Nancy Walsh

BARCELONA — Significant improvements in disease activity were observed among lupus patients treated with belimumab in a new analysis of data from an earlier study using a combined response end point, Dr. Ellen Ginzler said at the annual European Congress of Rheumatology.

The analysis used an evidence-based combined response end point that has been developed to improve the assessment of responses to drug intervention in clinical trials for systemic lupus erythematosus.

"The heterogeneity of lupus disease manifestations contributes to the difficulty of using a single index to adequately assess therapeutic response," Dr. Ginzler explained.

Belimumab (LymphoStat-B) is a monoclonal antibody that binds with high specificity to B lymphocyte stimulator (BLyS), which, being a potent costimulator of B cells, is thought to play a role in B-cell-mediated autoimmunity.

In the original analysis of the study results, the primary end point—reduction in disease activity as measured by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) as modified for the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) at 24 weeks—was not met.

The study included 449 patients with lupus who were randomized to receive placebo or belimumab in doses of 1, 4, or 10 mg/kg on days 0, 14, 28, and then monthly for 52 weeks.

The study continued in open-label fashion through week 76.

A subsequent analysis, however, determined that significant benefits were seen at 52 weeks among the 72% of patients who were serologically active at baseline, with titers of antinuclear anti-body of 1:80 or greater and/or titers of anti-double-stranded (ds) DNA of 30 IU or greater (Arthritis Rheum. 2006;54[suppl. 9]:S258).

Responses among this cohort have now been analyzed according to the new combined response end point, which defines efficacy as an improvement in SELENA-SLEDAI of four points or more and a British Isles Lupus Assessment Group (BILAG) score that reflects the number and severity of organ system flares.

The combined end point also reflects physician's global assessment and patient health-related quality of life as evaluated on the Short Form (SF)-36.

"Using this combined outcome efficacy measure, the response to belimumab therapy among patients who were serologically active at baseline was 46%, which is highly statistically significant at 52 weeks compared to a response rate of 29% with placebo," said Dr. Ginzler, who is professor of medicine and chief of rheumatology, State University of New York, Brooklyn.

By week 76 the response rate had risen to 56%.

At baseline, the mean SELANA-SLEDAI score was 9.6. Patients in the active treatment groups had 29% and 38% reductions in SELENA-SLEDAI scores at weeks 52 and 76, respectively.

At week 52 the belimumab-treated patients had fewer shifts to worse scores in three of the eight BILAG organ systems: musculoskeletal, neurologic, and cardiovascular-respiratory.

Patients who were classified as responders on the composite end point also had greater reductions in activated B cells and anti-ds DNA antibodies, along with greater improvements in the SF-36.

Combining multiple disease activity measures into a response end point improved the assessment of variable disease activity and was predictive of biomarker and quality of life improvements, Dr. Ginzler said.

"This combined end point has now been accepted by regulatory authorities and is being used in two global phase III studies of belimumab that have recently begun enrollment," she said.

The studies are being sponsored by Human Genome Sciences, Inc., manufacturer of LymphoStat-B, and GlaxoSmithKline. Dr. Ginzler has previously disclosed receiving research grants from Human Genome Sciences.

A single index cannot adequately assess treatment response in this heterogeneous disease. DR. GINZLER

BARCELONA — Significant improvements in disease activity were observed among lupus patients treated with belimumab in a new analysis of data from an earlier study using a combined response end point, Dr. Ellen Ginzler said at the annual European Congress of Rheumatology.

The analysis used an evidence-based combined response end point that has been developed to improve the assessment of responses to drug intervention in clinical trials for systemic lupus erythematosus.

"The heterogeneity of lupus disease manifestations contributes to the difficulty of using a single index to adequately assess therapeutic response," Dr. Ginzler explained.

Belimumab (LymphoStat-B) is a monoclonal antibody that binds with high specificity to B lymphocyte stimulator (BLyS), which, being a potent costimulator of B cells, is thought to play a role in B-cell-mediated autoimmunity.

In the original analysis of the study results, the primary end point—reduction in disease activity as measured by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) as modified for the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) at 24 weeks—was not met.

The study included 449 patients with lupus who were randomized to receive placebo or belimumab in doses of 1, 4, or 10 mg/kg on days 0, 14, 28, and then monthly for 52 weeks.

The study continued in open-label fashion through week 76.

A subsequent analysis, however, determined that significant benefits were seen at 52 weeks among the 72% of patients who were serologically active at baseline, with titers of antinuclear anti-body of 1:80 or greater and/or titers of anti-double-stranded (ds) DNA of 30 IU or greater (Arthritis Rheum. 2006;54[suppl. 9]:S258).

Responses among this cohort have now been analyzed according to the new combined response end point, which defines efficacy as an improvement in SELENA-SLEDAI of four points or more and a British Isles Lupus Assessment Group (BILAG) score that reflects the number and severity of organ system flares.

The combined end point also reflects physician's global assessment and patient health-related quality of life as evaluated on the Short Form (SF)-36.

"Using this combined outcome efficacy measure, the response to belimumab therapy among patients who were serologically active at baseline was 46%, which is highly statistically significant at 52 weeks compared to a response rate of 29% with placebo," said Dr. Ginzler, who is professor of medicine and chief of rheumatology, State University of New York, Brooklyn.

By week 76 the response rate had risen to 56%.

At baseline, the mean SELANA-SLEDAI score was 9.6. Patients in the active treatment groups had 29% and 38% reductions in SELENA-SLEDAI scores at weeks 52 and 76, respectively.

At week 52 the belimumab-treated patients had fewer shifts to worse scores in three of the eight BILAG organ systems: musculoskeletal, neurologic, and cardiovascular-respiratory.

Patients who were classified as responders on the composite end point also had greater reductions in activated B cells and anti-ds DNA antibodies, along with greater improvements in the SF-36.

Combining multiple disease activity measures into a response end point improved the assessment of variable disease activity and was predictive of biomarker and quality of life improvements, Dr. Ginzler said.

"This combined end point has now been accepted by regulatory authorities and is being used in two global phase III studies of belimumab that have recently begun enrollment," she said.

The studies are being sponsored by Human Genome Sciences, Inc., manufacturer of LymphoStat-B, and GlaxoSmithKline. Dr. Ginzler has previously disclosed receiving research grants from Human Genome Sciences.

A single index cannot adequately assess treatment response in this heterogeneous disease. DR. GINZLER

BARCELONA — Significant improvements in disease activity were observed among lupus patients treated with belimumab in a new analysis of data from an earlier study using a combined response end point, Dr. Ellen Ginzler said at the annual European Congress of Rheumatology.

The analysis used an evidence-based combined response end point that has been developed to improve the assessment of responses to drug intervention in clinical trials for systemic lupus erythematosus.

"The heterogeneity of lupus disease manifestations contributes to the difficulty of using a single index to adequately assess therapeutic response," Dr. Ginzler explained.

Belimumab (LymphoStat-B) is a monoclonal antibody that binds with high specificity to B lymphocyte stimulator (BLyS), which, being a potent costimulator of B cells, is thought to play a role in B-cell-mediated autoimmunity.

In the original analysis of the study results, the primary end point—reduction in disease activity as measured by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) as modified for the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) at 24 weeks—was not met.

The study included 449 patients with lupus who were randomized to receive placebo or belimumab in doses of 1, 4, or 10 mg/kg on days 0, 14, 28, and then monthly for 52 weeks.

The study continued in open-label fashion through week 76.

A subsequent analysis, however, determined that significant benefits were seen at 52 weeks among the 72% of patients who were serologically active at baseline, with titers of antinuclear anti-body of 1:80 or greater and/or titers of anti-double-stranded (ds) DNA of 30 IU or greater (Arthritis Rheum. 2006;54[suppl. 9]:S258).

Responses among this cohort have now been analyzed according to the new combined response end point, which defines efficacy as an improvement in SELENA-SLEDAI of four points or more and a British Isles Lupus Assessment Group (BILAG) score that reflects the number and severity of organ system flares.

The combined end point also reflects physician's global assessment and patient health-related quality of life as evaluated on the Short Form (SF)-36.

"Using this combined outcome efficacy measure, the response to belimumab therapy among patients who were serologically active at baseline was 46%, which is highly statistically significant at 52 weeks compared to a response rate of 29% with placebo," said Dr. Ginzler, who is professor of medicine and chief of rheumatology, State University of New York, Brooklyn.

By week 76 the response rate had risen to 56%.

At baseline, the mean SELANA-SLEDAI score was 9.6. Patients in the active treatment groups had 29% and 38% reductions in SELENA-SLEDAI scores at weeks 52 and 76, respectively.

At week 52 the belimumab-treated patients had fewer shifts to worse scores in three of the eight BILAG organ systems: musculoskeletal, neurologic, and cardiovascular-respiratory.

Patients who were classified as responders on the composite end point also had greater reductions in activated B cells and anti-ds DNA antibodies, along with greater improvements in the SF-36.

Combining multiple disease activity measures into a response end point improved the assessment of variable disease activity and was predictive of biomarker and quality of life improvements, Dr. Ginzler said.

"This combined end point has now been accepted by regulatory authorities and is being used in two global phase III studies of belimumab that have recently begun enrollment," she said.

The studies are being sponsored by Human Genome Sciences, Inc., manufacturer of LymphoStat-B, and GlaxoSmithKline. Dr. Ginzler has previously disclosed receiving research grants from Human Genome Sciences.

A single index cannot adequately assess treatment response in this heterogeneous disease. DR. GINZLER

MINNEAPOLIS – Data from a surveillance system in Maryland show that the burden of unintended pregnancy remains large, with multiple potential risks for both mothers and infants, according to Dr. Diana Cheng of the Maryland Department of Health and Mental Hygiene, Baltimore.

The Maryland Pregnancy Risk Assessment Monitoring System (PRAMS) was established by the Centers for Disease Control and Prevention with the goal of obtaining information about maternal behaviors and experiences that may be associated with adverse pregnancy outcomes.

Between 2001 and 2005, a random sample of 7,381 mothers completed the PRAMS survey from 2 to 6 months after delivery.

The survey included the following question: Thinking back to just before you got pregnant, how did you feel about becoming pregnant?

Available answers were “I wanted to be pregnant sooner,” “I wanted to be pregnant later,” “I wanted to be pregnant then,” or “I didn't want to be pregnant then or at any time in the future.”

Pregnancies were classified as intended if the mothers had wanted them then or sooner and as unintended if they said they wanted them later or not at all.

Analysis of the survey responses determined that 58% of the pregnancies were intended, while 42% were unintended, Dr. Cheng reported at the annual meeting of the Association of Reproductive Health Professionals.

Among women with intended pregnancies, 16% said they wanted their pregnancy sooner and 42% said they wanted their pregnancy then.

Among women with unintended pregnancies, 31% said they wanted their pregnancies later and 11% said they didn't want to be pregnant then or ever.

“We also looked at maternal behaviors and risk factors, and the group whose pregnancies were unwanted really fared much worse,” Dr. Cheng said. A total of 86% of the mothers whose pregnancies were unwanted did not take folic acid daily, 44% initiated prenatal care after the first trimester, and about 24% smoked during pregnancy.

Post partum, 37% did not breast-feed, 30% smoked, 27% reported depression, and 50% did not place their babies on their backs to sleep.

Moreover, 11% of women in this group reported a history of physical abuse.

In contrast, significantly lower percentages of women with intended pregnancies reported unhealthy behaviors. For example, among mothers in this group, 87% initiated prenatal care during the first trimester, 81% breast-fed, and 69% placed their babies on their backs for sleep.

A total of 10% of babies born to mothers whose pregnancies were unwanted were low birth weight, as were 7% of babies born to mothers whose pregnancies were intended.

The survey also found that 43% of the women were using birth control at the time they became pregnant.

“Discouragingly, the fact that this many women were using birth control and became pregnant anyway suggests inconsistent or improper use of contraceptives,” Dr. Cheng noted.

Among the women who did not use birth control, most said they did not think they could get pregnant at that time. Other reasons for failure to use contraceptives included cost and difficulties in obtaining birth control supplies, she noted.

Improving women's access to education about contraception will help couples better plan pregnancies and increase the rates of intended pregnancies, and counseling, particularly with the inclusion of the partner, can help clarify common misconceptions about birth control, she said.

Unwanted and mistimed births remain a huge educational challenge and opportunity for family planning organizations and specialists, Dr. Cheng concluded.

MINNEAPOLIS – Data from a surveillance system in Maryland show that the burden of unintended pregnancy remains large, with multiple potential risks for both mothers and infants, according to Dr. Diana Cheng of the Maryland Department of Health and Mental Hygiene, Baltimore.

The Maryland Pregnancy Risk Assessment Monitoring System (PRAMS) was established by the Centers for Disease Control and Prevention with the goal of obtaining information about maternal behaviors and experiences that may be associated with adverse pregnancy outcomes.

Between 2001 and 2005, a random sample of 7,381 mothers completed the PRAMS survey from 2 to 6 months after delivery.

The survey included the following question: Thinking back to just before you got pregnant, how did you feel about becoming pregnant?

Available answers were “I wanted to be pregnant sooner,” “I wanted to be pregnant later,” “I wanted to be pregnant then,” or “I didn't want to be pregnant then or at any time in the future.”

Pregnancies were classified as intended if the mothers had wanted them then or sooner and as unintended if they said they wanted them later or not at all.

Analysis of the survey responses determined that 58% of the pregnancies were intended, while 42% were unintended, Dr. Cheng reported at the annual meeting of the Association of Reproductive Health Professionals.

Among women with intended pregnancies, 16% said they wanted their pregnancy sooner and 42% said they wanted their pregnancy then.

Among women with unintended pregnancies, 31% said they wanted their pregnancies later and 11% said they didn't want to be pregnant then or ever.

“We also looked at maternal behaviors and risk factors, and the group whose pregnancies were unwanted really fared much worse,” Dr. Cheng said. A total of 86% of the mothers whose pregnancies were unwanted did not take folic acid daily, 44% initiated prenatal care after the first trimester, and about 24% smoked during pregnancy.

Post partum, 37% did not breast-feed, 30% smoked, 27% reported depression, and 50% did not place their babies on their backs to sleep.

Moreover, 11% of women in this group reported a history of physical abuse.

In contrast, significantly lower percentages of women with intended pregnancies reported unhealthy behaviors. For example, among mothers in this group, 87% initiated prenatal care during the first trimester, 81% breast-fed, and 69% placed their babies on their backs for sleep.

A total of 10% of babies born to mothers whose pregnancies were unwanted were low birth weight, as were 7% of babies born to mothers whose pregnancies were intended.

The survey also found that 43% of the women were using birth control at the time they became pregnant.

“Discouragingly, the fact that this many women were using birth control and became pregnant anyway suggests inconsistent or improper use of contraceptives,” Dr. Cheng noted.

Among the women who did not use birth control, most said they did not think they could get pregnant at that time. Other reasons for failure to use contraceptives included cost and difficulties in obtaining birth control supplies, she noted.

Improving women's access to education about contraception will help couples better plan pregnancies and increase the rates of intended pregnancies, and counseling, particularly with the inclusion of the partner, can help clarify common misconceptions about birth control, she said.

Unwanted and mistimed births remain a huge educational challenge and opportunity for family planning organizations and specialists, Dr. Cheng concluded.

MINNEAPOLIS – Data from a surveillance system in Maryland show that the burden of unintended pregnancy remains large, with multiple potential risks for both mothers and infants, according to Dr. Diana Cheng of the Maryland Department of Health and Mental Hygiene, Baltimore.

The Maryland Pregnancy Risk Assessment Monitoring System (PRAMS) was established by the Centers for Disease Control and Prevention with the goal of obtaining information about maternal behaviors and experiences that may be associated with adverse pregnancy outcomes.

Between 2001 and 2005, a random sample of 7,381 mothers completed the PRAMS survey from 2 to 6 months after delivery.

The survey included the following question: Thinking back to just before you got pregnant, how did you feel about becoming pregnant?

Available answers were “I wanted to be pregnant sooner,” “I wanted to be pregnant later,” “I wanted to be pregnant then,” or “I didn't want to be pregnant then or at any time in the future.”

Pregnancies were classified as intended if the mothers had wanted them then or sooner and as unintended if they said they wanted them later or not at all.

Analysis of the survey responses determined that 58% of the pregnancies were intended, while 42% were unintended, Dr. Cheng reported at the annual meeting of the Association of Reproductive Health Professionals.

Among women with intended pregnancies, 16% said they wanted their pregnancy sooner and 42% said they wanted their pregnancy then.

Among women with unintended pregnancies, 31% said they wanted their pregnancies later and 11% said they didn't want to be pregnant then or ever.

“We also looked at maternal behaviors and risk factors, and the group whose pregnancies were unwanted really fared much worse,” Dr. Cheng said. A total of 86% of the mothers whose pregnancies were unwanted did not take folic acid daily, 44% initiated prenatal care after the first trimester, and about 24% smoked during pregnancy.

Post partum, 37% did not breast-feed, 30% smoked, 27% reported depression, and 50% did not place their babies on their backs to sleep.

Moreover, 11% of women in this group reported a history of physical abuse.

In contrast, significantly lower percentages of women with intended pregnancies reported unhealthy behaviors. For example, among mothers in this group, 87% initiated prenatal care during the first trimester, 81% breast-fed, and 69% placed their babies on their backs for sleep.

A total of 10% of babies born to mothers whose pregnancies were unwanted were low birth weight, as were 7% of babies born to mothers whose pregnancies were intended.

The survey also found that 43% of the women were using birth control at the time they became pregnant.

“Discouragingly, the fact that this many women were using birth control and became pregnant anyway suggests inconsistent or improper use of contraceptives,” Dr. Cheng noted.

Among the women who did not use birth control, most said they did not think they could get pregnant at that time. Other reasons for failure to use contraceptives included cost and difficulties in obtaining birth control supplies, she noted.

Improving women's access to education about contraception will help couples better plan pregnancies and increase the rates of intended pregnancies, and counseling, particularly with the inclusion of the partner, can help clarify common misconceptions about birth control, she said.

Unwanted and mistimed births remain a huge educational challenge and opportunity for family planning organizations and specialists, Dr. Cheng concluded.

MINNEAPOLIS — Women who are content with combined oral contraceptives but are willing to try a nondaily method of birth control are more likely to be satisfied with the contraceptive ring than the patch, Dr. Mitchell D. Creinin said at the annual meeting of the Association of Reproductive Health Professionals.

This was the conclusion of a multicenter, open-label trial that enrolled 500 oral contraceptive (OC) users between June 2005 and September 2006, randomizing them to three menstrual cycles of either the ring or the patch.

The ring and the patch were introduced in the United States in 2002, but there has not been a trial comparing the two directly and there is no objective information on how to advise women who might be interested in switching from the pill to one of these newer methods, Dr. Creinin said.

In previous randomized trials, women found the ring and the patch superior or equal to the pill in terms of acceptability, but those trials typically randomized women to a pill or a new, otherwise unavailable method, he said.

To be eligible for the new study, women had to be satisfied current or recent users of the pill. A total of 84% were current users, and the remaining 16% had discontinued within the previous 3 months for reasons other than dissatisfaction with the OC.

The primary outcome measure was continuation rates after three cycles of the ring or patch, and the secondary outcome measure was intended use beyond the three cycles. The trial also compared side effects, adherence and retention problems, and overall acceptability, said Dr. Creinin, director of the division of gynecologic specialties, University of Pittsburgh. No daily diaries were used to record side effects or other daily concerns. “We felt that asking them to do something daily might have an impact on how they perceived the method,” he said.

During the trial the Food and Drug Administration issued a warning about increased estrogen exposure with the patch. This information was given to all subjects who were enrolled then, and it was incorporated into the informed consent form for all subsequent enrollees.

A total of 479 women were evaluated; 3 never started using the products, 6 withdrew consent during the study, and 12 were lost to follow-up. Among the 241 women randomized to the ring, the mean age was 26; among the 238 randomized to the patch, the mean age was 25. Mean body mass index was 23 in both groups, and 8% of both groups were smokers.

The primary outcome measure of continuation through three cycles was achieved by 95% and 88% of the ring and patch users, respectively. Moreover, when asked if they planned to continue with the nondaily method, 71% of the ring users said they would, compared with only 27% of the patch users, Dr. Creinin said.

Patch users also reported significantly more systemic side effects than ring users. Women using the patch were more likely to complain of longer and more painful menstrual cycles. A total of 38% of patch users had longer periods, compared with 9% of ring users, while 29% of patch users reported dysmenorrhea, compared with 16% of ring users.

Nausea was reported by 8% and 1% of patch and ring users, respectively.

Approximately half of the women had the patch fall off or took it off at some point during the three cycles, while about 40% of ring users had it fall out or took it out at some point. This was significantly more patch detachment and ring expulsion than has been reported in the literature. “I think it's important to convey this to your patients, to let them know that these nondaily methods do require some daily attention to ensure the products are still there,” he said.

“As far as overall acceptability, the bottom line was that women found the ring much more acceptable than the patch,” Dr. Creinin said. They also were more likely to recommend it to their friends.

Dr. Creinin disclosed that the study was funded by Organon. “However,” he said, “it was an investigator-initiated grant, meaning I wrote the proposal, wrote the protocol, picked the sites, supervised the sites, did the monitoring, did the data collection, and analyzed the data, with no requirements for approval from Organon.”

He also disclosed that he does consulting for Organon and receives research funding from Bayer and Organon.

MINNEAPOLIS — Women who are content with combined oral contraceptives but are willing to try a nondaily method of birth control are more likely to be satisfied with the contraceptive ring than the patch, Dr. Mitchell D. Creinin said at the annual meeting of the Association of Reproductive Health Professionals.

This was the conclusion of a multicenter, open-label trial that enrolled 500 oral contraceptive (OC) users between June 2005 and September 2006, randomizing them to three menstrual cycles of either the ring or the patch.

The ring and the patch were introduced in the United States in 2002, but there has not been a trial comparing the two directly and there is no objective information on how to advise women who might be interested in switching from the pill to one of these newer methods, Dr. Creinin said.

In previous randomized trials, women found the ring and the patch superior or equal to the pill in terms of acceptability, but those trials typically randomized women to a pill or a new, otherwise unavailable method, he said.

To be eligible for the new study, women had to be satisfied current or recent users of the pill. A total of 84% were current users, and the remaining 16% had discontinued within the previous 3 months for reasons other than dissatisfaction with the OC.

The primary outcome measure was continuation rates after three cycles of the ring or patch, and the secondary outcome measure was intended use beyond the three cycles. The trial also compared side effects, adherence and retention problems, and overall acceptability, said Dr. Creinin, director of the division of gynecologic specialties, University of Pittsburgh. No daily diaries were used to record side effects or other daily concerns. “We felt that asking them to do something daily might have an impact on how they perceived the method,” he said.

During the trial the Food and Drug Administration issued a warning about increased estrogen exposure with the patch. This information was given to all subjects who were enrolled then, and it was incorporated into the informed consent form for all subsequent enrollees.

A total of 479 women were evaluated; 3 never started using the products, 6 withdrew consent during the study, and 12 were lost to follow-up. Among the 241 women randomized to the ring, the mean age was 26; among the 238 randomized to the patch, the mean age was 25. Mean body mass index was 23 in both groups, and 8% of both groups were smokers.

The primary outcome measure of continuation through three cycles was achieved by 95% and 88% of the ring and patch users, respectively. Moreover, when asked if they planned to continue with the nondaily method, 71% of the ring users said they would, compared with only 27% of the patch users, Dr. Creinin said.

Patch users also reported significantly more systemic side effects than ring users. Women using the patch were more likely to complain of longer and more painful menstrual cycles. A total of 38% of patch users had longer periods, compared with 9% of ring users, while 29% of patch users reported dysmenorrhea, compared with 16% of ring users.

Nausea was reported by 8% and 1% of patch and ring users, respectively.

Approximately half of the women had the patch fall off or took it off at some point during the three cycles, while about 40% of ring users had it fall out or took it out at some point. This was significantly more patch detachment and ring expulsion than has been reported in the literature. “I think it's important to convey this to your patients, to let them know that these nondaily methods do require some daily attention to ensure the products are still there,” he said.

“As far as overall acceptability, the bottom line was that women found the ring much more acceptable than the patch,” Dr. Creinin said. They also were more likely to recommend it to their friends.

Dr. Creinin disclosed that the study was funded by Organon. “However,” he said, “it was an investigator-initiated grant, meaning I wrote the proposal, wrote the protocol, picked the sites, supervised the sites, did the monitoring, did the data collection, and analyzed the data, with no requirements for approval from Organon.”

He also disclosed that he does consulting for Organon and receives research funding from Bayer and Organon.

MINNEAPOLIS — Women who are content with combined oral contraceptives but are willing to try a nondaily method of birth control are more likely to be satisfied with the contraceptive ring than the patch, Dr. Mitchell D. Creinin said at the annual meeting of the Association of Reproductive Health Professionals.

This was the conclusion of a multicenter, open-label trial that enrolled 500 oral contraceptive (OC) users between June 2005 and September 2006, randomizing them to three menstrual cycles of either the ring or the patch.

The ring and the patch were introduced in the United States in 2002, but there has not been a trial comparing the two directly and there is no objective information on how to advise women who might be interested in switching from the pill to one of these newer methods, Dr. Creinin said.

In previous randomized trials, women found the ring and the patch superior or equal to the pill in terms of acceptability, but those trials typically randomized women to a pill or a new, otherwise unavailable method, he said.

To be eligible for the new study, women had to be satisfied current or recent users of the pill. A total of 84% were current users, and the remaining 16% had discontinued within the previous 3 months for reasons other than dissatisfaction with the OC.

The primary outcome measure was continuation rates after three cycles of the ring or patch, and the secondary outcome measure was intended use beyond the three cycles. The trial also compared side effects, adherence and retention problems, and overall acceptability, said Dr. Creinin, director of the division of gynecologic specialties, University of Pittsburgh. No daily diaries were used to record side effects or other daily concerns. “We felt that asking them to do something daily might have an impact on how they perceived the method,” he said.

During the trial the Food and Drug Administration issued a warning about increased estrogen exposure with the patch. This information was given to all subjects who were enrolled then, and it was incorporated into the informed consent form for all subsequent enrollees.

A total of 479 women were evaluated; 3 never started using the products, 6 withdrew consent during the study, and 12 were lost to follow-up. Among the 241 women randomized to the ring, the mean age was 26; among the 238 randomized to the patch, the mean age was 25. Mean body mass index was 23 in both groups, and 8% of both groups were smokers.

The primary outcome measure of continuation through three cycles was achieved by 95% and 88% of the ring and patch users, respectively. Moreover, when asked if they planned to continue with the nondaily method, 71% of the ring users said they would, compared with only 27% of the patch users, Dr. Creinin said.

Patch users also reported significantly more systemic side effects than ring users. Women using the patch were more likely to complain of longer and more painful menstrual cycles. A total of 38% of patch users had longer periods, compared with 9% of ring users, while 29% of patch users reported dysmenorrhea, compared with 16% of ring users.

Nausea was reported by 8% and 1% of patch and ring users, respectively.

Approximately half of the women had the patch fall off or took it off at some point during the three cycles, while about 40% of ring users had it fall out or took it out at some point. This was significantly more patch detachment and ring expulsion than has been reported in the literature. “I think it's important to convey this to your patients, to let them know that these nondaily methods do require some daily attention to ensure the products are still there,” he said.

“As far as overall acceptability, the bottom line was that women found the ring much more acceptable than the patch,” Dr. Creinin said. They also were more likely to recommend it to their friends.

Dr. Creinin disclosed that the study was funded by Organon. “However,” he said, “it was an investigator-initiated grant, meaning I wrote the proposal, wrote the protocol, picked the sites, supervised the sites, did the monitoring, did the data collection, and analyzed the data, with no requirements for approval from Organon.”

He also disclosed that he does consulting for Organon and receives research funding from Bayer and Organon.

NEW YORK – The recognition that Parkinson's disease is systemic, with identifiable prodromal features, is providing hope for early detection and possible early therapeutic intervention, Dr. Matthew Stern said at a meeting sponsored by the Parkinson's Disease Foundation.

“By the time the diagnosis [of Parkinson's disease] is made, the synuclein pathology is already fairly widespread, and much of the damage is done. We can't begin to think about preventing this damage until we've learned more about the preclinical phase,” said Dr. Stern, the Parker Family Professor of Neurology and director of the Parkinson's disease and movement disorder center, University of Pennsylvania, Philadelphia. This early phase is called Parkinson's disease-associated risk syndrome (PARS). It is divided into stages:

P Prephysiologic. The first phase represents genetic predisposition. “There has been a tremendous amount of work in the last 10–15 years in identifying genes that are associated with familial Parkinson's disease, and by studying those we are finding some clues as to the mechanisms of nerve degeneration,” said Dr. Stern.

P Preclinical. In this next phase, brain changes can be detected with neuroimaging, including single-photon emission computed tomography (SPECT) using 123I?-CIT as a dopamine transporter ligand, as well as with transcranial ultrasound.

P Premotor. During this phase, nonmotor features like olfactory dysfunction emerge.

P Prediagnostic. This final stage before a diagnosis is typically made is characterized by subtle progressive motor features.

“It is an increased understanding of the premotor phase that is changing our view of Parkinson's disease from a brain disorder to its being a systemic illness,” he said. About 75% of patients with early Parkinson's disease (PD) do poorly on the UPSIT (University of Pennsylvania Smell Identification Test), which is a simple “scratch and sniff” test. The olfactory loss is significant and begins with the degeneration of extranigral neurons in the olfactory bulb and anterior olfactory nucleus (Lancet Neurol. 2006;5:235-45).

Dr. Stern and colleagues are investigating tools like UPSIT for early screening. In a study in which 361 asymptomatic first-degree relatives of PD patients were screened with UPSIT, 40 had olfactory defects. Over the next 2 years, four of the 40 developed PD, and an additional five showed significant declines on SPECT imaging, he said. No patients in a control cohort among the relatives who were normosmic at baseline developed PD. The study concluded idiopathic olfactory dysfunction in family members of PD patients is associated with at least a 10% increased risk of the disease (Ann. Neurol. 2004;56:173-81).

Moreover, the olfactory defect seems to be specific for PD, and is not a feature of other parkinsonian syndromes. “Also, importantly, if your olfaction is intact, it significantly lowers the risk of developing Parkinson's disease,” he said.

Constipation is another common finding during premotor PD, as shown by the longitudinal Honolulu-Asia Aging Study. Late-life bowel movement frequency was assessed in 245 men aged 71–93 years. Though none had clinical PD, those with fewer bowel movements per day were more likely to have incidental Lewy bodies on postmortem examinations of the substantia nigra and locus ceruleus (Mov. Disord. 2007;22:1581-6). The presence of incidental Lewy bodies is common in the disease prodrome, suggesting GI tract involvement may be an early PD feature, he said.

A further possible early marker is rapid eye movement (REM) sleep behavior disorder (RBD), in which patients thrashing and call out during REM sleep. In a study of 54 polysomnographically confirmed cases of RBD and 54 age- and sex-matched controls, olfactory impairment was observed in 33 of the RBD group, versus 9 controls (Brain Res. Bull. 2006;70:386-90).

Subtle visual and cardiac abnormalities also have been identified in patients in the prodromal phase of PD, “which brings us to where we are today: in the process of designing the first large-scale screening study of PARS,” at UPenn and the Institute for Neurodegenerative Disorders in New Haven, Conn., Dr. Stern said.

The study will recruit thousands of patients and first-degree relatives for olfactory function testing and SPECT neuroimaging. “We will also look at some of these other preclinical markers and follow the patients over time. If, in fact, we can identify several hundred individuals who go on to develop Parkinson's disease, the next phase of the study will be to actually test an intervention for slowing or perhaps even preventing the onset of disease. Ultimately, we hope this will enable us to think about Parkinson's disease in the way we think about heart disease, as a condition that can be diagnosed before it becomes clinically manifest and disabling.”

Dr. Stern is a consultant for Novartis, Boehringer Ingelheim Pharmaceuticals Inc., Valeant Pharmaceuticals International, and Vernalis Pharmaceuticals Inc.

Imaging can detect asymptomatic neurologic changes. A SPECT scan of a patient with early PD shows reduced dopamine transporter binding on the as-yet unaffected side. Danna Jennings/Ken Marek/The Institute for Neurodegeneration

NEW YORK – The recognition that Parkinson's disease is systemic, with identifiable prodromal features, is providing hope for early detection and possible early therapeutic intervention, Dr. Matthew Stern said at a meeting sponsored by the Parkinson's Disease Foundation.

“By the time the diagnosis [of Parkinson's disease] is made, the synuclein pathology is already fairly widespread, and much of the damage is done. We can't begin to think about preventing this damage until we've learned more about the preclinical phase,” said Dr. Stern, the Parker Family Professor of Neurology and director of the Parkinson's disease and movement disorder center, University of Pennsylvania, Philadelphia. This early phase is called Parkinson's disease-associated risk syndrome (PARS). It is divided into stages:

P Prephysiologic. The first phase represents genetic predisposition. “There has been a tremendous amount of work in the last 10–15 years in identifying genes that are associated with familial Parkinson's disease, and by studying those we are finding some clues as to the mechanisms of nerve degeneration,” said Dr. Stern.

P Preclinical. In this next phase, brain changes can be detected with neuroimaging, including single-photon emission computed tomography (SPECT) using 123I?-CIT as a dopamine transporter ligand, as well as with transcranial ultrasound.

P Premotor. During this phase, nonmotor features like olfactory dysfunction emerge.

P Prediagnostic. This final stage before a diagnosis is typically made is characterized by subtle progressive motor features.

“It is an increased understanding of the premotor phase that is changing our view of Parkinson's disease from a brain disorder to its being a systemic illness,” he said. About 75% of patients with early Parkinson's disease (PD) do poorly on the UPSIT (University of Pennsylvania Smell Identification Test), which is a simple “scratch and sniff” test. The olfactory loss is significant and begins with the degeneration of extranigral neurons in the olfactory bulb and anterior olfactory nucleus (Lancet Neurol. 2006;5:235-45).

Dr. Stern and colleagues are investigating tools like UPSIT for early screening. In a study in which 361 asymptomatic first-degree relatives of PD patients were screened with UPSIT, 40 had olfactory defects. Over the next 2 years, four of the 40 developed PD, and an additional five showed significant declines on SPECT imaging, he said. No patients in a control cohort among the relatives who were normosmic at baseline developed PD. The study concluded idiopathic olfactory dysfunction in family members of PD patients is associated with at least a 10% increased risk of the disease (Ann. Neurol. 2004;56:173-81).

Moreover, the olfactory defect seems to be specific for PD, and is not a feature of other parkinsonian syndromes. “Also, importantly, if your olfaction is intact, it significantly lowers the risk of developing Parkinson's disease,” he said.

Constipation is another common finding during premotor PD, as shown by the longitudinal Honolulu-Asia Aging Study. Late-life bowel movement frequency was assessed in 245 men aged 71–93 years. Though none had clinical PD, those with fewer bowel movements per day were more likely to have incidental Lewy bodies on postmortem examinations of the substantia nigra and locus ceruleus (Mov. Disord. 2007;22:1581-6). The presence of incidental Lewy bodies is common in the disease prodrome, suggesting GI tract involvement may be an early PD feature, he said.

A further possible early marker is rapid eye movement (REM) sleep behavior disorder (RBD), in which patients thrashing and call out during REM sleep. In a study of 54 polysomnographically confirmed cases of RBD and 54 age- and sex-matched controls, olfactory impairment was observed in 33 of the RBD group, versus 9 controls (Brain Res. Bull. 2006;70:386-90).

Subtle visual and cardiac abnormalities also have been identified in patients in the prodromal phase of PD, “which brings us to where we are today: in the process of designing the first large-scale screening study of PARS,” at UPenn and the Institute for Neurodegenerative Disorders in New Haven, Conn., Dr. Stern said.

The study will recruit thousands of patients and first-degree relatives for olfactory function testing and SPECT neuroimaging. “We will also look at some of these other preclinical markers and follow the patients over time. If, in fact, we can identify several hundred individuals who go on to develop Parkinson's disease, the next phase of the study will be to actually test an intervention for slowing or perhaps even preventing the onset of disease. Ultimately, we hope this will enable us to think about Parkinson's disease in the way we think about heart disease, as a condition that can be diagnosed before it becomes clinically manifest and disabling.”

Dr. Stern is a consultant for Novartis, Boehringer Ingelheim Pharmaceuticals Inc., Valeant Pharmaceuticals International, and Vernalis Pharmaceuticals Inc.

Imaging can detect asymptomatic neurologic changes. A SPECT scan of a patient with early PD shows reduced dopamine transporter binding on the as-yet unaffected side. Danna Jennings/Ken Marek/The Institute for Neurodegeneration

NEW YORK – The recognition that Parkinson's disease is systemic, with identifiable prodromal features, is providing hope for early detection and possible early therapeutic intervention, Dr. Matthew Stern said at a meeting sponsored by the Parkinson's Disease Foundation.

“By the time the diagnosis [of Parkinson's disease] is made, the synuclein pathology is already fairly widespread, and much of the damage is done. We can't begin to think about preventing this damage until we've learned more about the preclinical phase,” said Dr. Stern, the Parker Family Professor of Neurology and director of the Parkinson's disease and movement disorder center, University of Pennsylvania, Philadelphia. This early phase is called Parkinson's disease-associated risk syndrome (PARS). It is divided into stages:

P Prephysiologic. The first phase represents genetic predisposition. “There has been a tremendous amount of work in the last 10–15 years in identifying genes that are associated with familial Parkinson's disease, and by studying those we are finding some clues as to the mechanisms of nerve degeneration,” said Dr. Stern.

P Preclinical. In this next phase, brain changes can be detected with neuroimaging, including single-photon emission computed tomography (SPECT) using 123I?-CIT as a dopamine transporter ligand, as well as with transcranial ultrasound.

P Premotor. During this phase, nonmotor features like olfactory dysfunction emerge.

P Prediagnostic. This final stage before a diagnosis is typically made is characterized by subtle progressive motor features.

“It is an increased understanding of the premotor phase that is changing our view of Parkinson's disease from a brain disorder to its being a systemic illness,” he said. About 75% of patients with early Parkinson's disease (PD) do poorly on the UPSIT (University of Pennsylvania Smell Identification Test), which is a simple “scratch and sniff” test. The olfactory loss is significant and begins with the degeneration of extranigral neurons in the olfactory bulb and anterior olfactory nucleus (Lancet Neurol. 2006;5:235-45).

Dr. Stern and colleagues are investigating tools like UPSIT for early screening. In a study in which 361 asymptomatic first-degree relatives of PD patients were screened with UPSIT, 40 had olfactory defects. Over the next 2 years, four of the 40 developed PD, and an additional five showed significant declines on SPECT imaging, he said. No patients in a control cohort among the relatives who were normosmic at baseline developed PD. The study concluded idiopathic olfactory dysfunction in family members of PD patients is associated with at least a 10% increased risk of the disease (Ann. Neurol. 2004;56:173-81).

Moreover, the olfactory defect seems to be specific for PD, and is not a feature of other parkinsonian syndromes. “Also, importantly, if your olfaction is intact, it significantly lowers the risk of developing Parkinson's disease,” he said.

Constipation is another common finding during premotor PD, as shown by the longitudinal Honolulu-Asia Aging Study. Late-life bowel movement frequency was assessed in 245 men aged 71–93 years. Though none had clinical PD, those with fewer bowel movements per day were more likely to have incidental Lewy bodies on postmortem examinations of the substantia nigra and locus ceruleus (Mov. Disord. 2007;22:1581-6). The presence of incidental Lewy bodies is common in the disease prodrome, suggesting GI tract involvement may be an early PD feature, he said.

A further possible early marker is rapid eye movement (REM) sleep behavior disorder (RBD), in which patients thrashing and call out during REM sleep. In a study of 54 polysomnographically confirmed cases of RBD and 54 age- and sex-matched controls, olfactory impairment was observed in 33 of the RBD group, versus 9 controls (Brain Res. Bull. 2006;70:386-90).

Subtle visual and cardiac abnormalities also have been identified in patients in the prodromal phase of PD, “which brings us to where we are today: in the process of designing the first large-scale screening study of PARS,” at UPenn and the Institute for Neurodegenerative Disorders in New Haven, Conn., Dr. Stern said.

The study will recruit thousands of patients and first-degree relatives for olfactory function testing and SPECT neuroimaging. “We will also look at some of these other preclinical markers and follow the patients over time. If, in fact, we can identify several hundred individuals who go on to develop Parkinson's disease, the next phase of the study will be to actually test an intervention for slowing or perhaps even preventing the onset of disease. Ultimately, we hope this will enable us to think about Parkinson's disease in the way we think about heart disease, as a condition that can be diagnosed before it becomes clinically manifest and disabling.”

Dr. Stern is a consultant for Novartis, Boehringer Ingelheim Pharmaceuticals Inc., Valeant Pharmaceuticals International, and Vernalis Pharmaceuticals Inc.

Imaging can detect asymptomatic neurologic changes. A SPECT scan of a patient with early PD shows reduced dopamine transporter binding on the as-yet unaffected side. Danna Jennings/Ken Marek/The Institute for Neurodegeneration

MINNEAPOLIS — The American Society for Colposcopy and Cervical Pathology has issued new consensus guidelines on the management of women with abnormal cervical screening tests and cervical intraepithelial neoplasia, emphasizing changes for special populations such as adolescents and immunosuppressed women, Nancy R. Berman announced at the annual meeting of the Association of Reproductive Health Professionals.

Since the initial 2001 consensus guidelines were published, there has been an increase in understanding of the natural history of cervical intraepithelial neoplasia (CIN) and how best to manage women with human papillomavirus-associated lesions. The revised guidelines reflect this increased knowledge and experience (Am. J. Obstet. Gynecol. 2007;197:346-55).

One new area of emphasis is the management of women aged 20 years and younger, who have a high prevalence of HPV infection and minor-grade cytologic abnormalities but who are at very low risk for invasive cervical cancer. It is now clear that the vast majority of HPV infections in this population clear spontaneously and are of little clinical significance, so procedures such as colposcopy for minor abnormalities should not be done.

“We need to leave adolescents alone; just let them get infected and clear,” said Ms. Berman, who is a member of the HPV expert committee of the Association of Reproductive Health Professionals.

Another change in the guidelines is in the management of postmenopausal or immunosuppressed women with atypical squamous cells of undetermined significance (ASCUS).

The 2001 guidelines recommended a course of intravaginal estrogen followed by repeat cervical cytology for postmenopausal women, and colposcopy referral for all immunosuppressed women.

In contrast, the new guidelines state that postmenopausal and immunosuppressed women should be managed in the same manner as women in the general population, according to Ms. Berman, who is a nurse practitioner with an internal medicine group practice in Southfield, Mich.

The prior recommendation for immunosuppressed women was based on early studies showing a very high prevalence of high-risk strains of HPV in HIV-positive women with ASCUS, as well as a high prevalence of CIN grade 2 or higher lesions. However, newer studies indicate that this is not always the case, and that HIV-positive women with ASCUS are similar to HIV-negative women with ASCUS, she said.

The management of pregnant women with low-grade squamous intraepithelial lesions (LSIL) also has been revised. According to the 2001 guidelines, these women were treated according to recommendations for high-grade squamous intraepithelial lesions (HSIL).

The new guidelines, which were finalized at ASCCP's 2006 consensus conference, state that colposcopy is preferred for pregnant, nonadolescent women; that endocervical curettage is unacceptable for pregnant women; and that deferring colposcopy until 6 weeks post partum is acceptable.

Management algorithms as well as the guidelines were published in the Journal of Lower Genital Tract Disease (2007;11:201-22) and can be found on the ASCCP Web site at www.asccp.org/consensus.shtml

The revised guidelines further state that for pregnant women with LSIL without suspected CIN 2-3 or cancer at the initial colposcopy, postpartum follow-up is recommended, and that additional colposcopic and cytologic examinations during pregnancy are unacceptable.

The guidelines were formulated by a group of 146 experts from 29 professional organizations, federal agencies, and national and international health organizations, who met for the ASCCP consensus conference in September 2006.

Ms. Berman disclosed that she is a consultant and speaker for Digene Corp. and a speaker for Merck & Co.

MINNEAPOLIS — The American Society for Colposcopy and Cervical Pathology has issued new consensus guidelines on the management of women with abnormal cervical screening tests and cervical intraepithelial neoplasia, emphasizing changes for special populations such as adolescents and immunosuppressed women, Nancy R. Berman announced at the annual meeting of the Association of Reproductive Health Professionals.

Since the initial 2001 consensus guidelines were published, there has been an increase in understanding of the natural history of cervical intraepithelial neoplasia (CIN) and how best to manage women with human papillomavirus-associated lesions. The revised guidelines reflect this increased knowledge and experience (Am. J. Obstet. Gynecol. 2007;197:346-55).

One new area of emphasis is the management of women aged 20 years and younger, who have a high prevalence of HPV infection and minor-grade cytologic abnormalities but who are at very low risk for invasive cervical cancer. It is now clear that the vast majority of HPV infections in this population clear spontaneously and are of little clinical significance, so procedures such as colposcopy for minor abnormalities should not be done.

“We need to leave adolescents alone; just let them get infected and clear,” said Ms. Berman, who is a member of the HPV expert committee of the Association of Reproductive Health Professionals.

Another change in the guidelines is in the management of postmenopausal or immunosuppressed women with atypical squamous cells of undetermined significance (ASCUS).

The 2001 guidelines recommended a course of intravaginal estrogen followed by repeat cervical cytology for postmenopausal women, and colposcopy referral for all immunosuppressed women.

In contrast, the new guidelines state that postmenopausal and immunosuppressed women should be managed in the same manner as women in the general population, according to Ms. Berman, who is a nurse practitioner with an internal medicine group practice in Southfield, Mich.

The prior recommendation for immunosuppressed women was based on early studies showing a very high prevalence of high-risk strains of HPV in HIV-positive women with ASCUS, as well as a high prevalence of CIN grade 2 or higher lesions. However, newer studies indicate that this is not always the case, and that HIV-positive women with ASCUS are similar to HIV-negative women with ASCUS, she said.

The management of pregnant women with low-grade squamous intraepithelial lesions (LSIL) also has been revised. According to the 2001 guidelines, these women were treated according to recommendations for high-grade squamous intraepithelial lesions (HSIL).

The new guidelines, which were finalized at ASCCP's 2006 consensus conference, state that colposcopy is preferred for pregnant, nonadolescent women; that endocervical curettage is unacceptable for pregnant women; and that deferring colposcopy until 6 weeks post partum is acceptable.

Management algorithms as well as the guidelines were published in the Journal of Lower Genital Tract Disease (2007;11:201-22) and can be found on the ASCCP Web site at www.asccp.org/consensus.shtml

The revised guidelines further state that for pregnant women with LSIL without suspected CIN 2-3 or cancer at the initial colposcopy, postpartum follow-up is recommended, and that additional colposcopic and cytologic examinations during pregnancy are unacceptable.

The guidelines were formulated by a group of 146 experts from 29 professional organizations, federal agencies, and national and international health organizations, who met for the ASCCP consensus conference in September 2006.

Ms. Berman disclosed that she is a consultant and speaker for Digene Corp. and a speaker for Merck & Co.

MINNEAPOLIS — The American Society for Colposcopy and Cervical Pathology has issued new consensus guidelines on the management of women with abnormal cervical screening tests and cervical intraepithelial neoplasia, emphasizing changes for special populations such as adolescents and immunosuppressed women, Nancy R. Berman announced at the annual meeting of the Association of Reproductive Health Professionals.

Since the initial 2001 consensus guidelines were published, there has been an increase in understanding of the natural history of cervical intraepithelial neoplasia (CIN) and how best to manage women with human papillomavirus-associated lesions. The revised guidelines reflect this increased knowledge and experience (Am. J. Obstet. Gynecol. 2007;197:346-55).

One new area of emphasis is the management of women aged 20 years and younger, who have a high prevalence of HPV infection and minor-grade cytologic abnormalities but who are at very low risk for invasive cervical cancer. It is now clear that the vast majority of HPV infections in this population clear spontaneously and are of little clinical significance, so procedures such as colposcopy for minor abnormalities should not be done.

“We need to leave adolescents alone; just let them get infected and clear,” said Ms. Berman, who is a member of the HPV expert committee of the Association of Reproductive Health Professionals.

Another change in the guidelines is in the management of postmenopausal or immunosuppressed women with atypical squamous cells of undetermined significance (ASCUS).

The 2001 guidelines recommended a course of intravaginal estrogen followed by repeat cervical cytology for postmenopausal women, and colposcopy referral for all immunosuppressed women.

In contrast, the new guidelines state that postmenopausal and immunosuppressed women should be managed in the same manner as women in the general population, according to Ms. Berman, who is a nurse practitioner with an internal medicine group practice in Southfield, Mich.

The prior recommendation for immunosuppressed women was based on early studies showing a very high prevalence of high-risk strains of HPV in HIV-positive women with ASCUS, as well as a high prevalence of CIN grade 2 or higher lesions. However, newer studies indicate that this is not always the case, and that HIV-positive women with ASCUS are similar to HIV-negative women with ASCUS, she said.

The management of pregnant women with low-grade squamous intraepithelial lesions (LSIL) also has been revised. According to the 2001 guidelines, these women were treated according to recommendations for high-grade squamous intraepithelial lesions (HSIL).

The new guidelines, which were finalized at ASCCP's 2006 consensus conference, state that colposcopy is preferred for pregnant, nonadolescent women; that endocervical curettage is unacceptable for pregnant women; and that deferring colposcopy until 6 weeks post partum is acceptable.

Management algorithms as well as the guidelines were published in the Journal of Lower Genital Tract Disease (2007;11:201-22) and can be found on the ASCCP Web site at www.asccp.org/consensus.shtml

The revised guidelines further state that for pregnant women with LSIL without suspected CIN 2-3 or cancer at the initial colposcopy, postpartum follow-up is recommended, and that additional colposcopic and cytologic examinations during pregnancy are unacceptable.

The guidelines were formulated by a group of 146 experts from 29 professional organizations, federal agencies, and national and international health organizations, who met for the ASCCP consensus conference in September 2006.

Ms. Berman disclosed that she is a consultant and speaker for Digene Corp. and a speaker for Merck & Co.

Fibromyalgia guidelines issued by the European League Against Rheumatism represent a work in progress on a field “that is very much in evolution,” Dr. Philip J. Mease said in an interview.

The recommendations were formulated by a European working group that included specialists from various fields including rheumatology, pain medicine, and neurology, who reviewed all the available trials through 2005.

“They have done a good job with a difficult challenge, because the trials are so different, both in terms of the outcome measures used and the treatment approaches tried,” said Dr. Mease, a rheumatologist who is clinical professor of medicine, University of Washington, Seattle, and chief of rheumatology clinical research, Swedish Hospital Medical Center, Seattle.

“Moreover, they used a balanced way of looking at both pharmacologic and nonpharmacologic approaches, to give the managing physician a choice of therapeutic approaches,” he said.

Among the general recommendations of the EULAR investigators were the concepts that fibromyalgia requires a comprehensive assessment of pain, function, and psychosocial context, and that treatment should be multidisciplinary, combining various modalities tailored to pain intensity, function, and associated features such as depression and fatigue. While recommendations were evidence based whenever possible, these general recommendations regarding the heterogeneity of fibromyalgia and the need for multidisciplinary treatment were based on expert opinion.

Among the recommendations for nonpharmacologic measures were for the use of heated pool treatment, with or without exercise. This modality was found to be effective in improving pain and function in several “fairly high quality” trials, according to the investigators.

They also suggested that cognitive-behavioral therapy may be beneficial for some patients. This recommendation was based on expert opinion, but the only two studies identified that evaluated this approach were of poor quality. However, they wrote, “This is another area in which the poor quality of trials has masked what experts believe to be a realistic reflection of possible benefits,” and cited potential improvements in pain and function (Ann. Rheum. Dis. July 20, 2007 [Epub doi:10.1136/ard.2007.071522]).

With regard to pharmacologic treatments, the working group recommended tramadol for the management of pain, based on two randomized controlled trials. They also favored the use of acetaminophen and other weak opioids.

However, they advised against the use of corticosteroids and strong opioids, because of their potential for significant long-term side effects and a scarcity of clinical trial data.

Antidepressants should be considered, the recommendations state, because of their ability to reduce pain and often to improve function. Amitriptyline, for example, was found to be beneficial in four of five trials that assessed pain according to a visual analogue scale (VAS).

The amitriptyline data exemplify a difficulty the investigators faced in their analysis when there were multiple trials evaluating the same drug, in that they averaged the effect sizes in these trials. With some trials being of high quality and others not, this may have skewed in an adverse way the effect size for amitriptyline, Dr. Mease observed.

Other antidepressants that have shown benefits in varying numbers and sizes of trials were fluoxetine, duloxetine, milnacipran, moclobemide, and pirlindole.

Finally, the investigators stated that tropisetron, pramipexole, and pregabalin reduce pain and should be considered for the treatment of fibromyalgia. This recommendation illustrates a further difficulty faced by EULAR. “Both pregabalin and pramipexole are recommended, but if you look at the specific trials they are vastly different,” Dr. Mease said. Pregabalin was evaluated in a multicenter, 500-plus patient trial that was very well controlled and excluded all other drugs that might influence fibromyalgia. In contrast, the pramipexole trial took place in a single center and, importantly, permitted the use of background drugs including opioids, he said.

The recommendations will be updated every 5 years, with the hope that clinical trials of good quality will add to the available evidence, according to the investigators.

Fibromyalgia guidelines issued by the European League Against Rheumatism represent a work in progress on a field “that is very much in evolution,” Dr. Philip J. Mease said in an interview.

The recommendations were formulated by a European working group that included specialists from various fields including rheumatology, pain medicine, and neurology, who reviewed all the available trials through 2005.

“They have done a good job with a difficult challenge, because the trials are so different, both in terms of the outcome measures used and the treatment approaches tried,” said Dr. Mease, a rheumatologist who is clinical professor of medicine, University of Washington, Seattle, and chief of rheumatology clinical research, Swedish Hospital Medical Center, Seattle.

“Moreover, they used a balanced way of looking at both pharmacologic and nonpharmacologic approaches, to give the managing physician a choice of therapeutic approaches,” he said.

Among the general recommendations of the EULAR investigators were the concepts that fibromyalgia requires a comprehensive assessment of pain, function, and psychosocial context, and that treatment should be multidisciplinary, combining various modalities tailored to pain intensity, function, and associated features such as depression and fatigue. While recommendations were evidence based whenever possible, these general recommendations regarding the heterogeneity of fibromyalgia and the need for multidisciplinary treatment were based on expert opinion.

Among the recommendations for nonpharmacologic measures were for the use of heated pool treatment, with or without exercise. This modality was found to be effective in improving pain and function in several “fairly high quality” trials, according to the investigators.

They also suggested that cognitive-behavioral therapy may be beneficial for some patients. This recommendation was based on expert opinion, but the only two studies identified that evaluated this approach were of poor quality. However, they wrote, “This is another area in which the poor quality of trials has masked what experts believe to be a realistic reflection of possible benefits,” and cited potential improvements in pain and function (Ann. Rheum. Dis. July 20, 2007 [Epub doi:10.1136/ard.2007.071522]).

With regard to pharmacologic treatments, the working group recommended tramadol for the management of pain, based on two randomized controlled trials. They also favored the use of acetaminophen and other weak opioids.

However, they advised against the use of corticosteroids and strong opioids, because of their potential for significant long-term side effects and a scarcity of clinical trial data.

Antidepressants should be considered, the recommendations state, because of their ability to reduce pain and often to improve function. Amitriptyline, for example, was found to be beneficial in four of five trials that assessed pain according to a visual analogue scale (VAS).

The amitriptyline data exemplify a difficulty the investigators faced in their analysis when there were multiple trials evaluating the same drug, in that they averaged the effect sizes in these trials. With some trials being of high quality and others not, this may have skewed in an adverse way the effect size for amitriptyline, Dr. Mease observed.

Other antidepressants that have shown benefits in varying numbers and sizes of trials were fluoxetine, duloxetine, milnacipran, moclobemide, and pirlindole.

Finally, the investigators stated that tropisetron, pramipexole, and pregabalin reduce pain and should be considered for the treatment of fibromyalgia. This recommendation illustrates a further difficulty faced by EULAR. “Both pregabalin and pramipexole are recommended, but if you look at the specific trials they are vastly different,” Dr. Mease said. Pregabalin was evaluated in a multicenter, 500-plus patient trial that was very well controlled and excluded all other drugs that might influence fibromyalgia. In contrast, the pramipexole trial took place in a single center and, importantly, permitted the use of background drugs including opioids, he said.

The recommendations will be updated every 5 years, with the hope that clinical trials of good quality will add to the available evidence, according to the investigators.

Fibromyalgia guidelines issued by the European League Against Rheumatism represent a work in progress on a field “that is very much in evolution,” Dr. Philip J. Mease said in an interview.

The recommendations were formulated by a European working group that included specialists from various fields including rheumatology, pain medicine, and neurology, who reviewed all the available trials through 2005.

“They have done a good job with a difficult challenge, because the trials are so different, both in terms of the outcome measures used and the treatment approaches tried,” said Dr. Mease, a rheumatologist who is clinical professor of medicine, University of Washington, Seattle, and chief of rheumatology clinical research, Swedish Hospital Medical Center, Seattle.

“Moreover, they used a balanced way of looking at both pharmacologic and nonpharmacologic approaches, to give the managing physician a choice of therapeutic approaches,” he said.

Among the general recommendations of the EULAR investigators were the concepts that fibromyalgia requires a comprehensive assessment of pain, function, and psychosocial context, and that treatment should be multidisciplinary, combining various modalities tailored to pain intensity, function, and associated features such as depression and fatigue. While recommendations were evidence based whenever possible, these general recommendations regarding the heterogeneity of fibromyalgia and the need for multidisciplinary treatment were based on expert opinion.

Among the recommendations for nonpharmacologic measures were for the use of heated pool treatment, with or without exercise. This modality was found to be effective in improving pain and function in several “fairly high quality” trials, according to the investigators.

They also suggested that cognitive-behavioral therapy may be beneficial for some patients. This recommendation was based on expert opinion, but the only two studies identified that evaluated this approach were of poor quality. However, they wrote, “This is another area in which the poor quality of trials has masked what experts believe to be a realistic reflection of possible benefits,” and cited potential improvements in pain and function (Ann. Rheum. Dis. July 20, 2007 [Epub doi:10.1136/ard.2007.071522]).

With regard to pharmacologic treatments, the working group recommended tramadol for the management of pain, based on two randomized controlled trials. They also favored the use of acetaminophen and other weak opioids.

However, they advised against the use of corticosteroids and strong opioids, because of their potential for significant long-term side effects and a scarcity of clinical trial data.

Antidepressants should be considered, the recommendations state, because of their ability to reduce pain and often to improve function. Amitriptyline, for example, was found to be beneficial in four of five trials that assessed pain according to a visual analogue scale (VAS).

The amitriptyline data exemplify a difficulty the investigators faced in their analysis when there were multiple trials evaluating the same drug, in that they averaged the effect sizes in these trials. With some trials being of high quality and others not, this may have skewed in an adverse way the effect size for amitriptyline, Dr. Mease observed.

Other antidepressants that have shown benefits in varying numbers and sizes of trials were fluoxetine, duloxetine, milnacipran, moclobemide, and pirlindole.

Finally, the investigators stated that tropisetron, pramipexole, and pregabalin reduce pain and should be considered for the treatment of fibromyalgia. This recommendation illustrates a further difficulty faced by EULAR. “Both pregabalin and pramipexole are recommended, but if you look at the specific trials they are vastly different,” Dr. Mease said. Pregabalin was evaluated in a multicenter, 500-plus patient trial that was very well controlled and excluded all other drugs that might influence fibromyalgia. In contrast, the pramipexole trial took place in a single center and, importantly, permitted the use of background drugs including opioids, he said.

The recommendations will be updated every 5 years, with the hope that clinical trials of good quality will add to the available evidence, according to the investigators.

NEW YORK — As an increasing number of medical therapies become available for the treatment of pulmonary arterial hypertension and clinical experience accrues, questions have begun to arise as to how to initiate and optimize treatment, and how best to assess response, according to Dr. Harold I. Palevsky.

“There was a time when the treatment of pulmonary hypertension was very simple. All we had to decide was whether or not a patient was capable of managing intravenous prostacyclin,” Dr. Palevsky said at a meeting sponsored by the Pulmonary Hypertension Association and the University of Michigan.

Now clinicians can choose from six Food and Drug Administration-approved therapies from three therapeutic classes, in addition to supportive therapies such as supplemental oxygen, digoxin, diuretics, and anticoagulants.

The three available prostacyclin derivatives are intravenous epoprostenol, inhaled iloprost, and subcutaneous or intravenous treprostinil. The two approved endothelin receptor antagonists are oral bosentan and oral ambrisentan, and the phosphodiesterase type 5 inhibitor is oral sildenafil.

Initial therapy is based primarily on an assessment of the patient's current and future risk, said Dr. Palevsky, professor of medicine, University of Pennsylvania, and director, pulmonary vascular disease program, University of Pennsylvania Health System, Philadelphia. A global risk assessment for the individual patient includes evaluation of WHO (World Health Organization) functional class, 6-minute walk test, serum B type natriuretic peptide (BNP) level, and echocardiography of right heart function. In addition, catheterization measures of pulmonary and cardiac pressures and cardiac output must be considered.

Accordingly, a patient with PAH and mildly impaired functional status, a 400-m 6-minute walk test, minimally elevated BNP, normal right heart function, and normal or near normal cardiac index would be considered low risk and a likely candidate for oral therapy, Dr. Palevsky said.

In contrast, the patient in WHO class IV, with a 6-minute walk test distance of less than 300 m, elevated BNP, and significant right ventricular dysfunction may require a more complex regimen involving inhaled or infused therapy.

Once therapy is initiated, periodic assessments are needed to identify progress. The goals of therapy are to improve cardiac output, because that will lead to improvement in the patient's functional capacity and quality of life, and to decrease vascular resistance, which is the determinant of right ventricular performance, he said.

For patients who do not improve on monotherapy, an option increasingly being explored is combination therapy.

“A fundamental question today is what model we should use,” said Dr. Palevsky, who is also chief of pulmonary, allergy, and critical care at Penn Presbyterian Medical Center, Philadelphia.

“One model is the one used for systemic hypertension, where you give one therapy, assess the response, and if that's not doing what you want, add a second drug, and if that's not enough add a third drug. The alternative is a cancer chemotherapy model, where you give the patient the best therapy up front aiming for remission, and then down-titrate to maintenance therapy,” he said.

Preliminary data from a U.S. trial comparing inhaled iloprost plus oral bosentan with bosentan alone suggest that the current stepwise approach might be problematic, he said.

The multicenter, double-blinded trial randomized 67 adults with PAH to 12 weeks of treatment with the endothelin receptor antagonist alone or in combination with the inhaled prostacyclin derivative.

Although this was primarily a safety study, the trial found that the combination group had an improvement in the 6-minute walk by a placebo-corrected 26 m (Am. J. Respir. Crit. Care Med. 2006;174:1257–63).

Moreover, one-third of the patients who had the combination improved by one functional class, Dr. Palevsky said.

In the open-label extension phase of the trial, 60 patients received the combination and were followed for 12 months. “What was concerning about this was that after the patients previously receiving monotherapy began also receiving iloprost they didn't catch up, raising the question of whether we need to be more aggressive in early treatment,” he said.

A similar study undertaken in Europe showed contrasting results. A total of 40 patients were randomized to receive bosentan alone or in combination with iloprost for 12 weeks, but an interim analysis found that the primary end point, the 6-minute walk test, was not met, and the trial was terminated (Eur. Respir. J. 2006;28:691–4).

Several other studies are underway investigating other combinations and addressing other questions, such as whether patients with early PAH can benefit from treatment. Newer agents also are being evaluated. “Whether any of the alternatives under investigation will supplant our current therapies is not yet known, but it's our dream. I'd love to be able to see the CADD pump in the Smithsonian before I retire,” Dr. Palevsky said, referring to the continuous infusion pump used with epoprostenol.

'I'd love to be able to see the CADD pump in the Smithsonian before I retire.' DR. PALEVSKY

NEW YORK — As an increasing number of medical therapies become available for the treatment of pulmonary arterial hypertension and clinical experience accrues, questions have begun to arise as to how to initiate and optimize treatment, and how best to assess response, according to Dr. Harold I. Palevsky.

“There was a time when the treatment of pulmonary hypertension was very simple. All we had to decide was whether or not a patient was capable of managing intravenous prostacyclin,” Dr. Palevsky said at a meeting sponsored by the Pulmonary Hypertension Association and the University of Michigan.

Now clinicians can choose from six Food and Drug Administration-approved therapies from three therapeutic classes, in addition to supportive therapies such as supplemental oxygen, digoxin, diuretics, and anticoagulants.

The three available prostacyclin derivatives are intravenous epoprostenol, inhaled iloprost, and subcutaneous or intravenous treprostinil. The two approved endothelin receptor antagonists are oral bosentan and oral ambrisentan, and the phosphodiesterase type 5 inhibitor is oral sildenafil.

Initial therapy is based primarily on an assessment of the patient's current and future risk, said Dr. Palevsky, professor of medicine, University of Pennsylvania, and director, pulmonary vascular disease program, University of Pennsylvania Health System, Philadelphia. A global risk assessment for the individual patient includes evaluation of WHO (World Health Organization) functional class, 6-minute walk test, serum B type natriuretic peptide (BNP) level, and echocardiography of right heart function. In addition, catheterization measures of pulmonary and cardiac pressures and cardiac output must be considered.

Accordingly, a patient with PAH and mildly impaired functional status, a 400-m 6-minute walk test, minimally elevated BNP, normal right heart function, and normal or near normal cardiac index would be considered low risk and a likely candidate for oral therapy, Dr. Palevsky said.

In contrast, the patient in WHO class IV, with a 6-minute walk test distance of less than 300 m, elevated BNP, and significant right ventricular dysfunction may require a more complex regimen involving inhaled or infused therapy.

Once therapy is initiated, periodic assessments are needed to identify progress. The goals of therapy are to improve cardiac output, because that will lead to improvement in the patient's functional capacity and quality of life, and to decrease vascular resistance, which is the determinant of right ventricular performance, he said.

For patients who do not improve on monotherapy, an option increasingly being explored is combination therapy.

“A fundamental question today is what model we should use,” said Dr. Palevsky, who is also chief of pulmonary, allergy, and critical care at Penn Presbyterian Medical Center, Philadelphia.

“One model is the one used for systemic hypertension, where you give one therapy, assess the response, and if that's not doing what you want, add a second drug, and if that's not enough add a third drug. The alternative is a cancer chemotherapy model, where you give the patient the best therapy up front aiming for remission, and then down-titrate to maintenance therapy,” he said.

Preliminary data from a U.S. trial comparing inhaled iloprost plus oral bosentan with bosentan alone suggest that the current stepwise approach might be problematic, he said.

The multicenter, double-blinded trial randomized 67 adults with PAH to 12 weeks of treatment with the endothelin receptor antagonist alone or in combination with the inhaled prostacyclin derivative.

Although this was primarily a safety study, the trial found that the combination group had an improvement in the 6-minute walk by a placebo-corrected 26 m (Am. J. Respir. Crit. Care Med. 2006;174:1257–63).

Moreover, one-third of the patients who had the combination improved by one functional class, Dr. Palevsky said.

In the open-label extension phase of the trial, 60 patients received the combination and were followed for 12 months. “What was concerning about this was that after the patients previously receiving monotherapy began also receiving iloprost they didn't catch up, raising the question of whether we need to be more aggressive in early treatment,” he said.

A similar study undertaken in Europe showed contrasting results. A total of 40 patients were randomized to receive bosentan alone or in combination with iloprost for 12 weeks, but an interim analysis found that the primary end point, the 6-minute walk test, was not met, and the trial was terminated (Eur. Respir. J. 2006;28:691–4).

Several other studies are underway investigating other combinations and addressing other questions, such as whether patients with early PAH can benefit from treatment. Newer agents also are being evaluated. “Whether any of the alternatives under investigation will supplant our current therapies is not yet known, but it's our dream. I'd love to be able to see the CADD pump in the Smithsonian before I retire,” Dr. Palevsky said, referring to the continuous infusion pump used with epoprostenol.

'I'd love to be able to see the CADD pump in the Smithsonian before I retire.' DR. PALEVSKY

NEW YORK — As an increasing number of medical therapies become available for the treatment of pulmonary arterial hypertension and clinical experience accrues, questions have begun to arise as to how to initiate and optimize treatment, and how best to assess response, according to Dr. Harold I. Palevsky.

“There was a time when the treatment of pulmonary hypertension was very simple. All we had to decide was whether or not a patient was capable of managing intravenous prostacyclin,” Dr. Palevsky said at a meeting sponsored by the Pulmonary Hypertension Association and the University of Michigan.

Now clinicians can choose from six Food and Drug Administration-approved therapies from three therapeutic classes, in addition to supportive therapies such as supplemental oxygen, digoxin, diuretics, and anticoagulants.

The three available prostacyclin derivatives are intravenous epoprostenol, inhaled iloprost, and subcutaneous or intravenous treprostinil. The two approved endothelin receptor antagonists are oral bosentan and oral ambrisentan, and the phosphodiesterase type 5 inhibitor is oral sildenafil.

Initial therapy is based primarily on an assessment of the patient's current and future risk, said Dr. Palevsky, professor of medicine, University of Pennsylvania, and director, pulmonary vascular disease program, University of Pennsylvania Health System, Philadelphia. A global risk assessment for the individual patient includes evaluation of WHO (World Health Organization) functional class, 6-minute walk test, serum B type natriuretic peptide (BNP) level, and echocardiography of right heart function. In addition, catheterization measures of pulmonary and cardiac pressures and cardiac output must be considered.

Accordingly, a patient with PAH and mildly impaired functional status, a 400-m 6-minute walk test, minimally elevated BNP, normal right heart function, and normal or near normal cardiac index would be considered low risk and a likely candidate for oral therapy, Dr. Palevsky said.

In contrast, the patient in WHO class IV, with a 6-minute walk test distance of less than 300 m, elevated BNP, and significant right ventricular dysfunction may require a more complex regimen involving inhaled or infused therapy.

Once therapy is initiated, periodic assessments are needed to identify progress. The goals of therapy are to improve cardiac output, because that will lead to improvement in the patient's functional capacity and quality of life, and to decrease vascular resistance, which is the determinant of right ventricular performance, he said.

For patients who do not improve on monotherapy, an option increasingly being explored is combination therapy.

“A fundamental question today is what model we should use,” said Dr. Palevsky, who is also chief of pulmonary, allergy, and critical care at Penn Presbyterian Medical Center, Philadelphia.

“One model is the one used for systemic hypertension, where you give one therapy, assess the response, and if that's not doing what you want, add a second drug, and if that's not enough add a third drug. The alternative is a cancer chemotherapy model, where you give the patient the best therapy up front aiming for remission, and then down-titrate to maintenance therapy,” he said.

Preliminary data from a U.S. trial comparing inhaled iloprost plus oral bosentan with bosentan alone suggest that the current stepwise approach might be problematic, he said.

The multicenter, double-blinded trial randomized 67 adults with PAH to 12 weeks of treatment with the endothelin receptor antagonist alone or in combination with the inhaled prostacyclin derivative.

Although this was primarily a safety study, the trial found that the combination group had an improvement in the 6-minute walk by a placebo-corrected 26 m (Am. J. Respir. Crit. Care Med. 2006;174:1257–63).

Moreover, one-third of the patients who had the combination improved by one functional class, Dr. Palevsky said.

In the open-label extension phase of the trial, 60 patients received the combination and were followed for 12 months. “What was concerning about this was that after the patients previously receiving monotherapy began also receiving iloprost they didn't catch up, raising the question of whether we need to be more aggressive in early treatment,” he said.

A similar study undertaken in Europe showed contrasting results. A total of 40 patients were randomized to receive bosentan alone or in combination with iloprost for 12 weeks, but an interim analysis found that the primary end point, the 6-minute walk test, was not met, and the trial was terminated (Eur. Respir. J. 2006;28:691–4).

Several other studies are underway investigating other combinations and addressing other questions, such as whether patients with early PAH can benefit from treatment. Newer agents also are being evaluated. “Whether any of the alternatives under investigation will supplant our current therapies is not yet known, but it's our dream. I'd love to be able to see the CADD pump in the Smithsonian before I retire,” Dr. Palevsky said, referring to the continuous infusion pump used with epoprostenol.

'I'd love to be able to see the CADD pump in the Smithsonian before I retire.' DR. PALEVSKY

The American College of Chest Physicians has issued updated clinical practice guidelines for the medical management of pulmonary arterial hypertension that reflect findings from several recent clinical trials as well as the additional drugs that have been approved since the previous guidelines were issued in 2004.

The guidelines include an evidence-based, updated treatment algorithm intended to assist physicians in decision making, as “the paradigm for treatment of pulmonary arterial hypertension (PAH) continues to advance rapidly” (Chest 2007;131:1917–28).

Providing new data were two “important” studies that showed survival benefits in patients treated with bosentan, which binds to both endothelin receptors (ETA and ETB), according to lead author Dr. David B. Badesch of the University of Colorado Health Sciences Center, Denver.

In the first study, 169 patients (aged 13–80 years) with class III or IV PAH were treated with bosentan as first-line therapy. Survival was 96% at 12 months and 89% at 24 months, in contrast to predicted survival rates from the earlier National Institutes of Health registry of 69% and 57%, respectively (Eur. Respir. J. 2005;25:244–9).

In the second study, survival in 139 patients treated with bosentan was compared with historical data from 346 patients who had been treated with epoprostenol. Survival estimates after 1 and 2 years were 97% and 91%, respectively, in the bosentan-treated group, and 91% and 84% in the epoprostenol-treated group (Thorax 2005;60:1025–30).

The baseline characteristics of the patients suggested that the patients in the epoprostenol cohort had more severe disease. Nonetheless, Cox regression analyses adjusting for baseline factors showed a greater probability of death in the epoprostenol group, with a hazard ratio of 2.2.

Bosentan also has now been evaluated in children with PAH associated with congenital heart disease or connective tissue disease. In a retrospective study, 86 children were treated with bosentan with or without concomitant epoprostenol or treprostinil. WHO functional class improved in 46% of patients and was unchanged in 44%, and survival estimates at 1 and 2 years were 98% and 91% (J. Am. Coll. Cardiol. 2005;46:697–704).

Another recent study included 245 patients (aged 12–78 years) who received bosentan, placebo, or one of two doses of a selective ETA endothelin receptor antagonist, sitaxsentan. At week 18, patients receiving the higher dose of sitaxsentan (100 mg/day) had significant improvements on a 6-minute walk test, compared with those receiving placebo. The incidence of elevated transaminases was 6% in the placebo group, 5% in the sitaxsentan low-dose (50 mg/day) group, 3% in the high-dose sitaxsentan group, and 11% in the bosentan group (J. Am. Coll. Cardiol. 2006;47:2049–56).

Sitaxsentan remains investigational in the United States, but has been approved for use in Europe and Canada.

A second selective ETA endothelin receptor antagonist, ambrisentan, was evaluated in a double-blind, dose-ranging study that included 64 adult patients with PAH. They were randomized to receive 1 mg, 2.5 mg, 5 mg, or 10 mg of ambrisentan orally once daily for 12 weeks.

The 6-minute walk test improved significantly for all groups, with a mean increase from baseline of 36.1 m. Improvements also were seen in WHO functional class, Borg dyspnea index, and cardiac index (J. Am. Coll. Cardiol. 2005;46:529–35).

Adverse events were mild, with elevated serum aminotransferase exceeding three times the upper limit of normal seen in 3.1% of patients. This drug was recently approved for class II and class III PAH in the United States.

The phosphodiesterase inhibitor sildenafil also is now approved for the treatment of all classes of PAH in a dosage of 20 mg three times daily. The drug was evaluated in a double-blind study that randomized 278 patients (mean age 50 years) to placebo or 20, 40, or 80 mg three times daily for 12 weeks.

Improvements were seen in the 6-minute walk test in all groups, with placebo-corrected treatment effects being 13%, 13.3%, and 14.7% in the 20-, 40-, and 80-mg groups, respectively. The incidence of clinical worsening did not differ significantly between the placebo and sildenafil groups.

Side effects included flushing, dyspepsia, and diarrhea.

In summarizing the treatment options, the authors noted that for patients in functional class II, the only current recommended drugs are sildenafil and subcutaneous and intravenous treprostinil, and suggested that sildenafil may be the first choice for most patients because of ease of administration and relative efficacy.

For patients in functional class III, five drugs are available: bosentan, sildenafil, intravenous epoprostenol, inhaled iloprost, and subcutaneous or intravenous treprostinil. For those with early class III disease, oral bosentan or sildenafil may be used, with the choice reflecting relative toxicities. For patients with more advanced disease, prostanoid therapy may be needed.

All the available agents are approved for patients with class IV PAH. However, the authors wrote, “[we] strongly encourage IV epoprostenol as the treatment of choice for these most critically ill patients. IV epoprostenol has a rapid and predictable onset of action, and most experts are familiar with how to titrate this drug in the acute setting.”

They also recommended that patients with PAH be referred to specialized centers because of the complex diagnostic and therapeutic considerations involved.

The American College of Chest Physicians has issued updated clinical practice guidelines for the medical management of pulmonary arterial hypertension that reflect findings from several recent clinical trials as well as the additional drugs that have been approved since the previous guidelines were issued in 2004.

The guidelines include an evidence-based, updated treatment algorithm intended to assist physicians in decision making, as “the paradigm for treatment of pulmonary arterial hypertension (PAH) continues to advance rapidly” (Chest 2007;131:1917–28).

Providing new data were two “important” studies that showed survival benefits in patients treated with bosentan, which binds to both endothelin receptors (ETA and ETB), according to lead author Dr. David B. Badesch of the University of Colorado Health Sciences Center, Denver.

In the first study, 169 patients (aged 13–80 years) with class III or IV PAH were treated with bosentan as first-line therapy. Survival was 96% at 12 months and 89% at 24 months, in contrast to predicted survival rates from the earlier National Institutes of Health registry of 69% and 57%, respectively (Eur. Respir. J. 2005;25:244–9).

In the second study, survival in 139 patients treated with bosentan was compared with historical data from 346 patients who had been treated with epoprostenol. Survival estimates after 1 and 2 years were 97% and 91%, respectively, in the bosentan-treated group, and 91% and 84% in the epoprostenol-treated group (Thorax 2005;60:1025–30).

The baseline characteristics of the patients suggested that the patients in the epoprostenol cohort had more severe disease. Nonetheless, Cox regression analyses adjusting for baseline factors showed a greater probability of death in the epoprostenol group, with a hazard ratio of 2.2.

Bosentan also has now been evaluated in children with PAH associated with congenital heart disease or connective tissue disease. In a retrospective study, 86 children were treated with bosentan with or without concomitant epoprostenol or treprostinil. WHO functional class improved in 46% of patients and was unchanged in 44%, and survival estimates at 1 and 2 years were 98% and 91% (J. Am. Coll. Cardiol. 2005;46:697–704).

Another recent study included 245 patients (aged 12–78 years) who received bosentan, placebo, or one of two doses of a selective ETA endothelin receptor antagonist, sitaxsentan. At week 18, patients receiving the higher dose of sitaxsentan (100 mg/day) had significant improvements on a 6-minute walk test, compared with those receiving placebo. The incidence of elevated transaminases was 6% in the placebo group, 5% in the sitaxsentan low-dose (50 mg/day) group, 3% in the high-dose sitaxsentan group, and 11% in the bosentan group (J. Am. Coll. Cardiol. 2006;47:2049–56).

Sitaxsentan remains investigational in the United States, but has been approved for use in Europe and Canada.

A second selective ETA endothelin receptor antagonist, ambrisentan, was evaluated in a double-blind, dose-ranging study that included 64 adult patients with PAH. They were randomized to receive 1 mg, 2.5 mg, 5 mg, or 10 mg of ambrisentan orally once daily for 12 weeks.

The 6-minute walk test improved significantly for all groups, with a mean increase from baseline of 36.1 m. Improvements also were seen in WHO functional class, Borg dyspnea index, and cardiac index (J. Am. Coll. Cardiol. 2005;46:529–35).

Adverse events were mild, with elevated serum aminotransferase exceeding three times the upper limit of normal seen in 3.1% of patients. This drug was recently approved for class II and class III PAH in the United States.

The phosphodiesterase inhibitor sildenafil also is now approved for the treatment of all classes of PAH in a dosage of 20 mg three times daily. The drug was evaluated in a double-blind study that randomized 278 patients (mean age 50 years) to placebo or 20, 40, or 80 mg three times daily for 12 weeks.

Improvements were seen in the 6-minute walk test in all groups, with placebo-corrected treatment effects being 13%, 13.3%, and 14.7% in the 20-, 40-, and 80-mg groups, respectively. The incidence of clinical worsening did not differ significantly between the placebo and sildenafil groups.

Side effects included flushing, dyspepsia, and diarrhea.

In summarizing the treatment options, the authors noted that for patients in functional class II, the only current recommended drugs are sildenafil and subcutaneous and intravenous treprostinil, and suggested that sildenafil may be the first choice for most patients because of ease of administration and relative efficacy.

For patients in functional class III, five drugs are available: bosentan, sildenafil, intravenous epoprostenol, inhaled iloprost, and subcutaneous or intravenous treprostinil. For those with early class III disease, oral bosentan or sildenafil may be used, with the choice reflecting relative toxicities. For patients with more advanced disease, prostanoid therapy may be needed.

All the available agents are approved for patients with class IV PAH. However, the authors wrote, “[we] strongly encourage IV epoprostenol as the treatment of choice for these most critically ill patients. IV epoprostenol has a rapid and predictable onset of action, and most experts are familiar with how to titrate this drug in the acute setting.”

They also recommended that patients with PAH be referred to specialized centers because of the complex diagnostic and therapeutic considerations involved.

The American College of Chest Physicians has issued updated clinical practice guidelines for the medical management of pulmonary arterial hypertension that reflect findings from several recent clinical trials as well as the additional drugs that have been approved since the previous guidelines were issued in 2004.

The guidelines include an evidence-based, updated treatment algorithm intended to assist physicians in decision making, as “the paradigm for treatment of pulmonary arterial hypertension (PAH) continues to advance rapidly” (Chest 2007;131:1917–28).

Providing new data were two “important” studies that showed survival benefits in patients treated with bosentan, which binds to both endothelin receptors (ETA and ETB), according to lead author Dr. David B. Badesch of the University of Colorado Health Sciences Center, Denver.

In the first study, 169 patients (aged 13–80 years) with class III or IV PAH were treated with bosentan as first-line therapy. Survival was 96% at 12 months and 89% at 24 months, in contrast to predicted survival rates from the earlier National Institutes of Health registry of 69% and 57%, respectively (Eur. Respir. J. 2005;25:244–9).

In the second study, survival in 139 patients treated with bosentan was compared with historical data from 346 patients who had been treated with epoprostenol. Survival estimates after 1 and 2 years were 97% and 91%, respectively, in the bosentan-treated group, and 91% and 84% in the epoprostenol-treated group (Thorax 2005;60:1025–30).

The baseline characteristics of the patients suggested that the patients in the epoprostenol cohort had more severe disease. Nonetheless, Cox regression analyses adjusting for baseline factors showed a greater probability of death in the epoprostenol group, with a hazard ratio of 2.2.

Bosentan also has now been evaluated in children with PAH associated with congenital heart disease or connective tissue disease. In a retrospective study, 86 children were treated with bosentan with or without concomitant epoprostenol or treprostinil. WHO functional class improved in 46% of patients and was unchanged in 44%, and survival estimates at 1 and 2 years were 98% and 91% (J. Am. Coll. Cardiol. 2005;46:697–704).

Another recent study included 245 patients (aged 12–78 years) who received bosentan, placebo, or one of two doses of a selective ETA endothelin receptor antagonist, sitaxsentan. At week 18, patients receiving the higher dose of sitaxsentan (100 mg/day) had significant improvements on a 6-minute walk test, compared with those receiving placebo. The incidence of elevated transaminases was 6% in the placebo group, 5% in the sitaxsentan low-dose (50 mg/day) group, 3% in the high-dose sitaxsentan group, and 11% in the bosentan group (J. Am. Coll. Cardiol. 2006;47:2049–56).

Sitaxsentan remains investigational in the United States, but has been approved for use in Europe and Canada.

A second selective ETA endothelin receptor antagonist, ambrisentan, was evaluated in a double-blind, dose-ranging study that included 64 adult patients with PAH. They were randomized to receive 1 mg, 2.5 mg, 5 mg, or 10 mg of ambrisentan orally once daily for 12 weeks.

The 6-minute walk test improved significantly for all groups, with a mean increase from baseline of 36.1 m. Improvements also were seen in WHO functional class, Borg dyspnea index, and cardiac index (J. Am. Coll. Cardiol. 2005;46:529–35).

Adverse events were mild, with elevated serum aminotransferase exceeding three times the upper limit of normal seen in 3.1% of patients. This drug was recently approved for class II and class III PAH in the United States.

The phosphodiesterase inhibitor sildenafil also is now approved for the treatment of all classes of PAH in a dosage of 20 mg three times daily. The drug was evaluated in a double-blind study that randomized 278 patients (mean age 50 years) to placebo or 20, 40, or 80 mg three times daily for 12 weeks.

Improvements were seen in the 6-minute walk test in all groups, with placebo-corrected treatment effects being 13%, 13.3%, and 14.7% in the 20-, 40-, and 80-mg groups, respectively. The incidence of clinical worsening did not differ significantly between the placebo and sildenafil groups.

Side effects included flushing, dyspepsia, and diarrhea.

In summarizing the treatment options, the authors noted that for patients in functional class II, the only current recommended drugs are sildenafil and subcutaneous and intravenous treprostinil, and suggested that sildenafil may be the first choice for most patients because of ease of administration and relative efficacy.

For patients in functional class III, five drugs are available: bosentan, sildenafil, intravenous epoprostenol, inhaled iloprost, and subcutaneous or intravenous treprostinil. For those with early class III disease, oral bosentan or sildenafil may be used, with the choice reflecting relative toxicities. For patients with more advanced disease, prostanoid therapy may be needed.

All the available agents are approved for patients with class IV PAH. However, the authors wrote, “[we] strongly encourage IV epoprostenol as the treatment of choice for these most critically ill patients. IV epoprostenol has a rapid and predictable onset of action, and most experts are familiar with how to titrate this drug in the acute setting.”

They also recommended that patients with PAH be referred to specialized centers because of the complex diagnostic and therapeutic considerations involved.

NEW YORK — Any patient with suspected pulmonary hypertension must have a thorough work-up, including right heart catheterization, before initiating treatment, Dr. Roxana Sulica said at a meeting sponsored by the Pulmonary Hypertension Association and the University of Michigan.

Because the typical presenting symptoms of pulmonary arterial hypertension (PAH) are subtle and nonspecific, with dyspnea, fatigue, and syncope or near syncope being the most common, a high index of suspicion is needed or the diagnosis may not be made until the disease is advanced and the prognosis is poor, she said.

Risk factors for PAH include underlying connective tissue disease, especially limited scleroderma and mixed connective tissue disease, a family history of PAH, the presence of congenital heart disease, and environmental factors such as exposure to anorexigens.

Clinical assessment of patients with possible PAH includes an electrocardiogram, which may show changes in the right ventricle, including right axis deviation, right atrial enlargement, and right ventricular hypertrophy, Dr. Sulica said.

A chest x-ray may reveal prominent proximal pulmonary arteries, peripheral hypovascularity, and reduced retrosternal air space.

An echocardiogram should then be done, and typical—but not diagnostic—findings on the echocardiogram include right atrial and ventricular enlargement, right ventricular dysfunction, and intraventricular septal flattening.

The definitive diagnosis of PAH can be made only by cardiac catheterization, which can exclude congenital heart disease, measure wedge pressure, and establish the degree of hemodynamic impairment, according to Dr. Sulica, who is director of the pulmonary hypertension program, Beth Israel Medical Center, New York.

The hemodynamic definition of PAH is a mean pulmonary artery pressure greater than 25 mm Hg, with a pulmonary capillary wedge pressure less than 15 mm Hg and a calculated pulmonary vascular resistance greater than 3 Wood units.

Right heart catheterization also permits a determination of the pulmonary vasodilator reserve through vasodilator testing using inhaled nitric oxide, intravenous epoprostenol, or intravenous adenosine. A positive response is defined as a reduction in mean pulmonary artery pressure of 10 mm Hg or more to a mean of 40 mm Hg or less, with an unchanged or increased cardiac output. Only positive responders should be given treatment with calcium channel blockers, Dr. Sulica cautioned.

New guidelines from the American College of Chest Physicians stress the limited role of calcium channel blockers, which have been studied for PAH for 2 decades.

The guidelines point to a study of 557 patients with idiopathic PAH who underwent acute pulmonary vasodilator testing, with the 70 positive responders receiving long-term oral calcium channel blocker monotherapy. By 1 year, only 38 (6.8% of the total group) showed a favorable clinical response (Circulation 2005;111:3105–11).

Another recent study found that inappropriate—and potentially harmful—calcium channel blocker use remains common. In a registry that enrolled 1,360 PAH patients, 31% were on calcium channel blockers at the time of referral to a tertiary care center (Eur. Respir. J. 2007 Sept. 5 [Epub doi:10.1183'09031936.00042107]).

In patients who are not responders to vasodilation, the use of calcium channel blockers can decrease cardiac output and systemic vascular resistance, without improving pulmonary artery pressure or pulmonary vascular resistance. Routine vasodilator testing before treatment initiation could eliminate this inappropriate use of calcium channel blockers, Dr. Sulica said.

The prognosis for PAH is still fairly poor. Two-year survival among patients with scleroderma complicated by PAH is only 40%, compared with 80% among those without pulmonary complications (Respir. Care 2006;51:368–81).

The prognosis also is grim for patients in advanced functional classes and those with poor exercise endurance, as well as for those whose hemodynamic findings include elevated right atrial pressure and reduced cardiac index.

“Screening patients with scleroderma can lead to an earlier diagnosis of PAH. Soon we may see if early treatment can improve the long-term prognosis,” Dr. Sulica said.

An echocardiogram shows right atrial and right ventricular enlargement that is impinging on the left side. Courtesy Dr. Terence Trow

NEW YORK — Any patient with suspected pulmonary hypertension must have a thorough work-up, including right heart catheterization, before initiating treatment, Dr. Roxana Sulica said at a meeting sponsored by the Pulmonary Hypertension Association and the University of Michigan.

Because the typical presenting symptoms of pulmonary arterial hypertension (PAH) are subtle and nonspecific, with dyspnea, fatigue, and syncope or near syncope being the most common, a high index of suspicion is needed or the diagnosis may not be made until the disease is advanced and the prognosis is poor, she said.

Risk factors for PAH include underlying connective tissue disease, especially limited scleroderma and mixed connective tissue disease, a family history of PAH, the presence of congenital heart disease, and environmental factors such as exposure to anorexigens.

Clinical assessment of patients with possible PAH includes an electrocardiogram, which may show changes in the right ventricle, including right axis deviation, right atrial enlargement, and right ventricular hypertrophy, Dr. Sulica said.

A chest x-ray may reveal prominent proximal pulmonary arteries, peripheral hypovascularity, and reduced retrosternal air space.

An echocardiogram should then be done, and typical—but not diagnostic—findings on the echocardiogram include right atrial and ventricular enlargement, right ventricular dysfunction, and intraventricular septal flattening.

The definitive diagnosis of PAH can be made only by cardiac catheterization, which can exclude congenital heart disease, measure wedge pressure, and establish the degree of hemodynamic impairment, according to Dr. Sulica, who is director of the pulmonary hypertension program, Beth Israel Medical Center, New York.

The hemodynamic definition of PAH is a mean pulmonary artery pressure greater than 25 mm Hg, with a pulmonary capillary wedge pressure less than 15 mm Hg and a calculated pulmonary vascular resistance greater than 3 Wood units.

Right heart catheterization also permits a determination of the pulmonary vasodilator reserve through vasodilator testing using inhaled nitric oxide, intravenous epoprostenol, or intravenous adenosine. A positive response is defined as a reduction in mean pulmonary artery pressure of 10 mm Hg or more to a mean of 40 mm Hg or less, with an unchanged or increased cardiac output. Only positive responders should be given treatment with calcium channel blockers, Dr. Sulica cautioned.

New guidelines from the American College of Chest Physicians stress the limited role of calcium channel blockers, which have been studied for PAH for 2 decades.

The guidelines point to a study of 557 patients with idiopathic PAH who underwent acute pulmonary vasodilator testing, with the 70 positive responders receiving long-term oral calcium channel blocker monotherapy. By 1 year, only 38 (6.8% of the total group) showed a favorable clinical response (Circulation 2005;111:3105–11).

Another recent study found that inappropriate—and potentially harmful—calcium channel blocker use remains common. In a registry that enrolled 1,360 PAH patients, 31% were on calcium channel blockers at the time of referral to a tertiary care center (Eur. Respir. J. 2007 Sept. 5 [Epub doi:10.1183'09031936.00042107]).

In patients who are not responders to vasodilation, the use of calcium channel blockers can decrease cardiac output and systemic vascular resistance, without improving pulmonary artery pressure or pulmonary vascular resistance. Routine vasodilator testing before treatment initiation could eliminate this inappropriate use of calcium channel blockers, Dr. Sulica said.

The prognosis for PAH is still fairly poor. Two-year survival among patients with scleroderma complicated by PAH is only 40%, compared with 80% among those without pulmonary complications (Respir. Care 2006;51:368–81).

The prognosis also is grim for patients in advanced functional classes and those with poor exercise endurance, as well as for those whose hemodynamic findings include elevated right atrial pressure and reduced cardiac index.

“Screening patients with scleroderma can lead to an earlier diagnosis of PAH. Soon we may see if early treatment can improve the long-term prognosis,” Dr. Sulica said.

An echocardiogram shows right atrial and right ventricular enlargement that is impinging on the left side. Courtesy Dr. Terence Trow

NEW YORK — Any patient with suspected pulmonary hypertension must have a thorough work-up, including right heart catheterization, before initiating treatment, Dr. Roxana Sulica said at a meeting sponsored by the Pulmonary Hypertension Association and the University of Michigan.

Because the typical presenting symptoms of pulmonary arterial hypertension (PAH) are subtle and nonspecific, with dyspnea, fatigue, and syncope or near syncope being the most common, a high index of suspicion is needed or the diagnosis may not be made until the disease is advanced and the prognosis is poor, she said.

Risk factors for PAH include underlying connective tissue disease, especially limited scleroderma and mixed connective tissue disease, a family history of PAH, the presence of congenital heart disease, and environmental factors such as exposure to anorexigens.

Clinical assessment of patients with possible PAH includes an electrocardiogram, which may show changes in the right ventricle, including right axis deviation, right atrial enlargement, and right ventricular hypertrophy, Dr. Sulica said.

A chest x-ray may reveal prominent proximal pulmonary arteries, peripheral hypovascularity, and reduced retrosternal air space.

An echocardiogram should then be done, and typical—but not diagnostic—findings on the echocardiogram include right atrial and ventricular enlargement, right ventricular dysfunction, and intraventricular septal flattening.

The definitive diagnosis of PAH can be made only by cardiac catheterization, which can exclude congenital heart disease, measure wedge pressure, and establish the degree of hemodynamic impairment, according to Dr. Sulica, who is director of the pulmonary hypertension program, Beth Israel Medical Center, New York.

The hemodynamic definition of PAH is a mean pulmonary artery pressure greater than 25 mm Hg, with a pulmonary capillary wedge pressure less than 15 mm Hg and a calculated pulmonary vascular resistance greater than 3 Wood units.

Right heart catheterization also permits a determination of the pulmonary vasodilator reserve through vasodilator testing using inhaled nitric oxide, intravenous epoprostenol, or intravenous adenosine. A positive response is defined as a reduction in mean pulmonary artery pressure of 10 mm Hg or more to a mean of 40 mm Hg or less, with an unchanged or increased cardiac output. Only positive responders should be given treatment with calcium channel blockers, Dr. Sulica cautioned.

New guidelines from the American College of Chest Physicians stress the limited role of calcium channel blockers, which have been studied for PAH for 2 decades.

The guidelines point to a study of 557 patients with idiopathic PAH who underwent acute pulmonary vasodilator testing, with the 70 positive responders receiving long-term oral calcium channel blocker monotherapy. By 1 year, only 38 (6.8% of the total group) showed a favorable clinical response (Circulation 2005;111:3105–11).

Another recent study found that inappropriate—and potentially harmful—calcium channel blocker use remains common. In a registry that enrolled 1,360 PAH patients, 31% were on calcium channel blockers at the time of referral to a tertiary care center (Eur. Respir. J. 2007 Sept. 5 [Epub doi:10.1183'09031936.00042107]).

In patients who are not responders to vasodilation, the use of calcium channel blockers can decrease cardiac output and systemic vascular resistance, without improving pulmonary artery pressure or pulmonary vascular resistance. Routine vasodilator testing before treatment initiation could eliminate this inappropriate use of calcium channel blockers, Dr. Sulica said.

The prognosis for PAH is still fairly poor. Two-year survival among patients with scleroderma complicated by PAH is only 40%, compared with 80% among those without pulmonary complications (Respir. Care 2006;51:368–81).

The prognosis also is grim for patients in advanced functional classes and those with poor exercise endurance, as well as for those whose hemodynamic findings include elevated right atrial pressure and reduced cardiac index.

“Screening patients with scleroderma can lead to an earlier diagnosis of PAH. Soon we may see if early treatment can improve the long-term prognosis,” Dr. Sulica said.

An echocardiogram shows right atrial and right ventricular enlargement that is impinging on the left side. Courtesy Dr. Terence Trow

The American College of Chest Physicians has issued updated clinical practice guidelines for the medical management of pulmonary arterial hypertension that reflect findings from several recent clinical trials as well as the additional drugs that have been approved since the previous guidelines were issued in 2004.

The guidelines include an evidence-based, updated treatment algorithm intended to assist physicians in decision making, as “the paradigm for treatment of pulmonary arterial hypertension (PAH) continues to advance rapidly” (Chest 2007;131:1917–28).

Two studies that demonstrated survival benefits in patients treated with bosentan, which binds to both endothelin receptors (ETA and ETB) provided new data, said lead author Dr. David B. Badesch of the University of Colorado Health Sciences Center, Denver.

In the first study, 169 patients (aged between 13 and 80 years) with class III or IV PAH were treated with bosentan as first-line therapy. Survival was 96% at 12 months and 89% at 24 months, in contrast to predicted survival rates from the earlier National Institutes of Health registry of 69% and 57%, respectively (Eur. Respir. J. 2005;25:244–9).

In the second study, survival in 139 patients treated with bosentan was compared with historical data from 346 patients who had been treated with epoprostenol. Survival estimates after 1 and 2 years were 97% and 91%, respectively, in the bosentan-treated group, and 91% and 84% in the epoprostenol-treated group (Thorax 2005;60:1025–30).

Bosentan also has now been evaluated in children with PAH associated with congenital heart disease or connective tissue disease. In a retrospective study, 86 children were treated with bosentan with or without concomitant epoprostenol or treprostinil. WHO functional class improved in 46% of patients and was unchanged in 44%, and survival estimates at 1 and 2 years were 98% and 91% (J. Am. Coll. Cardiol. 2005;46:697–704).

Another recent study included 245 patients (ranging in age from 12 years to 78 years) who received bosentan, placebo, or one of two doses of a selective ETA endothelin receptor antagonist, sitaxsentan. At week 18, patients receiving the higher dose of sitaxsentan (100 mg/day) had significant improvements on a 6-minute walk test, compared with those receiving placebo. The incidence of elevated transaminases was 6% in the placebo group, 5% in the sitaxsentan low-dose (50 mg/day) group, 3% in the high-dose sitaxsentan group, and 11% in the bosentan group (J. Am. Coll. Cardiol. 2006;47:2049–56).

Sitaxsentan remains investigational in the United States, but has been approved for use in Europe and Canada.

A second selective ETA endothelin receptor antagonist, ambrisentan, was evaluated in a double-blind, dose-ranging study that included 64 adult patients with PAH. They were randomized to receive 1 mg, 2.5 mg, 5 mg, or 10 mg of ambrisentan orally once daily for 12 weeks. The 6-minute walk test improved significantly for all groups, with a mean increase from baseline of 36.1 meters. Improvements also were seen in WHO functional class, Borg dyspnea index, and cardiac index (J. Am. Coll. Cardiol. 2005;46:529–35).

This drug was recently approved for class II and class III PAH in the United States.

The phosphodiesterase inhibitor sildenafil also is now approved for the treatment of all classes of PAH in a dosage of 20 mg three times daily. The drug was evaluated in a double-blind study that randomized 278 patients (mean age 50 years) to placebo or 20, 40, or 80 mg three times daily for 12 weeks.

In summarizing the treatment options, the authors noted that for patients in functional class II, the only current recommended drugs are sildenafil and subcutaneous and intravenous treprostinil, and suggested that sildenafil may be the first choice for most patients because of ease of administration and relative efficacy.

For patients in functional class III, five drugs are available: bosentan, sildenafil, intravenous epopro-stenol, inhaled iloprost, and subcutaneous or intravenous treprostinil. For those with early class III disease, oral bosentan or sildenafil may be used, with the choice reflecting relative toxicities. For patients with more advanced disease, prostanoid therapy may be needed.

All the available agents are approved for patients with class IV PAH. However, the authors wrote, “[we] strongly encourage IV epoprostenol as the treatment of choice for these most critically ill patients. IV epoprostenol has a rapid and predictable onset of action, and most experts are familiar with how to titrate this drug in the acute setting.”

In conclusion, they also strongly recommended that patients with PAH be referred to specialized centers because of the complexity of the diagnostic and therapeutic considerations involved.

The American College of Chest Physicians has issued updated clinical practice guidelines for the medical management of pulmonary arterial hypertension that reflect findings from several recent clinical trials as well as the additional drugs that have been approved since the previous guidelines were issued in 2004.

The guidelines include an evidence-based, updated treatment algorithm intended to assist physicians in decision making, as “the paradigm for treatment of pulmonary arterial hypertension (PAH) continues to advance rapidly” (Chest 2007;131:1917–28).

Two studies that demonstrated survival benefits in patients treated with bosentan, which binds to both endothelin receptors (ETA and ETB) provided new data, said lead author Dr. David B. Badesch of the University of Colorado Health Sciences Center, Denver.

In the first study, 169 patients (aged between 13 and 80 years) with class III or IV PAH were treated with bosentan as first-line therapy. Survival was 96% at 12 months and 89% at 24 months, in contrast to predicted survival rates from the earlier National Institutes of Health registry of 69% and 57%, respectively (Eur. Respir. J. 2005;25:244–9).

In the second study, survival in 139 patients treated with bosentan was compared with historical data from 346 patients who had been treated with epoprostenol. Survival estimates after 1 and 2 years were 97% and 91%, respectively, in the bosentan-treated group, and 91% and 84% in the epoprostenol-treated group (Thorax 2005;60:1025–30).

Bosentan also has now been evaluated in children with PAH associated with congenital heart disease or connective tissue disease. In a retrospective study, 86 children were treated with bosentan with or without concomitant epoprostenol or treprostinil. WHO functional class improved in 46% of patients and was unchanged in 44%, and survival estimates at 1 and 2 years were 98% and 91% (J. Am. Coll. Cardiol. 2005;46:697–704).

Another recent study included 245 patients (ranging in age from 12 years to 78 years) who received bosentan, placebo, or one of two doses of a selective ETA endothelin receptor antagonist, sitaxsentan. At week 18, patients receiving the higher dose of sitaxsentan (100 mg/day) had significant improvements on a 6-minute walk test, compared with those receiving placebo. The incidence of elevated transaminases was 6% in the placebo group, 5% in the sitaxsentan low-dose (50 mg/day) group, 3% in the high-dose sitaxsentan group, and 11% in the bosentan group (J. Am. Coll. Cardiol. 2006;47:2049–56).

Sitaxsentan remains investigational in the United States, but has been approved for use in Europe and Canada.

A second selective ETA endothelin receptor antagonist, ambrisentan, was evaluated in a double-blind, dose-ranging study that included 64 adult patients with PAH. They were randomized to receive 1 mg, 2.5 mg, 5 mg, or 10 mg of ambrisentan orally once daily for 12 weeks. The 6-minute walk test improved significantly for all groups, with a mean increase from baseline of 36.1 meters. Improvements also were seen in WHO functional class, Borg dyspnea index, and cardiac index (J. Am. Coll. Cardiol. 2005;46:529–35).

This drug was recently approved for class II and class III PAH in the United States.

The phosphodiesterase inhibitor sildenafil also is now approved for the treatment of all classes of PAH in a dosage of 20 mg three times daily. The drug was evaluated in a double-blind study that randomized 278 patients (mean age 50 years) to placebo or 20, 40, or 80 mg three times daily for 12 weeks.

In summarizing the treatment options, the authors noted that for patients in functional class II, the only current recommended drugs are sildenafil and subcutaneous and intravenous treprostinil, and suggested that sildenafil may be the first choice for most patients because of ease of administration and relative efficacy.

For patients in functional class III, five drugs are available: bosentan, sildenafil, intravenous epopro-stenol, inhaled iloprost, and subcutaneous or intravenous treprostinil. For those with early class III disease, oral bosentan or sildenafil may be used, with the choice reflecting relative toxicities. For patients with more advanced disease, prostanoid therapy may be needed.

All the available agents are approved for patients with class IV PAH. However, the authors wrote, “[we] strongly encourage IV epoprostenol as the treatment of choice for these most critically ill patients. IV epoprostenol has a rapid and predictable onset of action, and most experts are familiar with how to titrate this drug in the acute setting.”

In conclusion, they also strongly recommended that patients with PAH be referred to specialized centers because of the complexity of the diagnostic and therapeutic considerations involved.

The American College of Chest Physicians has issued updated clinical practice guidelines for the medical management of pulmonary arterial hypertension that reflect findings from several recent clinical trials as well as the additional drugs that have been approved since the previous guidelines were issued in 2004.

The guidelines include an evidence-based, updated treatment algorithm intended to assist physicians in decision making, as “the paradigm for treatment of pulmonary arterial hypertension (PAH) continues to advance rapidly” (Chest 2007;131:1917–28).

Two studies that demonstrated survival benefits in patients treated with bosentan, which binds to both endothelin receptors (ETA and ETB) provided new data, said lead author Dr. David B. Badesch of the University of Colorado Health Sciences Center, Denver.

In the first study, 169 patients (aged between 13 and 80 years) with class III or IV PAH were treated with bosentan as first-line therapy. Survival was 96% at 12 months and 89% at 24 months, in contrast to predicted survival rates from the earlier National Institutes of Health registry of 69% and 57%, respectively (Eur. Respir. J. 2005;25:244–9).

In the second study, survival in 139 patients treated with bosentan was compared with historical data from 346 patients who had been treated with epoprostenol. Survival estimates after 1 and 2 years were 97% and 91%, respectively, in the bosentan-treated group, and 91% and 84% in the epoprostenol-treated group (Thorax 2005;60:1025–30).

Bosentan also has now been evaluated in children with PAH associated with congenital heart disease or connective tissue disease. In a retrospective study, 86 children were treated with bosentan with or without concomitant epoprostenol or treprostinil. WHO functional class improved in 46% of patients and was unchanged in 44%, and survival estimates at 1 and 2 years were 98% and 91% (J. Am. Coll. Cardiol. 2005;46:697–704).

Another recent study included 245 patients (ranging in age from 12 years to 78 years) who received bosentan, placebo, or one of two doses of a selective ETA endothelin receptor antagonist, sitaxsentan. At week 18, patients receiving the higher dose of sitaxsentan (100 mg/day) had significant improvements on a 6-minute walk test, compared with those receiving placebo. The incidence of elevated transaminases was 6% in the placebo group, 5% in the sitaxsentan low-dose (50 mg/day) group, 3% in the high-dose sitaxsentan group, and 11% in the bosentan group (J. Am. Coll. Cardiol. 2006;47:2049–56).

Sitaxsentan remains investigational in the United States, but has been approved for use in Europe and Canada.

A second selective ETA endothelin receptor antagonist, ambrisentan, was evaluated in a double-blind, dose-ranging study that included 64 adult patients with PAH. They were randomized to receive 1 mg, 2.5 mg, 5 mg, or 10 mg of ambrisentan orally once daily for 12 weeks. The 6-minute walk test improved significantly for all groups, with a mean increase from baseline of 36.1 meters. Improvements also were seen in WHO functional class, Borg dyspnea index, and cardiac index (J. Am. Coll. Cardiol. 2005;46:529–35).

This drug was recently approved for class II and class III PAH in the United States.

The phosphodiesterase inhibitor sildenafil also is now approved for the treatment of all classes of PAH in a dosage of 20 mg three times daily. The drug was evaluated in a double-blind study that randomized 278 patients (mean age 50 years) to placebo or 20, 40, or 80 mg three times daily for 12 weeks.

In summarizing the treatment options, the authors noted that for patients in functional class II, the only current recommended drugs are sildenafil and subcutaneous and intravenous treprostinil, and suggested that sildenafil may be the first choice for most patients because of ease of administration and relative efficacy.

For patients in functional class III, five drugs are available: bosentan, sildenafil, intravenous epopro-stenol, inhaled iloprost, and subcutaneous or intravenous treprostinil. For those with early class III disease, oral bosentan or sildenafil may be used, with the choice reflecting relative toxicities. For patients with more advanced disease, prostanoid therapy may be needed.

All the available agents are approved for patients with class IV PAH. However, the authors wrote, “[we] strongly encourage IV epoprostenol as the treatment of choice for these most critically ill patients. IV epoprostenol has a rapid and predictable onset of action, and most experts are familiar with how to titrate this drug in the acute setting.”

In conclusion, they also strongly recommended that patients with PAH be referred to specialized centers because of the complexity of the diagnostic and therapeutic considerations involved.