or were lost to follow-up. Two patients (5%) in the venlafaxine group and six (15%) in the clonidine group cited adverse effects such as somnolence, dizziness, and dry mouth as their reason for discontinuing. Another 9% of the study participants discontinued because of noncompliance, which “had some effect on the observed differences between treatments in this study.”

Among the 35 women assigned to venlafaxine who completed the trial, there was a 42% decline in hot flashes during weeks 1–4, compared with the placebo group. Over the entire study period, the reduction in hot flashes was 41% with venlafaxine, compared with placebo, according to Dr. Boekhout and her colleagues.

Among the 28 women assigned to clonidine who completed the trial, hot flashes declined by only 26% during weeks 1–4 but then declined another 22% during the remainder of the study, for an overall reduction of approximately 45%.

Thus, both active agents decreased the frequency and severity of hot flashes compared with placebo, with no discernible difference between the two by week 12.

“A more rapid reduction of hot flashes suggests that venlafaxine is to be preferred over clonidine,” Dr. Boekhout and her co-investigators said (J. Clin. Oncol. 2011 Sept. 12 [doi:10.1200/JCO.2010.33.1298]).

It is “advisable to treat patients to manage hot flashes with venlafaxine 37.5 mg daily in the first week and increase the venlafaxine dose to 75 mg if greater efficacy is desired.”

A total of 14 patients (34%) in the clonidine group, 23 (56%) in the venlafaxine group, and 4 (20%) in the placebo group said that they wished to continue the study treatment at the end of the trial.

Women taking clonidine reported more symptoms of anxiety and women taking venlafaxine reported more symptoms of depression.

Sexual function and sleep quality did not differ between the two groups. However, the duration of this study may have been too short to permit adequate assessment of these adverse effects, according to the researchers.

View on the News

Small Numbers Mar Findings

The main weakness of this study was that “the patient numbers were too small to reliably identify suspected differences between the two active study arms,” said Dr. Charles L. Loprinzi, Dr. Debra L. Barton, and Dr. Rui Qin.

The unbalanced randomization scheme and the unequal dropout rates, which likely were due to perceived toxicities, meant that only 35 patients were available for analysis in the venlafaxine group, 28 in the clonidine group, and 17 in the placebo group. To detect a10% difference between the two active drugs, 156 subjects would have been needed per study arm, and to detect a 5% difference, 620 would have been needed.

“With the currently reported sample size … the power of detecting a 10% difference is only 29%,” they noted.

For clinicians, they added, available data suggest that multiple nonestrogenic options are available for treating hot flashes. “Our suggestion is that these nonhormonal options be tried in the order in which they are listed (an antidepressant, then an antiseizure medication, then clonidine), unless there are contraindications to particular drugs in individual patients,” they wrote.

DR. LOPRINZI, DR. BARTON, and DR. QIN are at the Mayo Clinic in Rochester, Minn. Dr. Loprinzi reported ties to Pfizer. These remarks were taken from their editorial accompanying Dr. Boekhout's report (J. Clin. Oncol. 2011 Sept. 12 [doi:10.120o/JCO.2011.37.5865]).

Major Finding: Both venlafaxine and clonidine reduced the frequency and severity of hot flashes by approximately 45%, compared with placebo.

Data Source: A prospective, randomized, double-blind, multicenter clinical trial comparing 12 weeks of venlafaxine, clonidine, or placebo for control of hot flashes in 102 Dutch women with breast cancer.

Disclosures: No financial conflicts of interest were reported.

Venlafaxine and clonidine both outperformed placebo in controlling hot flashes among women with breast cancer in a randomized, placebo-controlled trial.

Effective treatments for hot flashes may improve these patients' ability to continue their anticancer therapies, said Dr. Annelies H. Boekhout of The Netherlands Cancer Institute, Amsterdam, and her associates.

The selective serotonin reuptake inhibitor venlafaxine (Effexor) and the antihypertensive clonidine “both are often prescribed treatments and are recommended in clinical guidelines in the management of hot flashes. However, a three-arm trial comparing clonidine, venlafaxine, and placebo in patients with breast cancer has not been conducted” until now, they noted.

In their double-blind study at three Dutch hospitals, 102 women with breast cancer who experienced at least two hot flashes per day were stratified by age, duration of symptoms, concurrent endocrine therapy, and previous chemotherapy, and randomly assigned to receive 75 mg of venlafaxine (41 patients), 0.1 mg of clonidine (41 patients), or matching placebo (20 patients) daily for 12 weeks.

The study participants completed daily diaries recording the frequency and severity of hot flashes. They also reported every week on adverse events such as reduced appetite, nausea, sleepiness, dizziness, fatigue, dry mouth, and constipation. In addition, they recorded their sleep quality, anxiety, depression, and sexual function at 4 weeks and at the conclusion of treatment.

A total of 22 subjects (22%) either dropped out of the study or were lost to follow-up. Two patients (5%) in the venlafaxine group and six (15%) in the clonidine group cited adverse effects such as somnolence, dizziness, and dry mouth as their reason for discontinuing. Another 9% of the study participants discontinued because of noncompliance, which “had some effect on the observed differences between treatments in this study.”

Among the 35 women assigned to venlafaxine who completed the trial, there was a 42% decline in hot flashes during weeks 1–4, compared with the placebo group. Over the entire study period, the reduction in hot flashes was 41% with venlafaxine, compared with placebo, according to Dr. Boekhout and her colleagues.

Among the 28 women assigned to clonidine who completed the trial, hot flashes declined by only 26% during weeks 1–4 but then declined another 22% during the remainder of the study, for an overall reduction of approximately 45%.

Thus, both active agents decreased the frequency and severity of hot flashes compared with placebo, with no discernible difference between the two by week 12.

“A more rapid reduction of hot flashes suggests that venlafaxine is to be preferred over clonidine,” Dr. Boekhout and her co-investigators said (J. Clin. Oncol. 2011 Sept. 12 [doi:10.1200/JCO.2010.33.1298]).

It is “advisable to treat patients to manage hot flashes with venlafaxine 37.5 mg daily in the first week and increase the venlafaxine dose to 75 mg if greater efficacy is desired.”

A total of 14 patients (34%) in the clonidine group, 23 (56%) in the venlafaxine group, and 4 (20%) in the placebo group said that they wished to continue the study treatment at the end of the trial.

Women taking clonidine reported more symptoms of anxiety and women taking venlafaxine reported more symptoms of depression.

Sexual function and sleep quality did not differ between the two groups. However, the duration of this study may have been too short to permit adequate assessment of these adverse effects, according to the researchers.

View on the News

Small Numbers Mar Findings

The main weakness of this study was that “the patient numbers were too small to reliably identify suspected differences between the two active study arms,” said Dr. Charles L. Loprinzi, Dr. Debra L. Barton, and Dr. Rui Qin.

The unbalanced randomization scheme and the unequal dropout rates, which likely were due to perceived toxicities, meant that only 35 patients were available for analysis in the venlafaxine group, 28 in the clonidine group, and 17 in the placebo group. To detect a10% difference between the two active drugs, 156 subjects would have been needed per study arm, and to detect a 5% difference, 620 would have been needed.

“With the currently reported sample size … the power of detecting a 10% difference is only 29%,” they noted.

For clinicians, they added, available data suggest that multiple nonestrogenic options are available for treating hot flashes. “Our suggestion is that these nonhormonal options be tried in the order in which they are listed (an antidepressant, then an antiseizure medication, then clonidine), unless there are contraindications to particular drugs in individual patients,” they wrote.

DR. LOPRINZI, DR. BARTON, and DR. QIN are at the Mayo Clinic in Rochester, Minn. Dr. Loprinzi reported ties to Pfizer. These remarks were taken from their editorial accompanying Dr. Boekhout's report (J. Clin. Oncol. 2011 Sept. 12 [doi:10.120o/JCO.2011.37.5865]).

Major Finding: Black women's risk of death from any cause was increased in all categories of overweight and obesity, so that at a body mass index of 20 kg/m

Data Source: The ongoing, prospective follow-up Black Women's Health Study of 51,695 subjects in the United States who were aged 21–69 years at enrollment in 1995.

Disclosures: This study was supported by the National Cancer Institute. Dr. Boggs and her associates reported no relevant financial disclosures.

Among black women, the risk of death from any cause is increased for all categories of overweight and obesity, as it is in whites, according to a report in the Sept. 8 issue of the journal.

The hazard ratios also are similar in magnitude for black women as for white women and men, said Deborah A. Boggs, Sc.D., of the Slone Epidemiology Center at Boston University, and her associates (N. Engl. J. Med. 2011;365:901-8).

Previous studies of the link between overweight and mortality have included only a limited number of black subjects or have failed to report results on black subjects separately from those on whites, so it was uncertain whether the association was present in black women. Yet the prevalence of obesity and abdominal obesity both have risen fastest in black women, with projections that by 2020, 70% of black women will be obese and 90% will have abdominal obesity, the investigators noted.

Dr. Boggs and her colleagues used data on a subgroup of 51,695 subjects enrolled in the Black Women's Health Study (BWHS) to examine the relationship between risk of death and both overall and abdominal obesity.

They focused their analysis on the 33,916 subjects who had never smoked because this association can be confounded by the effects of smoking.

The BWHS is an ongoing prospective follow-up study of black women across the United States who were aged 21–69 years at enrollment in 1995 and who have been followed every 2 years since then.

The researchers found that the association between body mass index (BMI) and risk of death from any cause was curvilinear: lowest among women with a BMI of 20–25 kg/m

Among women with a BMI of 20 or higher, every 5-unit increase in BMI correlated with an 18% rise in the risk of death. “Previous studies involving black women have shown weaker associations of BMI with risk of death,” but those studies were small or otherwise flawed, the investigators said.

The higher mortality seen among women with the lowest BMI may have been associated with illness-related weight loss, they added.

Larger waist circumference was not significantly associated with increased risk of death except among nonobese black women.

In contrast, previous studies in white women and men found larger waist circumference to predict higher mortality risk, independently of BMI.

The positive association between BMI and risk of death was particularly strong for cardiovascular causes of death. For other causes of death, only a very high BMI was associated with increased risk. And there were no associations between BMI and risk of death from cancer in this study.

The link between BMI and risk of death from all causes was stronger among women with higher levels of education, but not significantly so. Such an association may be more evident among less-educated persons because they have higher absolute risks of death and because of other factors related to low socioeconomic status, such as psychosocial stress and limited access to care, Dr. Boggs and her associates said.

“Previous studies of BMI and risk of death involving blacks have included a greater proportion of less-educated participants. This difference may account in part for the stronger relationship in the present study than that previously reported among blacks,” they added.

Major Finding: Black women's risk of death from any cause was increased in all categories of overweight and obesity, so that at a body mass index of 20 kg/m

Data Source: The ongoing, prospective follow-up Black Women's Health Study of 51,695 subjects in the United States who were aged 21–69 years at enrollment in 1995.

Disclosures: This study was supported by the National Cancer Institute. Dr. Boggs and her associates reported no relevant financial disclosures.

Among black women, the risk of death from any cause is increased for all categories of overweight and obesity, as it is in whites, according to a report in the Sept. 8 issue of the journal.

The hazard ratios also are similar in magnitude for black women as for white women and men, said Deborah A. Boggs, Sc.D., of the Slone Epidemiology Center at Boston University, and her associates (N. Engl. J. Med. 2011;365:901-8).

Previous studies of the link between overweight and mortality have included only a limited number of black subjects or have failed to report results on black subjects separately from those on whites, so it was uncertain whether the association was present in black women. Yet the prevalence of obesity and abdominal obesity both have risen fastest in black women, with projections that by 2020, 70% of black women will be obese and 90% will have abdominal obesity, the investigators noted.

Dr. Boggs and her colleagues used data on a subgroup of 51,695 subjects enrolled in the Black Women's Health Study (BWHS) to examine the relationship between risk of death and both overall and abdominal obesity.

They focused their analysis on the 33,916 subjects who had never smoked because this association can be confounded by the effects of smoking.

The BWHS is an ongoing prospective follow-up study of black women across the United States who were aged 21–69 years at enrollment in 1995 and who have been followed every 2 years since then.

The researchers found that the association between body mass index (BMI) and risk of death from any cause was curvilinear: lowest among women with a BMI of 20–25 kg/m

Among women with a BMI of 20 or higher, every 5-unit increase in BMI correlated with an 18% rise in the risk of death. “Previous studies involving black women have shown weaker associations of BMI with risk of death,” but those studies were small or otherwise flawed, the investigators said.

The higher mortality seen among women with the lowest BMI may have been associated with illness-related weight loss, they added.

Larger waist circumference was not significantly associated with increased risk of death except among nonobese black women.

In contrast, previous studies in white women and men found larger waist circumference to predict higher mortality risk, independently of BMI.

The positive association between BMI and risk of death was particularly strong for cardiovascular causes of death. For other causes of death, only a very high BMI was associated with increased risk. And there were no associations between BMI and risk of death from cancer in this study.

The link between BMI and risk of death from all causes was stronger among women with higher levels of education, but not significantly so. Such an association may be more evident among less-educated persons because they have higher absolute risks of death and because of other factors related to low socioeconomic status, such as psychosocial stress and limited access to care, Dr. Boggs and her associates said.

“Previous studies of BMI and risk of death involving blacks have included a greater proportion of less-educated participants. This difference may account in part for the stronger relationship in the present study than that previously reported among blacks,” they added.

Major Finding: Black women's risk of death from any cause was increased in all categories of overweight and obesity, so that at a body mass index of 20 kg/m

Data Source: The ongoing, prospective follow-up Black Women's Health Study of 51,695 subjects in the United States who were aged 21–69 years at enrollment in 1995.

Disclosures: This study was supported by the National Cancer Institute. Dr. Boggs and her associates reported no relevant financial disclosures.

Among black women, the risk of death from any cause is increased for all categories of overweight and obesity, as it is in whites, according to a report in the Sept. 8 issue of the journal.

The hazard ratios also are similar in magnitude for black women as for white women and men, said Deborah A. Boggs, Sc.D., of the Slone Epidemiology Center at Boston University, and her associates (N. Engl. J. Med. 2011;365:901-8).

Previous studies of the link between overweight and mortality have included only a limited number of black subjects or have failed to report results on black subjects separately from those on whites, so it was uncertain whether the association was present in black women. Yet the prevalence of obesity and abdominal obesity both have risen fastest in black women, with projections that by 2020, 70% of black women will be obese and 90% will have abdominal obesity, the investigators noted.

Dr. Boggs and her colleagues used data on a subgroup of 51,695 subjects enrolled in the Black Women's Health Study (BWHS) to examine the relationship between risk of death and both overall and abdominal obesity.

They focused their analysis on the 33,916 subjects who had never smoked because this association can be confounded by the effects of smoking.

The BWHS is an ongoing prospective follow-up study of black women across the United States who were aged 21–69 years at enrollment in 1995 and who have been followed every 2 years since then.

The researchers found that the association between body mass index (BMI) and risk of death from any cause was curvilinear: lowest among women with a BMI of 20–25 kg/m

Among women with a BMI of 20 or higher, every 5-unit increase in BMI correlated with an 18% rise in the risk of death. “Previous studies involving black women have shown weaker associations of BMI with risk of death,” but those studies were small or otherwise flawed, the investigators said.

The higher mortality seen among women with the lowest BMI may have been associated with illness-related weight loss, they added.

Larger waist circumference was not significantly associated with increased risk of death except among nonobese black women.

In contrast, previous studies in white women and men found larger waist circumference to predict higher mortality risk, independently of BMI.

The positive association between BMI and risk of death was particularly strong for cardiovascular causes of death. For other causes of death, only a very high BMI was associated with increased risk. And there were no associations between BMI and risk of death from cancer in this study.

The link between BMI and risk of death from all causes was stronger among women with higher levels of education, but not significantly so. Such an association may be more evident among less-educated persons because they have higher absolute risks of death and because of other factors related to low socioeconomic status, such as psychosocial stress and limited access to care, Dr. Boggs and her associates said.

“Previous studies of BMI and risk of death involving blacks have included a greater proportion of less-educated participants. This difference may account in part for the stronger relationship in the present study than that previously reported among blacks,” they added.

Serial suboccipital injections of steroids rapidly relieve cluster headaches as a transitional treatment while patients wait for long-term prophylactic drugs to take effect, according to a randomized, double-blind, controlled clinical trial.

Compared with placebo injections, cortivazol injections reduced the number of headaches per day during the first 4 days of treatment, decreased the total number of attacks over 15 days while patients waited for verapamil to kick in, and shortened the interval until remission, reported Dr. Elizabeth Leroux of the Emergency Headache Centre, Lariboisière Hospital, Paris, and her associates.

Cluster headache is characterized by attacks of strong periorbital pain with ipsilateral autonomic signs, which recur up to eight times a day. Episodic cluster headaches occur in phases for weeks or months separated by long remissions. Ina10% of patients, episodic cluster headaches evolve into chronic cluster headaches.

Most patients are managed with a combination of acute therapy and prophylactic treatment. Transitional treatment is used to suppress attacks at the onset of a cluster while awaiting the delayed efficacy of preventive drugs such as verapamil or lithium. Oral steroids are widely used in this setting, but they can induce rebound attacks when patients are weaned off them and can cause serious adverse effects even when used briefly.

Suboccipital steroid injections have been proposed as an alternative to systemic steroids, but only one small, randomized, controlled trial on this approach has been published. Dr. Leroux and her colleagues, who have used suboccipital cortivazol injections for 10 years in their clinic, assessed their safety and efficacy when added to usual care. (Cortivazol is not available in the United States.)

During an 8-month period, the investigators enrolled 43 adults who presented to the Emergency Headache Center with frequent daily cluster headaches, including 28 with episodic and 15 with chronic cluster headache. The study subjects were randomly assigned to receive three suboccipital injections containing either cortivazol (21 patients) or saline (22 patients), given singly every 48–72 hours.

The injections were made under the occipital bone at the medial third between the inion and mastoid process, ipsilateral to the attack. Each injection was aimed in three directions: upward, at a 45-degree angle to the left, and at a 45-degree angle to the right.

Acute treatment with sumatriptan or oxygen was given as needed. Patients continued on any prophylactic agents they had been taking before the attack or were started on verapamil.

The study subjects completed daily diaries in which they recorded cluster headache attacks, medication use, and adverse effects for 90 days. All were telephoned after 3-11 months to assess their satisfaction with treatment.

The study's primary end point was to reduce the mean number of daily attacks to two or fewer on the second, third, and fourth days after the final injection. In all, 20 of 21 patients (95%) who received steroid injections reached this end point, compared with 12 of 22 controls (55%) who received placebo injections.

This significant benefit with active injections was the same for both episodic and chronic cluster headaches, reported the investigators (Lancet 2011 Sept. 7 [doi:10.1016/S1474-4422(11)70186-7]).

Patients given steroid injections also had fewer attacks during the first 15 days of the study than did those given placebo, and achieved remission a mean of 7 days earlier. Cortivazol also lowered the need for sumatriptan injections during the first 15 days of the study and reduced the need for verapamil in patients with the episodic type of cluster headache.

In addition, patients' scores of satisfaction with therapy were higher for steroid than for placebo injections.

In a post hoc analysis, 7 of 21 patients (33%) given cortivazol remained pain free from 4 days after the first injection until day 30, while only 2 of 22 control subjects (9%) did. Eleven (52%) in the cortivazol group remained pain free after the last injection to day 30, compared with only 4 (18%) in the control group.

The injections were safe and well tolerated. Adverse events – chiefly neck pain at the injection site and headache other than cluster headache – developed in 18 (86%) of the cortivazol group and 14 (64%) of the control group.

This study received no industry funding. Dr. Leroux and her associates reported ties to numerous industry sources, including Sanofi-Aventis, maker of the prefilled cortivazol syringes used in this study.

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Robust, Long-Awaited Data

The study by Dr. Leroux and her colleagues provides “long-awaited evidence in support of” suboccipital steroid injections for cluster headache, said Dr. David W. Dodick.

“Leroux and colleagues have provided the clinical and academic community with the largest and most robust controlled trial to date showing efficacy of suboccipital steroid injections for short-term transitional treatment of cluster headache,” he said.

The three-injection strategy used in the study is somewhat cumbersome. It remains to be seen if this strategy could potentially be replaced with a single injection of steroid and local anesthetic, as has been shown in several smaller studies, he noted.

DR. DODICK is in the department of neurology at the Mayo Clinic, Phoenix. He reported no financial conflicts of interest. These remarks were taken from his commentary accompanying Dr. Leroux's report (Lancet 2011 Sept. 7 [doi:10.1016/S1474-4422(11)70197-1]).

Serial suboccipital injections of steroids rapidly relieve cluster headaches as a transitional treatment while patients wait for long-term prophylactic drugs to take effect, according to a randomized, double-blind, controlled clinical trial.

Compared with placebo injections, cortivazol injections reduced the number of headaches per day during the first 4 days of treatment, decreased the total number of attacks over 15 days while patients waited for verapamil to kick in, and shortened the interval until remission, reported Dr. Elizabeth Leroux of the Emergency Headache Centre, Lariboisière Hospital, Paris, and her associates.

Cluster headache is characterized by attacks of strong periorbital pain with ipsilateral autonomic signs, which recur up to eight times a day. Episodic cluster headaches occur in phases for weeks or months separated by long remissions. Ina10% of patients, episodic cluster headaches evolve into chronic cluster headaches.

Most patients are managed with a combination of acute therapy and prophylactic treatment. Transitional treatment is used to suppress attacks at the onset of a cluster while awaiting the delayed efficacy of preventive drugs such as verapamil or lithium. Oral steroids are widely used in this setting, but they can induce rebound attacks when patients are weaned off them and can cause serious adverse effects even when used briefly.

Suboccipital steroid injections have been proposed as an alternative to systemic steroids, but only one small, randomized, controlled trial on this approach has been published. Dr. Leroux and her colleagues, who have used suboccipital cortivazol injections for 10 years in their clinic, assessed their safety and efficacy when added to usual care. (Cortivazol is not available in the United States.)

During an 8-month period, the investigators enrolled 43 adults who presented to the Emergency Headache Center with frequent daily cluster headaches, including 28 with episodic and 15 with chronic cluster headache. The study subjects were randomly assigned to receive three suboccipital injections containing either cortivazol (21 patients) or saline (22 patients), given singly every 48–72 hours.

The injections were made under the occipital bone at the medial third between the inion and mastoid process, ipsilateral to the attack. Each injection was aimed in three directions: upward, at a 45-degree angle to the left, and at a 45-degree angle to the right.

Acute treatment with sumatriptan or oxygen was given as needed. Patients continued on any prophylactic agents they had been taking before the attack or were started on verapamil.

The study subjects completed daily diaries in which they recorded cluster headache attacks, medication use, and adverse effects for 90 days. All were telephoned after 3-11 months to assess their satisfaction with treatment.

The study's primary end point was to reduce the mean number of daily attacks to two or fewer on the second, third, and fourth days after the final injection. In all, 20 of 21 patients (95%) who received steroid injections reached this end point, compared with 12 of 22 controls (55%) who received placebo injections.

This significant benefit with active injections was the same for both episodic and chronic cluster headaches, reported the investigators (Lancet 2011 Sept. 7 [doi:10.1016/S1474-4422(11)70186-7]).

Patients given steroid injections also had fewer attacks during the first 15 days of the study than did those given placebo, and achieved remission a mean of 7 days earlier. Cortivazol also lowered the need for sumatriptan injections during the first 15 days of the study and reduced the need for verapamil in patients with the episodic type of cluster headache.

In addition, patients' scores of satisfaction with therapy were higher for steroid than for placebo injections.

In a post hoc analysis, 7 of 21 patients (33%) given cortivazol remained pain free from 4 days after the first injection until day 30, while only 2 of 22 control subjects (9%) did. Eleven (52%) in the cortivazol group remained pain free after the last injection to day 30, compared with only 4 (18%) in the control group.

The injections were safe and well tolerated. Adverse events – chiefly neck pain at the injection site and headache other than cluster headache – developed in 18 (86%) of the cortivazol group and 14 (64%) of the control group.

This study received no industry funding. Dr. Leroux and her associates reported ties to numerous industry sources, including Sanofi-Aventis, maker of the prefilled cortivazol syringes used in this study.

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Robust, Long-Awaited Data

The study by Dr. Leroux and her colleagues provides “long-awaited evidence in support of” suboccipital steroid injections for cluster headache, said Dr. David W. Dodick.

“Leroux and colleagues have provided the clinical and academic community with the largest and most robust controlled trial to date showing efficacy of suboccipital steroid injections for short-term transitional treatment of cluster headache,” he said.

The three-injection strategy used in the study is somewhat cumbersome. It remains to be seen if this strategy could potentially be replaced with a single injection of steroid and local anesthetic, as has been shown in several smaller studies, he noted.

DR. DODICK is in the department of neurology at the Mayo Clinic, Phoenix. He reported no financial conflicts of interest. These remarks were taken from his commentary accompanying Dr. Leroux's report (Lancet 2011 Sept. 7 [doi:10.1016/S1474-4422(11)70197-1]).

Serial suboccipital injections of steroids rapidly relieve cluster headaches as a transitional treatment while patients wait for long-term prophylactic drugs to take effect, according to a randomized, double-blind, controlled clinical trial.

Compared with placebo injections, cortivazol injections reduced the number of headaches per day during the first 4 days of treatment, decreased the total number of attacks over 15 days while patients waited for verapamil to kick in, and shortened the interval until remission, reported Dr. Elizabeth Leroux of the Emergency Headache Centre, Lariboisière Hospital, Paris, and her associates.

Cluster headache is characterized by attacks of strong periorbital pain with ipsilateral autonomic signs, which recur up to eight times a day. Episodic cluster headaches occur in phases for weeks or months separated by long remissions. Ina10% of patients, episodic cluster headaches evolve into chronic cluster headaches.

Most patients are managed with a combination of acute therapy and prophylactic treatment. Transitional treatment is used to suppress attacks at the onset of a cluster while awaiting the delayed efficacy of preventive drugs such as verapamil or lithium. Oral steroids are widely used in this setting, but they can induce rebound attacks when patients are weaned off them and can cause serious adverse effects even when used briefly.

Suboccipital steroid injections have been proposed as an alternative to systemic steroids, but only one small, randomized, controlled trial on this approach has been published. Dr. Leroux and her colleagues, who have used suboccipital cortivazol injections for 10 years in their clinic, assessed their safety and efficacy when added to usual care. (Cortivazol is not available in the United States.)

During an 8-month period, the investigators enrolled 43 adults who presented to the Emergency Headache Center with frequent daily cluster headaches, including 28 with episodic and 15 with chronic cluster headache. The study subjects were randomly assigned to receive three suboccipital injections containing either cortivazol (21 patients) or saline (22 patients), given singly every 48–72 hours.

The injections were made under the occipital bone at the medial third between the inion and mastoid process, ipsilateral to the attack. Each injection was aimed in three directions: upward, at a 45-degree angle to the left, and at a 45-degree angle to the right.

Acute treatment with sumatriptan or oxygen was given as needed. Patients continued on any prophylactic agents they had been taking before the attack or were started on verapamil.

The study subjects completed daily diaries in which they recorded cluster headache attacks, medication use, and adverse effects for 90 days. All were telephoned after 3-11 months to assess their satisfaction with treatment.

The study's primary end point was to reduce the mean number of daily attacks to two or fewer on the second, third, and fourth days after the final injection. In all, 20 of 21 patients (95%) who received steroid injections reached this end point, compared with 12 of 22 controls (55%) who received placebo injections.

This significant benefit with active injections was the same for both episodic and chronic cluster headaches, reported the investigators (Lancet 2011 Sept. 7 [doi:10.1016/S1474-4422(11)70186-7]).

Patients given steroid injections also had fewer attacks during the first 15 days of the study than did those given placebo, and achieved remission a mean of 7 days earlier. Cortivazol also lowered the need for sumatriptan injections during the first 15 days of the study and reduced the need for verapamil in patients with the episodic type of cluster headache.

In addition, patients' scores of satisfaction with therapy were higher for steroid than for placebo injections.

In a post hoc analysis, 7 of 21 patients (33%) given cortivazol remained pain free from 4 days after the first injection until day 30, while only 2 of 22 control subjects (9%) did. Eleven (52%) in the cortivazol group remained pain free after the last injection to day 30, compared with only 4 (18%) in the control group.

The injections were safe and well tolerated. Adverse events – chiefly neck pain at the injection site and headache other than cluster headache – developed in 18 (86%) of the cortivazol group and 14 (64%) of the control group.

This study received no industry funding. Dr. Leroux and her associates reported ties to numerous industry sources, including Sanofi-Aventis, maker of the prefilled cortivazol syringes used in this study.

View on the News

Robust, Long-Awaited Data

The study by Dr. Leroux and her colleagues provides “long-awaited evidence in support of” suboccipital steroid injections for cluster headache, said Dr. David W. Dodick.

“Leroux and colleagues have provided the clinical and academic community with the largest and most robust controlled trial to date showing efficacy of suboccipital steroid injections for short-term transitional treatment of cluster headache,” he said.

The three-injection strategy used in the study is somewhat cumbersome. It remains to be seen if this strategy could potentially be replaced with a single injection of steroid and local anesthetic, as has been shown in several smaller studies, he noted.

DR. DODICK is in the department of neurology at the Mayo Clinic, Phoenix. He reported no financial conflicts of interest. These remarks were taken from his commentary accompanying Dr. Leroux's report (Lancet 2011 Sept. 7 [doi:10.1016/S1474-4422(11)70197-1]).

Major Finding: Just over 87% of medical school graduates have attained specialty board certification, and factors such as their age, gender, race/ethnicity, debt, and test scores were predictors of certification.

Data Source: A retrospective cohort study of ABMS certification in 42,440 physicians who graduated from U.S. medical schools in 1997-2000 and were followed through 2009.

Disclosures: This study was supported by the National Institute of General Medical Sciences, one of the National Institutes of Health. No financial conflicts of interest were reported.

Age at graduation, gender, race, and test scores were found to predict whether a physician would attain board certification in any of eight specialty categories, according a retrospective analysis.

“ABMS [American Board of Medical Specialties] member board certification is currently among the criteria used by HMOs, hospitals, and health insurance plans in evaluating physicians who wish to obtain privileges or join provider organizations, by medical school promotion committees in evaluating physician faculty members for promotion and tenure, and by the Accreditation Council for Graduate Medical Education as criteria for selection of physicians to serve as GME program directors and residency review committee members,” according to Donna B. Jeffe, Ph.D., and Dr. Dorothy A. Andriole of Washington University, St. Louis.

“Thus, ABMS member board certification is emerging as a de facto requirement for the full participation of physicians in the U.S. health care system, and non–board-certified physicians compose an increasingly marginalized group,” they noted.

To identify factors associated with achieving specialty certification, Dr. Jeffe and Dr. Andriole constructed a database with “deidentified” records for all medical students who graduated 1997-2000 and followed them for at least 8 years; a total of 42,440 graduates were included. These data were linked to testing records from the National Board of Medical Examiners as well as data from the Association of American Medical Colleges and the American Medical Association Physician Masterfile to track specialty certification.

The specialty categories included internal medicine, family medicine, pediatrics, emergency medicine, radiology, surgery (including several surgical subspecialties), ob.gyn., and a composite category comprising allergy/immunology, anesthesiology, dermatology, neurology, genetics, nuclear medicine, ophthalmology, pathology, and psychiatry.

Overall, 87.3% of the sample were board certified, the investigators said (JAMA 2011;306:961-70).

Physicians who were 28 years or older at medical school graduation were less likely to become certified, which is perhaps related to the fact that older graduates also were more likely to have failed an initial attempt at certification.

“Our findings suggest that older graduates may experience greater difficulties, regardless of specialty choice, in timely advancement along the GME continuum toward board certification,” Dr. Jeffe and Dr. Andriole said.

Women physicians were less likely than men to be board certified in three specialty categories, notably in obstetrics/gynecology, which is currently the category with the largest proportion of women physicians (79%).

Members of minority groups were less likely than white physicians to be board certified in every specialty except family medicine, “raising concerns about ongoing efforts by U.S. medical schools to increase the racial/ethnic diversity of the physician workforce,” they noted.

Physicians who had higher scores on Step 1 and Step 2 Clinical Knowledge tests on the U.S. Medical Licensing Examination were more likely than those with lower scores to become board certified. This finding “provides support for program directors' use of first-attempt licensing examination results among criteria for evaluating applicants in a range of specialties,” the researchers said.

Major Finding: Just over 87% of medical school graduates have attained specialty board certification, and factors such as their age, gender, race/ethnicity, debt, and test scores were predictors of certification.

Data Source: A retrospective cohort study of ABMS certification in 42,440 physicians who graduated from U.S. medical schools in 1997-2000 and were followed through 2009.

Disclosures: This study was supported by the National Institute of General Medical Sciences, one of the National Institutes of Health. No financial conflicts of interest were reported.

Age at graduation, gender, race, and test scores were found to predict whether a physician would attain board certification in any of eight specialty categories, according a retrospective analysis.

“ABMS [American Board of Medical Specialties] member board certification is currently among the criteria used by HMOs, hospitals, and health insurance plans in evaluating physicians who wish to obtain privileges or join provider organizations, by medical school promotion committees in evaluating physician faculty members for promotion and tenure, and by the Accreditation Council for Graduate Medical Education as criteria for selection of physicians to serve as GME program directors and residency review committee members,” according to Donna B. Jeffe, Ph.D., and Dr. Dorothy A. Andriole of Washington University, St. Louis.

“Thus, ABMS member board certification is emerging as a de facto requirement for the full participation of physicians in the U.S. health care system, and non–board-certified physicians compose an increasingly marginalized group,” they noted.

To identify factors associated with achieving specialty certification, Dr. Jeffe and Dr. Andriole constructed a database with “deidentified” records for all medical students who graduated 1997-2000 and followed them for at least 8 years; a total of 42,440 graduates were included. These data were linked to testing records from the National Board of Medical Examiners as well as data from the Association of American Medical Colleges and the American Medical Association Physician Masterfile to track specialty certification.

The specialty categories included internal medicine, family medicine, pediatrics, emergency medicine, radiology, surgery (including several surgical subspecialties), ob.gyn., and a composite category comprising allergy/immunology, anesthesiology, dermatology, neurology, genetics, nuclear medicine, ophthalmology, pathology, and psychiatry.

Overall, 87.3% of the sample were board certified, the investigators said (JAMA 2011;306:961-70).

Physicians who were 28 years or older at medical school graduation were less likely to become certified, which is perhaps related to the fact that older graduates also were more likely to have failed an initial attempt at certification.

“Our findings suggest that older graduates may experience greater difficulties, regardless of specialty choice, in timely advancement along the GME continuum toward board certification,” Dr. Jeffe and Dr. Andriole said.

Women physicians were less likely than men to be board certified in three specialty categories, notably in obstetrics/gynecology, which is currently the category with the largest proportion of women physicians (79%).

Members of minority groups were less likely than white physicians to be board certified in every specialty except family medicine, “raising concerns about ongoing efforts by U.S. medical schools to increase the racial/ethnic diversity of the physician workforce,” they noted.

Physicians who had higher scores on Step 1 and Step 2 Clinical Knowledge tests on the U.S. Medical Licensing Examination were more likely than those with lower scores to become board certified. This finding “provides support for program directors' use of first-attempt licensing examination results among criteria for evaluating applicants in a range of specialties,” the researchers said.

Major Finding: Just over 87% of medical school graduates have attained specialty board certification, and factors such as their age, gender, race/ethnicity, debt, and test scores were predictors of certification.

Data Source: A retrospective cohort study of ABMS certification in 42,440 physicians who graduated from U.S. medical schools in 1997-2000 and were followed through 2009.

Disclosures: This study was supported by the National Institute of General Medical Sciences, one of the National Institutes of Health. No financial conflicts of interest were reported.

Age at graduation, gender, race, and test scores were found to predict whether a physician would attain board certification in any of eight specialty categories, according a retrospective analysis.

“ABMS [American Board of Medical Specialties] member board certification is currently among the criteria used by HMOs, hospitals, and health insurance plans in evaluating physicians who wish to obtain privileges or join provider organizations, by medical school promotion committees in evaluating physician faculty members for promotion and tenure, and by the Accreditation Council for Graduate Medical Education as criteria for selection of physicians to serve as GME program directors and residency review committee members,” according to Donna B. Jeffe, Ph.D., and Dr. Dorothy A. Andriole of Washington University, St. Louis.

“Thus, ABMS member board certification is emerging as a de facto requirement for the full participation of physicians in the U.S. health care system, and non–board-certified physicians compose an increasingly marginalized group,” they noted.

To identify factors associated with achieving specialty certification, Dr. Jeffe and Dr. Andriole constructed a database with “deidentified” records for all medical students who graduated 1997-2000 and followed them for at least 8 years; a total of 42,440 graduates were included. These data were linked to testing records from the National Board of Medical Examiners as well as data from the Association of American Medical Colleges and the American Medical Association Physician Masterfile to track specialty certification.

The specialty categories included internal medicine, family medicine, pediatrics, emergency medicine, radiology, surgery (including several surgical subspecialties), ob.gyn., and a composite category comprising allergy/immunology, anesthesiology, dermatology, neurology, genetics, nuclear medicine, ophthalmology, pathology, and psychiatry.

Overall, 87.3% of the sample were board certified, the investigators said (JAMA 2011;306:961-70).

Physicians who were 28 years or older at medical school graduation were less likely to become certified, which is perhaps related to the fact that older graduates also were more likely to have failed an initial attempt at certification.

“Our findings suggest that older graduates may experience greater difficulties, regardless of specialty choice, in timely advancement along the GME continuum toward board certification,” Dr. Jeffe and Dr. Andriole said.

Women physicians were less likely than men to be board certified in three specialty categories, notably in obstetrics/gynecology, which is currently the category with the largest proportion of women physicians (79%).

Members of minority groups were less likely than white physicians to be board certified in every specialty except family medicine, “raising concerns about ongoing efforts by U.S. medical schools to increase the racial/ethnic diversity of the physician workforce,” they noted.

Physicians who had higher scores on Step 1 and Step 2 Clinical Knowledge tests on the U.S. Medical Licensing Examination were more likely than those with lower scores to become board certified. This finding “provides support for program directors' use of first-attempt licensing examination results among criteria for evaluating applicants in a range of specialties,” the researchers said.

Major Finding: RA patients who received methotrexate plus golimumab showed significantly better RAMRIS scores on MRI than did those who received MTX alone, as early as week 12 and continuing through week 24.

Data Source: A substudy of the GO-BEFORE study, involving 318 patients with active RA whose response to treatment was monitored via MRI.

Disclosures: This study was funded by Centocor and Schering-Plough. The investigators reported no other financial disclosures.

Adding golimumab to methotrexate therapy lessened synovitis, osteitis, and bone erosion to a greater degree than did placebo plus methotrexate, a study has shown.

These improvements were evident as early as the 12th week of treatment on serial magnetic resonance imaging exams, which proved to be much more sensitive than conventional radiography at demonstrating the changes, said Dr. Mikkel Ostergaard, professor of rheumatology at Copenhagen University Hospital at Glostrup, Denmark, and his associates.

They reported the results of a substudy of the 1-year GO-BEFORE (Golimumab Before Employing Methotrexate as the First-Line Option in the Treatment of Rheumatoid Arthritis of Early Onset) study, a large randomized controlled trial comparing various combinations of oral methotrexate (MTX), golimumab injections, and placebo in rheumatoid arthritis (RA) patients. GO-BEFORE's findings demonstrated that after 28 weeks, “golimumab in combination with MTX reduced signs and symptoms and radiographic progression of RA in MTX-naive patients, with a safety profile similar to other anti-[tumor necrosis factor] agents,” the investigators said.

Their substudy involved 318 of these subjects who underwent serial MRI evaluations of the wrist and metacarpophalangeal joints at 12 and 24 weeks. Synovitis and osteitis (bone marrow edema), which signal heavy infiltration by inflammatory cells including osteoclasts, are precursors of new bone erosions. These changes are visible on MRI well before conventional radiography can detect them.

The MRIs were assessed by two readers and an adjudicator using the Rheumatoid Arthritis MRI Scoring (RAMRIS) system, “which has demonstrated very good reliability and a high level of sensitivity to change.” Study subjects who received MTX plus golimumab showed significantly better RAMRIS scores than did those who received MTX alone, as early as week 12 and continuing through week 24, Dr. Ostergaard and his colleagues said (Arthritis Rheum. 2011 Aug. 31 [doi 10.1002/art.30592]).

For example, at week 12, synovitis scores decreased by 1.92 points for the wrist and metacarpophalangeal joints and by 0.85 points for the wrist alone with combined therapy, compared with 0.14 points and 0.02 points with MTX alone. Bone edema–osteitis score decreased by 1.82 points with combined therapy but only by 0.56 points with MTX alone, and bone erosion scores decreased by 0.40 points vs. 0.24 points.

“Similar trends were observed in the sensitivity analyses conducted for the mean change in RAMRIS scores from baseline to week 24,” they added.

In a series of MRIs that were representative of the substudy population as a whole, “images show bone edema that was extensive at baseline, markedly decreased at week 12, and nearly resolved at week 24,” they noted.

The researchers emphasized that the substudy confirmed the conclusion of the entire GO-BEFORE clinical trial, but that MRI demonstrated the statistically significant difference between study groups in less than half the time (12 weeks rather than 28 weeks) and using fewer than half the subjects (318 patients rather than 637 patients). This documents that MRI is a more sensitive tool for detecting structural damage than conventional radiography, they said.

Major Finding: RA patients who received methotrexate plus golimumab showed significantly better RAMRIS scores on MRI than did those who received MTX alone, as early as week 12 and continuing through week 24.

Data Source: A substudy of the GO-BEFORE study, involving 318 patients with active RA whose response to treatment was monitored via MRI.

Disclosures: This study was funded by Centocor and Schering-Plough. The investigators reported no other financial disclosures.

Adding golimumab to methotrexate therapy lessened synovitis, osteitis, and bone erosion to a greater degree than did placebo plus methotrexate, a study has shown.

These improvements were evident as early as the 12th week of treatment on serial magnetic resonance imaging exams, which proved to be much more sensitive than conventional radiography at demonstrating the changes, said Dr. Mikkel Ostergaard, professor of rheumatology at Copenhagen University Hospital at Glostrup, Denmark, and his associates.

They reported the results of a substudy of the 1-year GO-BEFORE (Golimumab Before Employing Methotrexate as the First-Line Option in the Treatment of Rheumatoid Arthritis of Early Onset) study, a large randomized controlled trial comparing various combinations of oral methotrexate (MTX), golimumab injections, and placebo in rheumatoid arthritis (RA) patients. GO-BEFORE's findings demonstrated that after 28 weeks, “golimumab in combination with MTX reduced signs and symptoms and radiographic progression of RA in MTX-naive patients, with a safety profile similar to other anti-[tumor necrosis factor] agents,” the investigators said.

Their substudy involved 318 of these subjects who underwent serial MRI evaluations of the wrist and metacarpophalangeal joints at 12 and 24 weeks. Synovitis and osteitis (bone marrow edema), which signal heavy infiltration by inflammatory cells including osteoclasts, are precursors of new bone erosions. These changes are visible on MRI well before conventional radiography can detect them.

The MRIs were assessed by two readers and an adjudicator using the Rheumatoid Arthritis MRI Scoring (RAMRIS) system, “which has demonstrated very good reliability and a high level of sensitivity to change.” Study subjects who received MTX plus golimumab showed significantly better RAMRIS scores than did those who received MTX alone, as early as week 12 and continuing through week 24, Dr. Ostergaard and his colleagues said (Arthritis Rheum. 2011 Aug. 31 [doi 10.1002/art.30592]).

For example, at week 12, synovitis scores decreased by 1.92 points for the wrist and metacarpophalangeal joints and by 0.85 points for the wrist alone with combined therapy, compared with 0.14 points and 0.02 points with MTX alone. Bone edema–osteitis score decreased by 1.82 points with combined therapy but only by 0.56 points with MTX alone, and bone erosion scores decreased by 0.40 points vs. 0.24 points.

“Similar trends were observed in the sensitivity analyses conducted for the mean change in RAMRIS scores from baseline to week 24,” they added.

In a series of MRIs that were representative of the substudy population as a whole, “images show bone edema that was extensive at baseline, markedly decreased at week 12, and nearly resolved at week 24,” they noted.

The researchers emphasized that the substudy confirmed the conclusion of the entire GO-BEFORE clinical trial, but that MRI demonstrated the statistically significant difference between study groups in less than half the time (12 weeks rather than 28 weeks) and using fewer than half the subjects (318 patients rather than 637 patients). This documents that MRI is a more sensitive tool for detecting structural damage than conventional radiography, they said.

Major Finding: RA patients who received methotrexate plus golimumab showed significantly better RAMRIS scores on MRI than did those who received MTX alone, as early as week 12 and continuing through week 24.

Data Source: A substudy of the GO-BEFORE study, involving 318 patients with active RA whose response to treatment was monitored via MRI.

Disclosures: This study was funded by Centocor and Schering-Plough. The investigators reported no other financial disclosures.

Adding golimumab to methotrexate therapy lessened synovitis, osteitis, and bone erosion to a greater degree than did placebo plus methotrexate, a study has shown.

These improvements were evident as early as the 12th week of treatment on serial magnetic resonance imaging exams, which proved to be much more sensitive than conventional radiography at demonstrating the changes, said Dr. Mikkel Ostergaard, professor of rheumatology at Copenhagen University Hospital at Glostrup, Denmark, and his associates.

They reported the results of a substudy of the 1-year GO-BEFORE (Golimumab Before Employing Methotrexate as the First-Line Option in the Treatment of Rheumatoid Arthritis of Early Onset) study, a large randomized controlled trial comparing various combinations of oral methotrexate (MTX), golimumab injections, and placebo in rheumatoid arthritis (RA) patients. GO-BEFORE's findings demonstrated that after 28 weeks, “golimumab in combination with MTX reduced signs and symptoms and radiographic progression of RA in MTX-naive patients, with a safety profile similar to other anti-[tumor necrosis factor] agents,” the investigators said.

Their substudy involved 318 of these subjects who underwent serial MRI evaluations of the wrist and metacarpophalangeal joints at 12 and 24 weeks. Synovitis and osteitis (bone marrow edema), which signal heavy infiltration by inflammatory cells including osteoclasts, are precursors of new bone erosions. These changes are visible on MRI well before conventional radiography can detect them.

The MRIs were assessed by two readers and an adjudicator using the Rheumatoid Arthritis MRI Scoring (RAMRIS) system, “which has demonstrated very good reliability and a high level of sensitivity to change.” Study subjects who received MTX plus golimumab showed significantly better RAMRIS scores than did those who received MTX alone, as early as week 12 and continuing through week 24, Dr. Ostergaard and his colleagues said (Arthritis Rheum. 2011 Aug. 31 [doi 10.1002/art.30592]).

For example, at week 12, synovitis scores decreased by 1.92 points for the wrist and metacarpophalangeal joints and by 0.85 points for the wrist alone with combined therapy, compared with 0.14 points and 0.02 points with MTX alone. Bone edema–osteitis score decreased by 1.82 points with combined therapy but only by 0.56 points with MTX alone, and bone erosion scores decreased by 0.40 points vs. 0.24 points.

“Similar trends were observed in the sensitivity analyses conducted for the mean change in RAMRIS scores from baseline to week 24,” they added.

In a series of MRIs that were representative of the substudy population as a whole, “images show bone edema that was extensive at baseline, markedly decreased at week 12, and nearly resolved at week 24,” they noted.

The researchers emphasized that the substudy confirmed the conclusion of the entire GO-BEFORE clinical trial, but that MRI demonstrated the statistically significant difference between study groups in less than half the time (12 weeks rather than 28 weeks) and using fewer than half the subjects (318 patients rather than 637 patients). This documents that MRI is a more sensitive tool for detecting structural damage than conventional radiography, they said.

Major Finding: Over time, 23% of study subjects showed progression of diastolic dysfunction, compared with only 9% who showed improvement in diastolic dysfunction; in a subset of healthy subjects, 20% showed progression of diastolic dysfunction, compared with only 5% who showed improvement.

Data Source: A population-based cohort study involving 1,402 older adults whose heart function was followed for 4 years and again for an additional 6 years.

Disclosures: This study was supported by the National Heart, Lung, and Blood Institute, the National Center for Research Resources, the Mayo Foundation, the National Institutes of Health, the Rochester Epidemiology Project, and the National Institute on Aging. No financial conflicts of interest were reported.

The prevalence of diastolic dysfunction increases as people age, even among healthy adults, according to a longitudinal study.

Results of the study add to the findings of previous cross-sectional community studies that diastolic dysfunction is highly prevalent in older adults, demonstrating that during 10 years of follow-up, middle-aged and elderly people were nearly three times more likely to show deteriorating diastolic function than improving diastolic function.

“That diastolic dysfunction worsened even in healthy persons supports the concept that aging may be accompanied by progressive deterioration in diastolic function. This age-related progression of diastolic dysfunction in the population contributes to the pathophysiologic substrate from which overt heart failure emerges,” said Dr. Garvan C. Kane of Mayo Clinic and Medical School, Rochester, Minn., and his associates.

Previously, the investigators had performed two cross-sectional analyses of diastolic function in community residents aged 45 and older participating in the Olmsted County Heart Function Study in 1997-2000 and again in 2001-2004. They now report the results of 6 years of further follow-up of a subset of 1,402 of these subjects, which tracked within-patient changes in diastolic function over time.

In all, 90% of the study subjects were white, and 81% lived in urban settings.

Over time, 23% of subjects showed progression of diastolic dysfunction, compared with only 9% who showed improvement in diastolic dysfunction. The remaining 68% of subjects showed no change in diastolic dysfunction.

“A similar pattern of worsening diastolic function also was observed in a subset of [531] healthy participants” who had been free of hypertension, diabetes, coronary artery disease, and heart failure at baseline. About 20% showed worsening diastolic function, compared with 5% who showed improvement in diastolic dysfunction over time. The remaining 75% showed no change in diastolic dysfunction.

“However, to put diastolic dysfunction in context, it should be noted that only about 1 in 4 persons with moderate or severe diastolic dysfunction at examination 2 developed incident heart failure during follow-up. This suggests that superimposed clinical events play an important role in the transition from asymptomatic diastolic dysfunction to overt heart failure with preserved LVEF [left ventricular ejection fraction],” Dr. Kane and his colleagues said (JAMA 2011;306:856-63).

“Specifically, our findings are consistent with the hypothesis that a combination of cardiovascular aging and superimposed cardiovascular disease accelerates the deterioration in diastolic function, setting the stage for symptomatic heart failure with preserved LVEF in elderly persons,” they noted.

It follows that preventing such superimposed events by addressing risk factors, particularly hypertension, “might be fundamental to reducing heart failure with preserved LVEF,” they added.

Major Finding: Over time, 23% of study subjects showed progression of diastolic dysfunction, compared with only 9% who showed improvement in diastolic dysfunction; in a subset of healthy subjects, 20% showed progression of diastolic dysfunction, compared with only 5% who showed improvement.

Data Source: A population-based cohort study involving 1,402 older adults whose heart function was followed for 4 years and again for an additional 6 years.

Disclosures: This study was supported by the National Heart, Lung, and Blood Institute, the National Center for Research Resources, the Mayo Foundation, the National Institutes of Health, the Rochester Epidemiology Project, and the National Institute on Aging. No financial conflicts of interest were reported.

The prevalence of diastolic dysfunction increases as people age, even among healthy adults, according to a longitudinal study.

Results of the study add to the findings of previous cross-sectional community studies that diastolic dysfunction is highly prevalent in older adults, demonstrating that during 10 years of follow-up, middle-aged and elderly people were nearly three times more likely to show deteriorating diastolic function than improving diastolic function.

“That diastolic dysfunction worsened even in healthy persons supports the concept that aging may be accompanied by progressive deterioration in diastolic function. This age-related progression of diastolic dysfunction in the population contributes to the pathophysiologic substrate from which overt heart failure emerges,” said Dr. Garvan C. Kane of Mayo Clinic and Medical School, Rochester, Minn., and his associates.

Previously, the investigators had performed two cross-sectional analyses of diastolic function in community residents aged 45 and older participating in the Olmsted County Heart Function Study in 1997-2000 and again in 2001-2004. They now report the results of 6 years of further follow-up of a subset of 1,402 of these subjects, which tracked within-patient changes in diastolic function over time.

In all, 90% of the study subjects were white, and 81% lived in urban settings.

Over time, 23% of subjects showed progression of diastolic dysfunction, compared with only 9% who showed improvement in diastolic dysfunction. The remaining 68% of subjects showed no change in diastolic dysfunction.

“A similar pattern of worsening diastolic function also was observed in a subset of [531] healthy participants” who had been free of hypertension, diabetes, coronary artery disease, and heart failure at baseline. About 20% showed worsening diastolic function, compared with 5% who showed improvement in diastolic dysfunction over time. The remaining 75% showed no change in diastolic dysfunction.

“However, to put diastolic dysfunction in context, it should be noted that only about 1 in 4 persons with moderate or severe diastolic dysfunction at examination 2 developed incident heart failure during follow-up. This suggests that superimposed clinical events play an important role in the transition from asymptomatic diastolic dysfunction to overt heart failure with preserved LVEF [left ventricular ejection fraction],” Dr. Kane and his colleagues said (JAMA 2011;306:856-63).

“Specifically, our findings are consistent with the hypothesis that a combination of cardiovascular aging and superimposed cardiovascular disease accelerates the deterioration in diastolic function, setting the stage for symptomatic heart failure with preserved LVEF in elderly persons,” they noted.

It follows that preventing such superimposed events by addressing risk factors, particularly hypertension, “might be fundamental to reducing heart failure with preserved LVEF,” they added.

Major Finding: Over time, 23% of study subjects showed progression of diastolic dysfunction, compared with only 9% who showed improvement in diastolic dysfunction; in a subset of healthy subjects, 20% showed progression of diastolic dysfunction, compared with only 5% who showed improvement.

Data Source: A population-based cohort study involving 1,402 older adults whose heart function was followed for 4 years and again for an additional 6 years.

Disclosures: This study was supported by the National Heart, Lung, and Blood Institute, the National Center for Research Resources, the Mayo Foundation, the National Institutes of Health, the Rochester Epidemiology Project, and the National Institute on Aging. No financial conflicts of interest were reported.

The prevalence of diastolic dysfunction increases as people age, even among healthy adults, according to a longitudinal study.

Results of the study add to the findings of previous cross-sectional community studies that diastolic dysfunction is highly prevalent in older adults, demonstrating that during 10 years of follow-up, middle-aged and elderly people were nearly three times more likely to show deteriorating diastolic function than improving diastolic function.

“That diastolic dysfunction worsened even in healthy persons supports the concept that aging may be accompanied by progressive deterioration in diastolic function. This age-related progression of diastolic dysfunction in the population contributes to the pathophysiologic substrate from which overt heart failure emerges,” said Dr. Garvan C. Kane of Mayo Clinic and Medical School, Rochester, Minn., and his associates.

Previously, the investigators had performed two cross-sectional analyses of diastolic function in community residents aged 45 and older participating in the Olmsted County Heart Function Study in 1997-2000 and again in 2001-2004. They now report the results of 6 years of further follow-up of a subset of 1,402 of these subjects, which tracked within-patient changes in diastolic function over time.

In all, 90% of the study subjects were white, and 81% lived in urban settings.

Over time, 23% of subjects showed progression of diastolic dysfunction, compared with only 9% who showed improvement in diastolic dysfunction. The remaining 68% of subjects showed no change in diastolic dysfunction.

“A similar pattern of worsening diastolic function also was observed in a subset of [531] healthy participants” who had been free of hypertension, diabetes, coronary artery disease, and heart failure at baseline. About 20% showed worsening diastolic function, compared with 5% who showed improvement in diastolic dysfunction over time. The remaining 75% showed no change in diastolic dysfunction.

“However, to put diastolic dysfunction in context, it should be noted that only about 1 in 4 persons with moderate or severe diastolic dysfunction at examination 2 developed incident heart failure during follow-up. This suggests that superimposed clinical events play an important role in the transition from asymptomatic diastolic dysfunction to overt heart failure with preserved LVEF [left ventricular ejection fraction],” Dr. Kane and his colleagues said (JAMA 2011;306:856-63).

“Specifically, our findings are consistent with the hypothesis that a combination of cardiovascular aging and superimposed cardiovascular disease accelerates the deterioration in diastolic function, setting the stage for symptomatic heart failure with preserved LVEF in elderly persons,” they noted.

It follows that preventing such superimposed events by addressing risk factors, particularly hypertension, “might be fundamental to reducing heart failure with preserved LVEF,” they added.

Nearly one in five patients with advanced cognitive and functional impairment who are in their final days of life is subjected to a burdensome, potentially unnecessary transition in health care, such as being moved from a nursing home to a hospital, according to a reportin the Sept. 29 issue of the New England Journal of Medicine.

The frequency of such transitions varies widely from between regions of the United States, with rates as high as 37% of the cognitively impaired decedents in some states. And the rate appears to be increasing, said Pedro Gozalo, Ph.D., of the program in public health at Brown University, Providence, R.I., and his associates.

The transfer itself can be traumatic for these easily confused and physically frail patients, and it opens the door to fragmentation of care and medical errors, said the researchers. Once hospitalized, many such people near death are subjected to further disturbances such as insertion of feeding tubes or transfer to an intensive care unit. However, hospitalization is usually avoidable in patients with advanced dementia because most of the medical problems that arise at the end of life are predictable and "can be treated with equal efficacy in the nursing home," the investigators said.

They examined Medicare data covering all nursing home residents in the United States and defined "burdensome transitions" according to interviews with families and the expert opinions of geriatricians and palliative medicine specialists. Such transitions thus included transfers during the last 90 days of life from a nursing home to a hospital, transfers from a nursing home to a hospital and on to a different nursing home, and multiple hospitalizations.

The researchers retrospectively identified 474,829 nursing home residents with advanced dementia who were in their last 120 days of life in 2000-2007. Their mean age was 86 years.

A total of 90,228 of these people (19%) had at least one burdensome transition during their final 90 days of life. This included more than 55,000 who were transferred within hours of their deaths, nearly 13,000 who were transferred from one nursing home to a hospital and then to another nursing home, and more than 38,000 who were hospitalized multiple times, the researchers reported (New Engl. J. Med. 2011;365:1212-21).

The rate of burdensome transitions was lowest in Alaska (2%) and highest in Louisiana (37%). Several other southern states, California, and New York also had high rates. The lowest rates after Alaska’s were in upper-Midwest and northwestern states and Hawaii.

The nationwide rate of burdensome transitions rose from 17.4% of decedents in 2000 to 19.6% in 2007.

These transitions were more common among black and Hispanic patients than among whites, among men than women, and among patients who had no advance directive than those who did.

Burdensome transitions were associated with what the researchers identified as several markers of poor end-of-life care, including transfer to an ICU during a patient’s final days, referral to hospice care within 3 days of death, the presence of stage 4 decubitus ulcers, and insertion of a feeding tube.

Dr. Gozalo and his colleagues noted that a previous study found that "96% of family members report that comfort is the primary goal of care for their relatives with advanced dementia. Yet as we found, the pattern of transitions among nursing home residents with advanced cognitive impairment is often inconsistent with that goal."

The authors said that financial incentives probably underlie many of the burdensome transitions. "Hospitalization generally qualifies a nursing home resident with Medicaid coverage to receive Medicare payments for skilled services, which reimburse the nursing home at a higher rate. In addition, states’ Medicaid payment rates and bed-holding policies that pay nursing homes to keep a bed open for hospitalized residents are associated with increased rates of hospitalization.

"These financial incentives probably result in health care transitions that contribute not only to excessive costs but also to a poorer quality of end-of-life care," the investigators said.

"Ultimately, a decline in burdensome transitions will come about through a combination of improved provider incentives and decision making that elicits and respects the choices of patients," they said.

This study was supported by the National Institute on Aging. One of Dr. Gozalo’s associates reported being a consultant for the Manor Care nursing home chain and for Point Right, a company that provides information services in long-term care. Another associate reported ties to the Robert Wood Johnson Foundation.

Nearly one in five patients with advanced cognitive and functional impairment who are in their final days of life is subjected to a burdensome, potentially unnecessary transition in health care, such as being moved from a nursing home to a hospital, according to a reportin the Sept. 29 issue of the New England Journal of Medicine.

The frequency of such transitions varies widely from between regions of the United States, with rates as high as 37% of the cognitively impaired decedents in some states. And the rate appears to be increasing, said Pedro Gozalo, Ph.D., of the program in public health at Brown University, Providence, R.I., and his associates.

The transfer itself can be traumatic for these easily confused and physically frail patients, and it opens the door to fragmentation of care and medical errors, said the researchers. Once hospitalized, many such people near death are subjected to further disturbances such as insertion of feeding tubes or transfer to an intensive care unit. However, hospitalization is usually avoidable in patients with advanced dementia because most of the medical problems that arise at the end of life are predictable and "can be treated with equal efficacy in the nursing home," the investigators said.

They examined Medicare data covering all nursing home residents in the United States and defined "burdensome transitions" according to interviews with families and the expert opinions of geriatricians and palliative medicine specialists. Such transitions thus included transfers during the last 90 days of life from a nursing home to a hospital, transfers from a nursing home to a hospital and on to a different nursing home, and multiple hospitalizations.

The researchers retrospectively identified 474,829 nursing home residents with advanced dementia who were in their last 120 days of life in 2000-2007. Their mean age was 86 years.

A total of 90,228 of these people (19%) had at least one burdensome transition during their final 90 days of life. This included more than 55,000 who were transferred within hours of their deaths, nearly 13,000 who were transferred from one nursing home to a hospital and then to another nursing home, and more than 38,000 who were hospitalized multiple times, the researchers reported (New Engl. J. Med. 2011;365:1212-21).

The rate of burdensome transitions was lowest in Alaska (2%) and highest in Louisiana (37%). Several other southern states, California, and New York also had high rates. The lowest rates after Alaska’s were in upper-Midwest and northwestern states and Hawaii.

The nationwide rate of burdensome transitions rose from 17.4% of decedents in 2000 to 19.6% in 2007.

These transitions were more common among black and Hispanic patients than among whites, among men than women, and among patients who had no advance directive than those who did.

Burdensome transitions were associated with what the researchers identified as several markers of poor end-of-life care, including transfer to an ICU during a patient’s final days, referral to hospice care within 3 days of death, the presence of stage 4 decubitus ulcers, and insertion of a feeding tube.

Dr. Gozalo and his colleagues noted that a previous study found that "96% of family members report that comfort is the primary goal of care for their relatives with advanced dementia. Yet as we found, the pattern of transitions among nursing home residents with advanced cognitive impairment is often inconsistent with that goal."

The authors said that financial incentives probably underlie many of the burdensome transitions. "Hospitalization generally qualifies a nursing home resident with Medicaid coverage to receive Medicare payments for skilled services, which reimburse the nursing home at a higher rate. In addition, states’ Medicaid payment rates and bed-holding policies that pay nursing homes to keep a bed open for hospitalized residents are associated with increased rates of hospitalization.

"These financial incentives probably result in health care transitions that contribute not only to excessive costs but also to a poorer quality of end-of-life care," the investigators said.

"Ultimately, a decline in burdensome transitions will come about through a combination of improved provider incentives and decision making that elicits and respects the choices of patients," they said.

This study was supported by the National Institute on Aging. One of Dr. Gozalo’s associates reported being a consultant for the Manor Care nursing home chain and for Point Right, a company that provides information services in long-term care. Another associate reported ties to the Robert Wood Johnson Foundation.

Nearly one in five patients with advanced cognitive and functional impairment who are in their final days of life is subjected to a burdensome, potentially unnecessary transition in health care, such as being moved from a nursing home to a hospital, according to a reportin the Sept. 29 issue of the New England Journal of Medicine.

The frequency of such transitions varies widely from between regions of the United States, with rates as high as 37% of the cognitively impaired decedents in some states. And the rate appears to be increasing, said Pedro Gozalo, Ph.D., of the program in public health at Brown University, Providence, R.I., and his associates.

The transfer itself can be traumatic for these easily confused and physically frail patients, and it opens the door to fragmentation of care and medical errors, said the researchers. Once hospitalized, many such people near death are subjected to further disturbances such as insertion of feeding tubes or transfer to an intensive care unit. However, hospitalization is usually avoidable in patients with advanced dementia because most of the medical problems that arise at the end of life are predictable and "can be treated with equal efficacy in the nursing home," the investigators said.

They examined Medicare data covering all nursing home residents in the United States and defined "burdensome transitions" according to interviews with families and the expert opinions of geriatricians and palliative medicine specialists. Such transitions thus included transfers during the last 90 days of life from a nursing home to a hospital, transfers from a nursing home to a hospital and on to a different nursing home, and multiple hospitalizations.

The researchers retrospectively identified 474,829 nursing home residents with advanced dementia who were in their last 120 days of life in 2000-2007. Their mean age was 86 years.

A total of 90,228 of these people (19%) had at least one burdensome transition during their final 90 days of life. This included more than 55,000 who were transferred within hours of their deaths, nearly 13,000 who were transferred from one nursing home to a hospital and then to another nursing home, and more than 38,000 who were hospitalized multiple times, the researchers reported (New Engl. J. Med. 2011;365:1212-21).

The rate of burdensome transitions was lowest in Alaska (2%) and highest in Louisiana (37%). Several other southern states, California, and New York also had high rates. The lowest rates after Alaska’s were in upper-Midwest and northwestern states and Hawaii.

The nationwide rate of burdensome transitions rose from 17.4% of decedents in 2000 to 19.6% in 2007.

These transitions were more common among black and Hispanic patients than among whites, among men than women, and among patients who had no advance directive than those who did.

Burdensome transitions were associated with what the researchers identified as several markers of poor end-of-life care, including transfer to an ICU during a patient’s final days, referral to hospice care within 3 days of death, the presence of stage 4 decubitus ulcers, and insertion of a feeding tube.

Dr. Gozalo and his colleagues noted that a previous study found that "96% of family members report that comfort is the primary goal of care for their relatives with advanced dementia. Yet as we found, the pattern of transitions among nursing home residents with advanced cognitive impairment is often inconsistent with that goal."

The authors said that financial incentives probably underlie many of the burdensome transitions. "Hospitalization generally qualifies a nursing home resident with Medicaid coverage to receive Medicare payments for skilled services, which reimburse the nursing home at a higher rate. In addition, states’ Medicaid payment rates and bed-holding policies that pay nursing homes to keep a bed open for hospitalized residents are associated with increased rates of hospitalization.

"These financial incentives probably result in health care transitions that contribute not only to excessive costs but also to a poorer quality of end-of-life care," the investigators said.

"Ultimately, a decline in burdensome transitions will come about through a combination of improved provider incentives and decision making that elicits and respects the choices of patients," they said.

This study was supported by the National Institute on Aging. One of Dr. Gozalo’s associates reported being a consultant for the Manor Care nursing home chain and for Point Right, a company that provides information services in long-term care. Another associate reported ties to the Robert Wood Johnson Foundation.

The compound cytisine, an extract of acacia seeds that has been used in Eastern Europe for more than 40 years as an aid to smoking cessation, was found effective in the first placebo-controlled randomized trial of the agent that meets modern regulatory standards, according to a report in the Sept. 29 issue of the New England Journal of Medicine.

Cytisine is a partial agonist that binds with high affinity to a subtype of the nicotinic acetylcholine receptor, which is also the primary target of the smoking-cessation drug varenicline. It has been available across Eastern Europe under the brand name Tabex since 1964, said Robert West, Ph.D., of the Cancer Research U.K. Health Behavior Research Centre, department of epidemiology and public health, University College London, and his associates.

© milosluz/istockphoto.com

Because of its "unusual history of development," no preclinical studies, dosing studies, or large comparative trials have been reported to date. "We conducted a study to assess cytisine’s efficacy and safety in a context that could be replicated globally, with a relatively short treatment course (25 days) and minimal contact with health professionals," they noted.

Their aim was to determine whether the agent would be particularly beneficial for the millions of smokers who live in "countries in which the average household income is less than $200 per week and in which treatment of this kind is not paid for by insurance plans or national health care systems."

Unlike other pharmacotherapies for smoking cessation, cytisine is inexpensive; a full course of treatment costs the equivalent of $15 in Poland and $6 in Russia. This "may make it an attractive treatment option for smokers in low-income and middle-income countries," the researchers noted.

They performed a single-center, double-blind trial in which 740 subjects were randomly assigned to either active drug or placebo in equal numbers. "Behavioral support and the number of follow-up sessions were kept to a minimum to simulate, as much as possible, what might happen in a routine clinical situation" in low-income regions.

This included a baseline clinic visit where the drug was dispensed, telephone calls from staff on the target quit day (day 5) and 1 week later, a clinic visit 1 month after the target quit date, further follow-up calls, and a clinic visit for those who remained abstinent at 6 and 12 months following the conclusion of treatment.

The study participants were adults who smoked 10 or more cigarettes per day and were willing to try to stop smoking permanently. At baseline, all reported heavy smoking and showed high concentrations of carbon monoxide in exhaled breath, and all scored high on the Fagerström Test for Nicotine Dependence. Approximately half the study subjects were manual laborers, and more than 80% said they had tried to quit smoking previously.

The primary efficacy outcome was 12 months of sustained smoking abstinence after the end of treatment. This rate was 8.4% with cytisine, significantly better than the 2.4% rate with placebo.

"The net improvement in the abstinence rate with cytisine was 6 percentage points. The relative rate of abstinence in the cytisine group as compared with that in the placebo group was 3.4," Dr. West and his colleagues said (N. Engl. J. Med. 2011;365:1193-200).

This 3.4 relative difference in smoking cessation between cytisine and placebo "was higher than previous studies have shown for varenicline (2.3) and nicotine-replacement therapy (1.6). However, the absolute difference in the rate of abstinence between participants receiving cytisine and those receiving placebo in this trial (6 percentage points) was lower than that shown for varenicline and similar to that shown for nicotine-replacement therapy," they noted.

The rates of drug discontinuation or dose reduction were similar between subjects taking the active drug and those taking placebo. There were no serious adverse effects attributed to cytisine. The incidence of minor gastrointestinal adverse effects, chiefly stomach ache, dyspepsia, and nausea, was higher with cytisine than with placebo.

Using more intensive behavioral support along with cytisine may improve absolute quit rates. "Also, the treatment period was only 4 weeks, as compared with 8 weeks for nicotine-replacement therapy and 12 weeks for varenicline, and it is possible that efficacy could be improved by a longer regimen," the investigators added.

This study was supported by University College London, the U.K. National Prevention Research Initiative, Cancer Research U.K., and the U.K. National Institute for Health Research. Cytisine and matching placebo were provided at no cost by the manufacturer, Sopharma AD. Dr. West and his associates reported ties to Pfizer, McNeil, Celtic, Johnson & Johnson, and GlaxoSmithKline, and Dr. West holds a patent pending on a nicotine delivery device.

The compound cytisine, an extract of acacia seeds that has been used in Eastern Europe for more than 40 years as an aid to smoking cessation, was found effective in the first placebo-controlled randomized trial of the agent that meets modern regulatory standards, according to a report in the Sept. 29 issue of the New England Journal of Medicine.

Cytisine is a partial agonist that binds with high affinity to a subtype of the nicotinic acetylcholine receptor, which is also the primary target of the smoking-cessation drug varenicline. It has been available across Eastern Europe under the brand name Tabex since 1964, said Robert West, Ph.D., of the Cancer Research U.K. Health Behavior Research Centre, department of epidemiology and public health, University College London, and his associates.

© milosluz/istockphoto.com

Because of its "unusual history of development," no preclinical studies, dosing studies, or large comparative trials have been reported to date. "We conducted a study to assess cytisine’s efficacy and safety in a context that could be replicated globally, with a relatively short treatment course (25 days) and minimal contact with health professionals," they noted.

Their aim was to determine whether the agent would be particularly beneficial for the millions of smokers who live in "countries in which the average household income is less than $200 per week and in which treatment of this kind is not paid for by insurance plans or national health care systems."

Unlike other pharmacotherapies for smoking cessation, cytisine is inexpensive; a full course of treatment costs the equivalent of $15 in Poland and $6 in Russia. This "may make it an attractive treatment option for smokers in low-income and middle-income countries," the researchers noted.

They performed a single-center, double-blind trial in which 740 subjects were randomly assigned to either active drug or placebo in equal numbers. "Behavioral support and the number of follow-up sessions were kept to a minimum to simulate, as much as possible, what might happen in a routine clinical situation" in low-income regions.

This included a baseline clinic visit where the drug was dispensed, telephone calls from staff on the target quit day (day 5) and 1 week later, a clinic visit 1 month after the target quit date, further follow-up calls, and a clinic visit for those who remained abstinent at 6 and 12 months following the conclusion of treatment.

The study participants were adults who smoked 10 or more cigarettes per day and were willing to try to stop smoking permanently. At baseline, all reported heavy smoking and showed high concentrations of carbon monoxide in exhaled breath, and all scored high on the Fagerström Test for Nicotine Dependence. Approximately half the study subjects were manual laborers, and more than 80% said they had tried to quit smoking previously.

The primary efficacy outcome was 12 months of sustained smoking abstinence after the end of treatment. This rate was 8.4% with cytisine, significantly better than the 2.4% rate with placebo.

"The net improvement in the abstinence rate with cytisine was 6 percentage points. The relative rate of abstinence in the cytisine group as compared with that in the placebo group was 3.4," Dr. West and his colleagues said (N. Engl. J. Med. 2011;365:1193-200).

This 3.4 relative difference in smoking cessation between cytisine and placebo "was higher than previous studies have shown for varenicline (2.3) and nicotine-replacement therapy (1.6). However, the absolute difference in the rate of abstinence between participants receiving cytisine and those receiving placebo in this trial (6 percentage points) was lower than that shown for varenicline and similar to that shown for nicotine-replacement therapy," they noted.

The rates of drug discontinuation or dose reduction were similar between subjects taking the active drug and those taking placebo. There were no serious adverse effects attributed to cytisine. The incidence of minor gastrointestinal adverse effects, chiefly stomach ache, dyspepsia, and nausea, was higher with cytisine than with placebo.

Using more intensive behavioral support along with cytisine may improve absolute quit rates. "Also, the treatment period was only 4 weeks, as compared with 8 weeks for nicotine-replacement therapy and 12 weeks for varenicline, and it is possible that efficacy could be improved by a longer regimen," the investigators added.

This study was supported by University College London, the U.K. National Prevention Research Initiative, Cancer Research U.K., and the U.K. National Institute for Health Research. Cytisine and matching placebo were provided at no cost by the manufacturer, Sopharma AD. Dr. West and his associates reported ties to Pfizer, McNeil, Celtic, Johnson & Johnson, and GlaxoSmithKline, and Dr. West holds a patent pending on a nicotine delivery device.

The compound cytisine, an extract of acacia seeds that has been used in Eastern Europe for more than 40 years as an aid to smoking cessation, was found effective in the first placebo-controlled randomized trial of the agent that meets modern regulatory standards, according to a report in the Sept. 29 issue of the New England Journal of Medicine.

Cytisine is a partial agonist that binds with high affinity to a subtype of the nicotinic acetylcholine receptor, which is also the primary target of the smoking-cessation drug varenicline. It has been available across Eastern Europe under the brand name Tabex since 1964, said Robert West, Ph.D., of the Cancer Research U.K. Health Behavior Research Centre, department of epidemiology and public health, University College London, and his associates.

© milosluz/istockphoto.com

Because of its "unusual history of development," no preclinical studies, dosing studies, or large comparative trials have been reported to date. "We conducted a study to assess cytisine’s efficacy and safety in a context that could be replicated globally, with a relatively short treatment course (25 days) and minimal contact with health professionals," they noted.

Their aim was to determine whether the agent would be particularly beneficial for the millions of smokers who live in "countries in which the average household income is less than $200 per week and in which treatment of this kind is not paid for by insurance plans or national health care systems."

Unlike other pharmacotherapies for smoking cessation, cytisine is inexpensive; a full course of treatment costs the equivalent of $15 in Poland and $6 in Russia. This "may make it an attractive treatment option for smokers in low-income and middle-income countries," the researchers noted.

They performed a single-center, double-blind trial in which 740 subjects were randomly assigned to either active drug or placebo in equal numbers. "Behavioral support and the number of follow-up sessions were kept to a minimum to simulate, as much as possible, what might happen in a routine clinical situation" in low-income regions.

This included a baseline clinic visit where the drug was dispensed, telephone calls from staff on the target quit day (day 5) and 1 week later, a clinic visit 1 month after the target quit date, further follow-up calls, and a clinic visit for those who remained abstinent at 6 and 12 months following the conclusion of treatment.

The study participants were adults who smoked 10 or more cigarettes per day and were willing to try to stop smoking permanently. At baseline, all reported heavy smoking and showed high concentrations of carbon monoxide in exhaled breath, and all scored high on the Fagerström Test for Nicotine Dependence. Approximately half the study subjects were manual laborers, and more than 80% said they had tried to quit smoking previously.

The primary efficacy outcome was 12 months of sustained smoking abstinence after the end of treatment. This rate was 8.4% with cytisine, significantly better than the 2.4% rate with placebo.

"The net improvement in the abstinence rate with cytisine was 6 percentage points. The relative rate of abstinence in the cytisine group as compared with that in the placebo group was 3.4," Dr. West and his colleagues said (N. Engl. J. Med. 2011;365:1193-200).

This 3.4 relative difference in smoking cessation between cytisine and placebo "was higher than previous studies have shown for varenicline (2.3) and nicotine-replacement therapy (1.6). However, the absolute difference in the rate of abstinence between participants receiving cytisine and those receiving placebo in this trial (6 percentage points) was lower than that shown for varenicline and similar to that shown for nicotine-replacement therapy," they noted.

The rates of drug discontinuation or dose reduction were similar between subjects taking the active drug and those taking placebo. There were no serious adverse effects attributed to cytisine. The incidence of minor gastrointestinal adverse effects, chiefly stomach ache, dyspepsia, and nausea, was higher with cytisine than with placebo.

Using more intensive behavioral support along with cytisine may improve absolute quit rates. "Also, the treatment period was only 4 weeks, as compared with 8 weeks for nicotine-replacement therapy and 12 weeks for varenicline, and it is possible that efficacy could be improved by a longer regimen," the investigators added.

This study was supported by University College London, the U.K. National Prevention Research Initiative, Cancer Research U.K., and the U.K. National Institute for Health Research. Cytisine and matching placebo were provided at no cost by the manufacturer, Sopharma AD. Dr. West and his associates reported ties to Pfizer, McNeil, Celtic, Johnson & Johnson, and GlaxoSmithKline, and Dr. West holds a patent pending on a nicotine delivery device.

Atypical antipsychotics are effective in only a few of the many off-label conditions for which they are currently used, according to a meta-analysis in the Sept. 28 issue of JAMA.

In particular, there is no good evidence to support the use of atypical antipsychotics for substance abuse disorder, eating disorders, or insomnia. And the evidence for using them for posttraumatic stress disorder and personality disorders is characterized as "mixed," said Dr. Alicia Ruelaz Maher of Rand Health, Southern California Evidence-Based Practice Center, Santa Monica, and her colleagues.

Atypical antipsychotics are approved for use in schizophrenia, bipolar disorder, and, for select agents, depression. But their use has rapidly increased in recent years, and it is estimated that their off-label use doubled between 1995 and 2008.

Dr. Maher and her colleagues reviewed 2,066 articles published through May 2011 on the off-label use of aripiprazole, asenapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone. For their meta-analysis, Dr. Maher and her colleagues included 162 efficacy trials and 231 trials or large observational studies that addressed adverse events (JAMA 2011;306:1359-69).

Among their findings were the following:

• "First, aripiprazole, olanzapine, and risperidone were associated with small but statistically significant benefits for the treatment of behavioral symptoms in dementia." These drugs improved psychosis, agitation, and symptoms such as hallucinations, suspiciousness, dysphoria, anxiety, aggression, disinhibition, and apathy, though they did so only to a degree "considered to be the minimum clinically observable change."

• In three large and very recent trials not included in previous meta-analyses, quetiapine showed significant benefits for generalized anxiety disorder. However, "we classified the strength of evidence for this outcome as ‘moderate,’ based on the inconsistency of results and because all [the trials] were funded by manufacturers."

• Risperidone was associated with significant improvement in OCD. But that finding was tempered by the fact there may have been publication bias affecting the pooled results.

• "The strength of evidence has decreased from moderate to low for [use of] quetiapine in patients with OCD."

• New evidence indicates that atypical antipsychotics are ineffective for eating disorders and substance abuse disorder.

• The level of evidence is mixed regarding personality disorders, and is moderate for an association of risperidone with improving PTSD."

Dr. Maher and her colleagues cautioned that most of the studies they reviewed – for example, 27 of the 38 trials of dementia and 12 of the 14 trials of anxiety – were sponsored by drug manufacturers. And they found no studies at all on the off-label use of three newer atypical antipsychotic drugs: asenapine, iloperidone, and paliperidone.

In addition, studies published after June 1, 2011, including a large randomized, control trial of risperidone for patients with military-related PTSD and symptoms resistant to selective serotonin reuptake inhibitors, were not included in the current review.

Still, evidence found in the meta-analysis should provide guidance to clinicians who are considering off-label prescribing of atypical antipsychotics, the investigators wrote.

This study was supported by the Agency for Healthcare Research and Quality, with some support from the Department of Veterans Affairs. One of Dr. Maher’s colleagues reported ties to Eli Lilly.

Atypical antipsychotics are effective in only a few of the many off-label conditions for which they are currently used, according to a meta-analysis in the Sept. 28 issue of JAMA.

In particular, there is no good evidence to support the use of atypical antipsychotics for substance abuse disorder, eating disorders, or insomnia. And the evidence for using them for posttraumatic stress disorder and personality disorders is characterized as "mixed," said Dr. Alicia Ruelaz Maher of Rand Health, Southern California Evidence-Based Practice Center, Santa Monica, and her colleagues.

Atypical antipsychotics are approved for use in schizophrenia, bipolar disorder, and, for select agents, depression. But their use has rapidly increased in recent years, and it is estimated that their off-label use doubled between 1995 and 2008.

Dr. Maher and her colleagues reviewed 2,066 articles published through May 2011 on the off-label use of aripiprazole, asenapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone. For their meta-analysis, Dr. Maher and her colleagues included 162 efficacy trials and 231 trials or large observational studies that addressed adverse events (JAMA 2011;306:1359-69).

Among their findings were the following:

• "First, aripiprazole, olanzapine, and risperidone were associated with small but statistically significant benefits for the treatment of behavioral symptoms in dementia." These drugs improved psychosis, agitation, and symptoms such as hallucinations, suspiciousness, dysphoria, anxiety, aggression, disinhibition, and apathy, though they did so only to a degree "considered to be the minimum clinically observable change."

• In three large and very recent trials not included in previous meta-analyses, quetiapine showed significant benefits for generalized anxiety disorder. However, "we classified the strength of evidence for this outcome as ‘moderate,’ based on the inconsistency of results and because all [the trials] were funded by manufacturers."

• Risperidone was associated with significant improvement in OCD. But that finding was tempered by the fact there may have been publication bias affecting the pooled results.

• "The strength of evidence has decreased from moderate to low for [use of] quetiapine in patients with OCD."

• New evidence indicates that atypical antipsychotics are ineffective for eating disorders and substance abuse disorder.

• The level of evidence is mixed regarding personality disorders, and is moderate for an association of risperidone with improving PTSD."

Dr. Maher and her colleagues cautioned that most of the studies they reviewed – for example, 27 of the 38 trials of dementia and 12 of the 14 trials of anxiety – were sponsored by drug manufacturers. And they found no studies at all on the off-label use of three newer atypical antipsychotic drugs: asenapine, iloperidone, and paliperidone.

In addition, studies published after June 1, 2011, including a large randomized, control trial of risperidone for patients with military-related PTSD and symptoms resistant to selective serotonin reuptake inhibitors, were not included in the current review.

Still, evidence found in the meta-analysis should provide guidance to clinicians who are considering off-label prescribing of atypical antipsychotics, the investigators wrote.

This study was supported by the Agency for Healthcare Research and Quality, with some support from the Department of Veterans Affairs. One of Dr. Maher’s colleagues reported ties to Eli Lilly.

Atypical antipsychotics are effective in only a few of the many off-label conditions for which they are currently used, according to a meta-analysis in the Sept. 28 issue of JAMA.

In particular, there is no good evidence to support the use of atypical antipsychotics for substance abuse disorder, eating disorders, or insomnia. And the evidence for using them for posttraumatic stress disorder and personality disorders is characterized as "mixed," said Dr. Alicia Ruelaz Maher of Rand Health, Southern California Evidence-Based Practice Center, Santa Monica, and her colleagues.

Atypical antipsychotics are approved for use in schizophrenia, bipolar disorder, and, for select agents, depression. But their use has rapidly increased in recent years, and it is estimated that their off-label use doubled between 1995 and 2008.

Dr. Maher and her colleagues reviewed 2,066 articles published through May 2011 on the off-label use of aripiprazole, asenapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone. For their meta-analysis, Dr. Maher and her colleagues included 162 efficacy trials and 231 trials or large observational studies that addressed adverse events (JAMA 2011;306:1359-69).

Among their findings were the following:

• "First, aripiprazole, olanzapine, and risperidone were associated with small but statistically significant benefits for the treatment of behavioral symptoms in dementia." These drugs improved psychosis, agitation, and symptoms such as hallucinations, suspiciousness, dysphoria, anxiety, aggression, disinhibition, and apathy, though they did so only to a degree "considered to be the minimum clinically observable change."

• In three large and very recent trials not included in previous meta-analyses, quetiapine showed significant benefits for generalized anxiety disorder. However, "we classified the strength of evidence for this outcome as ‘moderate,’ based on the inconsistency of results and because all [the trials] were funded by manufacturers."

• Risperidone was associated with significant improvement in OCD. But that finding was tempered by the fact there may have been publication bias affecting the pooled results.

• "The strength of evidence has decreased from moderate to low for [use of] quetiapine in patients with OCD."

• New evidence indicates that atypical antipsychotics are ineffective for eating disorders and substance abuse disorder.

• The level of evidence is mixed regarding personality disorders, and is moderate for an association of risperidone with improving PTSD."

Dr. Maher and her colleagues cautioned that most of the studies they reviewed – for example, 27 of the 38 trials of dementia and 12 of the 14 trials of anxiety – were sponsored by drug manufacturers. And they found no studies at all on the off-label use of three newer atypical antipsychotic drugs: asenapine, iloperidone, and paliperidone.

In addition, studies published after June 1, 2011, including a large randomized, control trial of risperidone for patients with military-related PTSD and symptoms resistant to selective serotonin reuptake inhibitors, were not included in the current review.

Still, evidence found in the meta-analysis should provide guidance to clinicians who are considering off-label prescribing of atypical antipsychotics, the investigators wrote.

This study was supported by the Agency for Healthcare Research and Quality, with some support from the Department of Veterans Affairs. One of Dr. Maher’s colleagues reported ties to Eli Lilly.

Even at doses three times higher than usual, saw palmetto extract was no better than placebo at improving lower urinary tract symptoms attributed to benign prostatic hyperplasia in a study in the Sept. 28 issue of JAMA.

Extracts from the fruit of the saw palmetto dwarf palm tree are the most widely used plant extracts in the United States and Europe for urinary symptoms. They are purported to have anti-androgenic, anti-inflammatory, and antiproliferative effects, but none of these properties have been proved.

A meta-analysis from approximately 10 years ago showed that, compared with placebo, saw palmetto significantly reduced nocturia and improved peak uroflow, as well as being rated by study subjects as more beneficial. But more recent clinical trials and reviews of the literature have had more negative findings.

"We conducted a randomized clinical trial to determine if a standard daily dose of saw palmetto extract increased to a double and then a triple daily dose over 72 weeks would improve lower urinary tract symptoms attributed to benign prostatic hypertrophy," said Dr. Michael J. Barry of Massachusetts General Hospital, Boston, and his associates in the Complementary and Alternative Medicine for Urological Symptoms (CAMUS) study group.

This study design allowed an adequate duration of treatment – 24 weeks at each dose level – to assess outcomes, they noted.

The double-blind trial included 369 men aged 45 years and older who had a peak uroflow rate of at least 4 mL per second and a score of 8-24 on the American Urological Association Symptom Index (AUASI) at baseline. They were treated at 11 sites across North America with a standard dose (320 mg/day) of gelcaps containing saw palmetto extract or placebo, which was escalated to 640 mg/day at 24 weeks and 960 mg/day at 48 weeks.

The primary outcome measure was the change in AUASI score at 72 weeks. This decreased only slightly, and to nearly the same degree, in both groups: The reduction was 2.20 points with saw palmetto and 2.99 points with placebo, the investigators said (JAMA 2011;306:1344-51).

The result was the same in a per-protocol analysis of the 151 subjects who received saw palmetto and the 155 who received placebo for the entire duration of the study.

Similarly, the proportion of men who achieved a minimal (3-point) decrease in AUASI score over time was 42.6% with saw palmetto and 44.2% with placebo, slightly favoring placebo. A dose-response analysis showed that saw palmetto was no better than placebo at any dose level.

Further analyses also showed that the active treatment was no better than placebo for a wide range of secondary outcomes including change in BPH Index scores and change in measures of nocturia, peak uroflow, postvoiding residual volume, and incontinence.

The trial also did not reveal any subgroup of patients, such as men with higher PSA levels or men with lower peak uroflow, who showed "a clinically important differential response" to saw palmetto, compared with placebo.

At the conclusion of the study, two measures of patient satisfaction with treatment did not differ between the two groups. Both men who received saw palmetto and men who received placebo rated their symptoms as "between ‘a little better’ and ‘about the same.’ "

This study was supported by the National Institutes of Health, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Center for Complementary and Alternative Medicine, and the NIH Office of Dietary Supplements. Saw palmetto extract and matching placebo gelcaps were donated by Rottapharm/Madaus, Cologne, Germany. This study was conducted under an Investigational New Drug Application from the Food and Drug Administration. Dr. Barry’s associates reported ties to numerous industry sources.

Even at doses three times higher than usual, saw palmetto extract was no better than placebo at improving lower urinary tract symptoms attributed to benign prostatic hyperplasia in a study in the Sept. 28 issue of JAMA.

Extracts from the fruit of the saw palmetto dwarf palm tree are the most widely used plant extracts in the United States and Europe for urinary symptoms. They are purported to have anti-androgenic, anti-inflammatory, and antiproliferative effects, but none of these properties have been proved.

A meta-analysis from approximately 10 years ago showed that, compared with placebo, saw palmetto significantly reduced nocturia and improved peak uroflow, as well as being rated by study subjects as more beneficial. But more recent clinical trials and reviews of the literature have had more negative findings.

"We conducted a randomized clinical trial to determine if a standard daily dose of saw palmetto extract increased to a double and then a triple daily dose over 72 weeks would improve lower urinary tract symptoms attributed to benign prostatic hypertrophy," said Dr. Michael J. Barry of Massachusetts General Hospital, Boston, and his associates in the Complementary and Alternative Medicine for Urological Symptoms (CAMUS) study group.

This study design allowed an adequate duration of treatment – 24 weeks at each dose level – to assess outcomes, they noted.

The double-blind trial included 369 men aged 45 years and older who had a peak uroflow rate of at least 4 mL per second and a score of 8-24 on the American Urological Association Symptom Index (AUASI) at baseline. They were treated at 11 sites across North America with a standard dose (320 mg/day) of gelcaps containing saw palmetto extract or placebo, which was escalated to 640 mg/day at 24 weeks and 960 mg/day at 48 weeks.

The primary outcome measure was the change in AUASI score at 72 weeks. This decreased only slightly, and to nearly the same degree, in both groups: The reduction was 2.20 points with saw palmetto and 2.99 points with placebo, the investigators said (JAMA 2011;306:1344-51).

The result was the same in a per-protocol analysis of the 151 subjects who received saw palmetto and the 155 who received placebo for the entire duration of the study.

Similarly, the proportion of men who achieved a minimal (3-point) decrease in AUASI score over time was 42.6% with saw palmetto and 44.2% with placebo, slightly favoring placebo. A dose-response analysis showed that saw palmetto was no better than placebo at any dose level.

Further analyses also showed that the active treatment was no better than placebo for a wide range of secondary outcomes including change in BPH Index scores and change in measures of nocturia, peak uroflow, postvoiding residual volume, and incontinence.

The trial also did not reveal any subgroup of patients, such as men with higher PSA levels or men with lower peak uroflow, who showed "a clinically important differential response" to saw palmetto, compared with placebo.

At the conclusion of the study, two measures of patient satisfaction with treatment did not differ between the two groups. Both men who received saw palmetto and men who received placebo rated their symptoms as "between ‘a little better’ and ‘about the same.’ "

This study was supported by the National Institutes of Health, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Center for Complementary and Alternative Medicine, and the NIH Office of Dietary Supplements. Saw palmetto extract and matching placebo gelcaps were donated by Rottapharm/Madaus, Cologne, Germany. This study was conducted under an Investigational New Drug Application from the Food and Drug Administration. Dr. Barry’s associates reported ties to numerous industry sources.

Even at doses three times higher than usual, saw palmetto extract was no better than placebo at improving lower urinary tract symptoms attributed to benign prostatic hyperplasia in a study in the Sept. 28 issue of JAMA.

Extracts from the fruit of the saw palmetto dwarf palm tree are the most widely used plant extracts in the United States and Europe for urinary symptoms. They are purported to have anti-androgenic, anti-inflammatory, and antiproliferative effects, but none of these properties have been proved.

A meta-analysis from approximately 10 years ago showed that, compared with placebo, saw palmetto significantly reduced nocturia and improved peak uroflow, as well as being rated by study subjects as more beneficial. But more recent clinical trials and reviews of the literature have had more negative findings.

"We conducted a randomized clinical trial to determine if a standard daily dose of saw palmetto extract increased to a double and then a triple daily dose over 72 weeks would improve lower urinary tract symptoms attributed to benign prostatic hypertrophy," said Dr. Michael J. Barry of Massachusetts General Hospital, Boston, and his associates in the Complementary and Alternative Medicine for Urological Symptoms (CAMUS) study group.

This study design allowed an adequate duration of treatment – 24 weeks at each dose level – to assess outcomes, they noted.

The double-blind trial included 369 men aged 45 years and older who had a peak uroflow rate of at least 4 mL per second and a score of 8-24 on the American Urological Association Symptom Index (AUASI) at baseline. They were treated at 11 sites across North America with a standard dose (320 mg/day) of gelcaps containing saw palmetto extract or placebo, which was escalated to 640 mg/day at 24 weeks and 960 mg/day at 48 weeks.

The primary outcome measure was the change in AUASI score at 72 weeks. This decreased only slightly, and to nearly the same degree, in both groups: The reduction was 2.20 points with saw palmetto and 2.99 points with placebo, the investigators said (JAMA 2011;306:1344-51).

The result was the same in a per-protocol analysis of the 151 subjects who received saw palmetto and the 155 who received placebo for the entire duration of the study.

Similarly, the proportion of men who achieved a minimal (3-point) decrease in AUASI score over time was 42.6% with saw palmetto and 44.2% with placebo, slightly favoring placebo. A dose-response analysis showed that saw palmetto was no better than placebo at any dose level.

Further analyses also showed that the active treatment was no better than placebo for a wide range of secondary outcomes including change in BPH Index scores and change in measures of nocturia, peak uroflow, postvoiding residual volume, and incontinence.

The trial also did not reveal any subgroup of patients, such as men with higher PSA levels or men with lower peak uroflow, who showed "a clinically important differential response" to saw palmetto, compared with placebo.

At the conclusion of the study, two measures of patient satisfaction with treatment did not differ between the two groups. Both men who received saw palmetto and men who received placebo rated their symptoms as "between ‘a little better’ and ‘about the same.’ "

This study was supported by the National Institutes of Health, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Center for Complementary and Alternative Medicine, and the NIH Office of Dietary Supplements. Saw palmetto extract and matching placebo gelcaps were donated by Rottapharm/Madaus, Cologne, Germany. This study was conducted under an Investigational New Drug Application from the Food and Drug Administration. Dr. Barry’s associates reported ties to numerous industry sources.