Associated Professional Sleep Societies (APSS): Sleep 2012

BOSTON – Treatment with continuous positive airway pressure does double duty in patients with obstructive sleep apnea by improving their mood while promoting restful sleep, Dr. Charles Bae reported at the annual meeting of the Associated Professional Sleep Societies.

In a retrospective study of 769 adults with OSA, the Cleveland Clinic neurologist and his colleagues observed a significant decrease in depressive symptoms as measured by the Patient Health Questionnaire 9 (PHQ-9) among patients who used a CPAP device.

"A number of studies have confirmed an association between obstructive sleep apnea and depressive symptoms, but until now none have looked specifically at the link between CPAP and symptom severity as measured by PHQ-9," Dr. Bae said in an interview. "Our goal was to assess the impact of CPAP therapy on patient mood by measuring the change in depressive symptoms following treatment."

Toward this end, the investigators reviewed data for all of the adult patients (18 years or older) with OSA seen at the Cleveland Clinic Sleep Disorders Center from January 2008 to July 2011. Patients who met study criteria had been treated with CPAP and had at least two outpatient visits (one before and one within 30 days after initiating CPAP), had completed the PHQ-9 questionnaire, and had a pre-CPAP score on the questionnaire of at least 5, Dr. Bae said.

Of the 769 study patients (mean age, 51.8 years), 654 were characterized as adherent to CPAP therapy based on self-reported use of the device 4 or more hours per night; the remaining 115 used the device either inconsistently or for fewer than 4 hours per night and were considered nonadherent. The baseline PHQ-9 scores for patients in the adherent and nonadherent groups were similar, at 11.2 and 11.8, respectively. Significant decreases from baseline in PHQ-9 scores were observed in both groups, but the difference was "significantly more robust" in the adherent group at 3.8, compared with 2.0 in the nonadherent group, Dr. Bae reported.

The results were even more robust among patients who had reported sleepiness at baseline, according to Dr. Bae. Specifically, in the patients who had a minimum score of 10 on the Epworth Sleepiness Scale prior to CPAP, ESS scores decreased by 4.0 in the adherent group vs. 2.8 in the nonadherent group, he said. In the CPAP-adherent group, there was a significant difference between sleepy vs. nonsleepy patients in their average decrease in PHQ-9 score. "The PHQ-9 score dropped 4.3 points among patients whose [ESS] score was at least 10 at baseline, compared with 3.1 points among those whose score was less than 10," he said.

Marital status was also examined as a covariate in the multiple regression model and appeared to have an effect. The mean PHQ-9 score decrease among the 475 married patients after CPAP was 4.0, compared with 3.0 among single patients and 2.3 among divorced patients, Dr. Bae said, noting that the difference between married and divorced patients was significant.

While the specific mechanisms contributing to the mood improvements associated with CPAP treatment in OSA patients can’t be ascertained from a retrospective study, the findings are fairly intuitive, according to Dr. Bae. When people sleep better, "a lot of things look better," he said.

Dr. Bae disclosed no relevant conflicts of interest.

BOSTON – Treatment with continuous positive airway pressure does double duty in patients with obstructive sleep apnea by improving their mood while promoting restful sleep, Dr. Charles Bae reported at the annual meeting of the Associated Professional Sleep Societies.

In a retrospective study of 769 adults with OSA, the Cleveland Clinic neurologist and his colleagues observed a significant decrease in depressive symptoms as measured by the Patient Health Questionnaire 9 (PHQ-9) among patients who used a CPAP device.

"A number of studies have confirmed an association between obstructive sleep apnea and depressive symptoms, but until now none have looked specifically at the link between CPAP and symptom severity as measured by PHQ-9," Dr. Bae said in an interview. "Our goal was to assess the impact of CPAP therapy on patient mood by measuring the change in depressive symptoms following treatment."

Toward this end, the investigators reviewed data for all of the adult patients (18 years or older) with OSA seen at the Cleveland Clinic Sleep Disorders Center from January 2008 to July 2011. Patients who met study criteria had been treated with CPAP and had at least two outpatient visits (one before and one within 30 days after initiating CPAP), had completed the PHQ-9 questionnaire, and had a pre-CPAP score on the questionnaire of at least 5, Dr. Bae said.

Of the 769 study patients (mean age, 51.8 years), 654 were characterized as adherent to CPAP therapy based on self-reported use of the device 4 or more hours per night; the remaining 115 used the device either inconsistently or for fewer than 4 hours per night and were considered nonadherent. The baseline PHQ-9 scores for patients in the adherent and nonadherent groups were similar, at 11.2 and 11.8, respectively. Significant decreases from baseline in PHQ-9 scores were observed in both groups, but the difference was "significantly more robust" in the adherent group at 3.8, compared with 2.0 in the nonadherent group, Dr. Bae reported.

The results were even more robust among patients who had reported sleepiness at baseline, according to Dr. Bae. Specifically, in the patients who had a minimum score of 10 on the Epworth Sleepiness Scale prior to CPAP, ESS scores decreased by 4.0 in the adherent group vs. 2.8 in the nonadherent group, he said. In the CPAP-adherent group, there was a significant difference between sleepy vs. nonsleepy patients in their average decrease in PHQ-9 score. "The PHQ-9 score dropped 4.3 points among patients whose [ESS] score was at least 10 at baseline, compared with 3.1 points among those whose score was less than 10," he said.

Marital status was also examined as a covariate in the multiple regression model and appeared to have an effect. The mean PHQ-9 score decrease among the 475 married patients after CPAP was 4.0, compared with 3.0 among single patients and 2.3 among divorced patients, Dr. Bae said, noting that the difference between married and divorced patients was significant.

While the specific mechanisms contributing to the mood improvements associated with CPAP treatment in OSA patients can’t be ascertained from a retrospective study, the findings are fairly intuitive, according to Dr. Bae. When people sleep better, "a lot of things look better," he said.

Dr. Bae disclosed no relevant conflicts of interest.

BOSTON – Treatment with continuous positive airway pressure does double duty in patients with obstructive sleep apnea by improving their mood while promoting restful sleep, Dr. Charles Bae reported at the annual meeting of the Associated Professional Sleep Societies.

In a retrospective study of 769 adults with OSA, the Cleveland Clinic neurologist and his colleagues observed a significant decrease in depressive symptoms as measured by the Patient Health Questionnaire 9 (PHQ-9) among patients who used a CPAP device.

"A number of studies have confirmed an association between obstructive sleep apnea and depressive symptoms, but until now none have looked specifically at the link between CPAP and symptom severity as measured by PHQ-9," Dr. Bae said in an interview. "Our goal was to assess the impact of CPAP therapy on patient mood by measuring the change in depressive symptoms following treatment."

Toward this end, the investigators reviewed data for all of the adult patients (18 years or older) with OSA seen at the Cleveland Clinic Sleep Disorders Center from January 2008 to July 2011. Patients who met study criteria had been treated with CPAP and had at least two outpatient visits (one before and one within 30 days after initiating CPAP), had completed the PHQ-9 questionnaire, and had a pre-CPAP score on the questionnaire of at least 5, Dr. Bae said.

Of the 769 study patients (mean age, 51.8 years), 654 were characterized as adherent to CPAP therapy based on self-reported use of the device 4 or more hours per night; the remaining 115 used the device either inconsistently or for fewer than 4 hours per night and were considered nonadherent. The baseline PHQ-9 scores for patients in the adherent and nonadherent groups were similar, at 11.2 and 11.8, respectively. Significant decreases from baseline in PHQ-9 scores were observed in both groups, but the difference was "significantly more robust" in the adherent group at 3.8, compared with 2.0 in the nonadherent group, Dr. Bae reported.

The results were even more robust among patients who had reported sleepiness at baseline, according to Dr. Bae. Specifically, in the patients who had a minimum score of 10 on the Epworth Sleepiness Scale prior to CPAP, ESS scores decreased by 4.0 in the adherent group vs. 2.8 in the nonadherent group, he said. In the CPAP-adherent group, there was a significant difference between sleepy vs. nonsleepy patients in their average decrease in PHQ-9 score. "The PHQ-9 score dropped 4.3 points among patients whose [ESS] score was at least 10 at baseline, compared with 3.1 points among those whose score was less than 10," he said.

Marital status was also examined as a covariate in the multiple regression model and appeared to have an effect. The mean PHQ-9 score decrease among the 475 married patients after CPAP was 4.0, compared with 3.0 among single patients and 2.3 among divorced patients, Dr. Bae said, noting that the difference between married and divorced patients was significant.

While the specific mechanisms contributing to the mood improvements associated with CPAP treatment in OSA patients can’t be ascertained from a retrospective study, the findings are fairly intuitive, according to Dr. Bae. When people sleep better, "a lot of things look better," he said.

Dr. Bae disclosed no relevant conflicts of interest.

BOSTON – Adaptive servoventilation is more reliably effective than continuous positive airway pressure is for the prolonged treatment of complex sleep apnea, a study has shown.

Prior studies have shown that the adaptive ventilatory support method, which continuously monitors and analyzes a patient’s breathing pattern and adds variable amounts of inspiratory pressure support to low levels of background expiratory positive airway pressure as needed, is initially more effective than is continuous positive airway pressure (CPAP) in complex sleep apnea patients. But sustained efficacy over time has not been established, according to Dr. Timothy I. Morgenthaler of the Center for Sleep Medicine at the Mayo Clinic in Rochester, Minn.

"The concern is that residual central breathing events may resolve over time with CPAP therapy, which is less expensive than adaptive servoventilation [ASV] and therefore may be a better option," he said at the annual meeting of the Associated Professional Sleep Societies.

To evaluate the longer-term efficacy of ASV relative to CPAP in individuals with complex sleep apnea syndrome (CSAS), Dr. Morgenthaler and his colleagues conducted a multicenter, prospective trial of 66 patients with CSAS, defined as those meeting the criteria for obstructive sleep apnea on diagnostic polysomnography who also had a central apnea index (CAI) score of 10 or higher while on optimal CPAP. The participants were randomized to treatment with either CPAP (n = 33) or ASV (n = 33), both titrated to optimal settings. Clinical and polysomnographic measures were collected at baseline and after 90 days of therapy, he said.

In addition to having a diagnosis of CSAS, eligible patients were older than 18 years and were naive to positive airway pressure treatment. The mean age of the study participants was 59.2 years, and the mean body mass index was 35.0 kg/m², with no between-group differences. Additionally, about 9% of the patients had congestive heart failure and 13.6% reported chronic opiate use, Dr. Morgenthaler reported.

At baseline, the mean apnea-hypopnea index (AHI) and CAI scores were 37.7 and 3.2, respectively. After second-night treatment titration, the AHI scores were 4.7 in the ASV group vs. 14.1 in the CPAP group, and the respective CAI scores were 1.1 and 8.8, said Dr. Morgenthaler. At 90 days, the AHI for the ASV group was 4.4, compared with 9.9 for CPAP, and the respective CAI scores were 0.7 and 4.8, he said.

"In the intention-to-treat analysis, treatment was successful [defined as an AHI of less than 10] in 89.7% of the adaptive servoventilation group," while only 64.5% of the CPAP patients attained similar success, Dr. Morgenthaler stated, noting that there were no significant differences between the groups with respect to compliance, Epworth Sleepiness Scale (ESS) changes, or sleep apnea quality of life index (SAQLI) scores.

Although significantly more ASV patients showed evidence of treatment efficacy based on polysomnographic measures than did CPAP patients, "there were no similar symptomatic differences between the groups," Dr. Morgenthaler acknowledged. It is possible, but yet to be determined, that ASV-induced improvements on polysomnography will translate into other positive health outcomes, such as maximal suppression of Cheyne-Stokes respiration and central sleep apnea (CSR-CSA), as well as improvement in brain natriuretic peptide, in patients with heart failure, he said.

Dr. Morgenthaler disclosed that this study was supported by a grant from ResMed, the manufacturer of the ASV device used in the investigation.

BOSTON – Adaptive servoventilation is more reliably effective than continuous positive airway pressure is for the prolonged treatment of complex sleep apnea, a study has shown.

Prior studies have shown that the adaptive ventilatory support method, which continuously monitors and analyzes a patient’s breathing pattern and adds variable amounts of inspiratory pressure support to low levels of background expiratory positive airway pressure as needed, is initially more effective than is continuous positive airway pressure (CPAP) in complex sleep apnea patients. But sustained efficacy over time has not been established, according to Dr. Timothy I. Morgenthaler of the Center for Sleep Medicine at the Mayo Clinic in Rochester, Minn.

"The concern is that residual central breathing events may resolve over time with CPAP therapy, which is less expensive than adaptive servoventilation [ASV] and therefore may be a better option," he said at the annual meeting of the Associated Professional Sleep Societies.

To evaluate the longer-term efficacy of ASV relative to CPAP in individuals with complex sleep apnea syndrome (CSAS), Dr. Morgenthaler and his colleagues conducted a multicenter, prospective trial of 66 patients with CSAS, defined as those meeting the criteria for obstructive sleep apnea on diagnostic polysomnography who also had a central apnea index (CAI) score of 10 or higher while on optimal CPAP. The participants were randomized to treatment with either CPAP (n = 33) or ASV (n = 33), both titrated to optimal settings. Clinical and polysomnographic measures were collected at baseline and after 90 days of therapy, he said.

In addition to having a diagnosis of CSAS, eligible patients were older than 18 years and were naive to positive airway pressure treatment. The mean age of the study participants was 59.2 years, and the mean body mass index was 35.0 kg/m², with no between-group differences. Additionally, about 9% of the patients had congestive heart failure and 13.6% reported chronic opiate use, Dr. Morgenthaler reported.

At baseline, the mean apnea-hypopnea index (AHI) and CAI scores were 37.7 and 3.2, respectively. After second-night treatment titration, the AHI scores were 4.7 in the ASV group vs. 14.1 in the CPAP group, and the respective CAI scores were 1.1 and 8.8, said Dr. Morgenthaler. At 90 days, the AHI for the ASV group was 4.4, compared with 9.9 for CPAP, and the respective CAI scores were 0.7 and 4.8, he said.

"In the intention-to-treat analysis, treatment was successful [defined as an AHI of less than 10] in 89.7% of the adaptive servoventilation group," while only 64.5% of the CPAP patients attained similar success, Dr. Morgenthaler stated, noting that there were no significant differences between the groups with respect to compliance, Epworth Sleepiness Scale (ESS) changes, or sleep apnea quality of life index (SAQLI) scores.

Although significantly more ASV patients showed evidence of treatment efficacy based on polysomnographic measures than did CPAP patients, "there were no similar symptomatic differences between the groups," Dr. Morgenthaler acknowledged. It is possible, but yet to be determined, that ASV-induced improvements on polysomnography will translate into other positive health outcomes, such as maximal suppression of Cheyne-Stokes respiration and central sleep apnea (CSR-CSA), as well as improvement in brain natriuretic peptide, in patients with heart failure, he said.

Dr. Morgenthaler disclosed that this study was supported by a grant from ResMed, the manufacturer of the ASV device used in the investigation.

BOSTON – Adaptive servoventilation is more reliably effective than continuous positive airway pressure is for the prolonged treatment of complex sleep apnea, a study has shown.

Prior studies have shown that the adaptive ventilatory support method, which continuously monitors and analyzes a patient’s breathing pattern and adds variable amounts of inspiratory pressure support to low levels of background expiratory positive airway pressure as needed, is initially more effective than is continuous positive airway pressure (CPAP) in complex sleep apnea patients. But sustained efficacy over time has not been established, according to Dr. Timothy I. Morgenthaler of the Center for Sleep Medicine at the Mayo Clinic in Rochester, Minn.

"The concern is that residual central breathing events may resolve over time with CPAP therapy, which is less expensive than adaptive servoventilation [ASV] and therefore may be a better option," he said at the annual meeting of the Associated Professional Sleep Societies.

To evaluate the longer-term efficacy of ASV relative to CPAP in individuals with complex sleep apnea syndrome (CSAS), Dr. Morgenthaler and his colleagues conducted a multicenter, prospective trial of 66 patients with CSAS, defined as those meeting the criteria for obstructive sleep apnea on diagnostic polysomnography who also had a central apnea index (CAI) score of 10 or higher while on optimal CPAP. The participants were randomized to treatment with either CPAP (n = 33) or ASV (n = 33), both titrated to optimal settings. Clinical and polysomnographic measures were collected at baseline and after 90 days of therapy, he said.

In addition to having a diagnosis of CSAS, eligible patients were older than 18 years and were naive to positive airway pressure treatment. The mean age of the study participants was 59.2 years, and the mean body mass index was 35.0 kg/m², with no between-group differences. Additionally, about 9% of the patients had congestive heart failure and 13.6% reported chronic opiate use, Dr. Morgenthaler reported.

At baseline, the mean apnea-hypopnea index (AHI) and CAI scores were 37.7 and 3.2, respectively. After second-night treatment titration, the AHI scores were 4.7 in the ASV group vs. 14.1 in the CPAP group, and the respective CAI scores were 1.1 and 8.8, said Dr. Morgenthaler. At 90 days, the AHI for the ASV group was 4.4, compared with 9.9 for CPAP, and the respective CAI scores were 0.7 and 4.8, he said.

"In the intention-to-treat analysis, treatment was successful [defined as an AHI of less than 10] in 89.7% of the adaptive servoventilation group," while only 64.5% of the CPAP patients attained similar success, Dr. Morgenthaler stated, noting that there were no significant differences between the groups with respect to compliance, Epworth Sleepiness Scale (ESS) changes, or sleep apnea quality of life index (SAQLI) scores.

Although significantly more ASV patients showed evidence of treatment efficacy based on polysomnographic measures than did CPAP patients, "there were no similar symptomatic differences between the groups," Dr. Morgenthaler acknowledged. It is possible, but yet to be determined, that ASV-induced improvements on polysomnography will translate into other positive health outcomes, such as maximal suppression of Cheyne-Stokes respiration and central sleep apnea (CSR-CSA), as well as improvement in brain natriuretic peptide, in patients with heart failure, he said.

Dr. Morgenthaler disclosed that this study was supported by a grant from ResMed, the manufacturer of the ASV device used in the investigation.

BOSTON – The promise of shorter time to sleep, longer sleep duration, and fewer side effects associated with the experimental sleep drug suvorexant has sleep medicine clinicians and their patients eagerly anticipating the approval of the first-in-class agent.

Suvorexant’s mechanism of action in targeting the orexin system, which promotes wakefulness, sets it apart from some of the currently available sleep medications, according to Dr. Michael Thorpy, director of the Sleep-Wake Disorders Center at the Montefiore Medical Center in New York. "The effects of the new drug are fairly localized because it targets a more specific receptor than the GABA agonists, which have a more generalized effect and thus more side effects." Importantly, suvorexant does not depress the central nervous system or respiratory function and thus may be a good option for patients with suspected sleep apnea, he noted.

Two pivotal phase III studies of the drug were presented at the meeting. Both randomized, double-blind, placebo-controlled trials were 3-month studies designed to confirm the safety and efficacy outcomes of an initial 4-week proof-of-concept study in patients with primary insomnia. Each trial evaluated two dose regimens: 40 mg for patients 18-64 years and 30 mg for those older than 65 years in the first trial; and 20 mg and 15 mg, respectively, in the second trial, explained Dr. Andrew D. Krystal, professor of psychiatry and behavioral sciences at Duke University Medical Center, Durham, N.C., and an investigator for both trials.*

Efficacy measures were patient self-reported time to sleep onset (sTSO), self-reported total sleep time (sTST), and self-reported wake after sleep onset (sWASO), as well as the polysomnographic end points of latency to onset of persistent sleep (LPS) and wake after persistent sleep onset (WASO), he said.

In the first trial, which randomized 1,021 patients, suvorexant at 40 mg and 30 mg was significantly better than placebo was in all end points at 1 and 3 months, Dr. Krystal reported. Specifically, at 3 months, the mean differences from placebo in change from baseline were an increase of 19.7 minutes for sTST, and decreases of 8.4 minutes for sTSO, 6.9 minutes for sWASO, 9.4 minutes for LPS, and 22.9 minutes for WASO.

Similarly, significant changes were observed in the second trial, with the exception of the drug’s effect on LPS at 3 months, which was not significant – a finding the investigators attributed to high placebo response, Dr. Krystal said. In this study, the mean differences from placebo in change from baseline at 3 months were an increase of 25.1 minutes for sTST and decreases of 13.2 minutes for sTSO, 8.9 minutes for sWASO, 3.6 minutes for LPS, and 29.4 minutes for WASO.

Both studies also measured the time it took patients to fall into continuous sleep and the time they spent awake during the first night of use, comparing the results with those reported before starting the drug, Dr. Krystal said. In the first trial, "patients [taking suvorexant] entered into continuous sleep 30.6 minutes faster and spent 58.0 fewer minutes awake during the night, compared to before they started taking the drug," he said. Similarly, in the second trial, the suvorexant patients entered into continuous sleep 34.7 minutes faster and spent 63.3 fewer minutes awake during the night, compared with before they started the drug. The respective placebo group improvements in the two trials were 13.0-20.3 minutes and 19.6-21.3 minutes, he said.

Both dose regimens of suvorexant in the trials were well tolerated with no evidence of clinically important rebound or withdrawal on discontinuation, Dr. Krystal reported. "Over the 3-month period, the overall incidence of adverse events in the higher-dose groups was 25.1%, compared with 13.8% for the placebo group in the first trial, and 22.2%, compared with 16.4%, in the second, and no serious drug-related adverse events were observed in either trial with the high dose of the drug," he said. The most common adverse events that occurred at least 5% more frequently in the high dose suvorexant group, compared with placebo, were sleepiness and headache, he noted.

There were no significant next-day objective residual effects associated with the study drug relative to placebo, as measured by the Digit Symbol Substitution Test, Dr. Krystal said. At 3 months, the incidence of next day sleepiness was about 10% in high-dose suvorexant patients and 3% among placebo patients.

While the drug was well tolerated in two short-term trials, "longer trials will be more telling," Dr. Thorpy said. "The orexin inhibitors were first investigated because of their effect on metabolism, so there is a possibility that, in the longer-term studies, we might see weight changes or other metabolic effects."

Although suvorexant, which has not yet been submitted to the Food and Drug Administration for approval, promises to be a valuable addition to the sleep therapy arsenal, "medications in the management of insomnia can only go so far," Dr. Thorpy stressed. "Some of the more important therapies are behavioral. No sleep pill will work with someone who has bad sleep hygiene or sleep/wake cycle issues. For optimal efficacy, all medications should be used in combination with behavioral interventions."

Dr. Krystal is a consultant to Merck, which funded both trials. Dr. Thorpy said that he had no relevant conflicts of interest.

* Correction, 6/21/12: An earlier version of this story implied that Dr. Andrew D. Krystal presented the results of the two trials described in the article. He was an investigator for the studies, but did not present them.

BOSTON – The promise of shorter time to sleep, longer sleep duration, and fewer side effects associated with the experimental sleep drug suvorexant has sleep medicine clinicians and their patients eagerly anticipating the approval of the first-in-class agent.

Suvorexant’s mechanism of action in targeting the orexin system, which promotes wakefulness, sets it apart from some of the currently available sleep medications, according to Dr. Michael Thorpy, director of the Sleep-Wake Disorders Center at the Montefiore Medical Center in New York. "The effects of the new drug are fairly localized because it targets a more specific receptor than the GABA agonists, which have a more generalized effect and thus more side effects." Importantly, suvorexant does not depress the central nervous system or respiratory function and thus may be a good option for patients with suspected sleep apnea, he noted.

Two pivotal phase III studies of the drug were presented at the meeting. Both randomized, double-blind, placebo-controlled trials were 3-month studies designed to confirm the safety and efficacy outcomes of an initial 4-week proof-of-concept study in patients with primary insomnia. Each trial evaluated two dose regimens: 40 mg for patients 18-64 years and 30 mg for those older than 65 years in the first trial; and 20 mg and 15 mg, respectively, in the second trial, explained Dr. Andrew D. Krystal, professor of psychiatry and behavioral sciences at Duke University Medical Center, Durham, N.C., and an investigator for both trials.*

Efficacy measures were patient self-reported time to sleep onset (sTSO), self-reported total sleep time (sTST), and self-reported wake after sleep onset (sWASO), as well as the polysomnographic end points of latency to onset of persistent sleep (LPS) and wake after persistent sleep onset (WASO), he said.

In the first trial, which randomized 1,021 patients, suvorexant at 40 mg and 30 mg was significantly better than placebo was in all end points at 1 and 3 months, Dr. Krystal reported. Specifically, at 3 months, the mean differences from placebo in change from baseline were an increase of 19.7 minutes for sTST, and decreases of 8.4 minutes for sTSO, 6.9 minutes for sWASO, 9.4 minutes for LPS, and 22.9 minutes for WASO.

Similarly, significant changes were observed in the second trial, with the exception of the drug’s effect on LPS at 3 months, which was not significant – a finding the investigators attributed to high placebo response, Dr. Krystal said. In this study, the mean differences from placebo in change from baseline at 3 months were an increase of 25.1 minutes for sTST and decreases of 13.2 minutes for sTSO, 8.9 minutes for sWASO, 3.6 minutes for LPS, and 29.4 minutes for WASO.

Both studies also measured the time it took patients to fall into continuous sleep and the time they spent awake during the first night of use, comparing the results with those reported before starting the drug, Dr. Krystal said. In the first trial, "patients [taking suvorexant] entered into continuous sleep 30.6 minutes faster and spent 58.0 fewer minutes awake during the night, compared to before they started taking the drug," he said. Similarly, in the second trial, the suvorexant patients entered into continuous sleep 34.7 minutes faster and spent 63.3 fewer minutes awake during the night, compared with before they started the drug. The respective placebo group improvements in the two trials were 13.0-20.3 minutes and 19.6-21.3 minutes, he said.

Both dose regimens of suvorexant in the trials were well tolerated with no evidence of clinically important rebound or withdrawal on discontinuation, Dr. Krystal reported. "Over the 3-month period, the overall incidence of adverse events in the higher-dose groups was 25.1%, compared with 13.8% for the placebo group in the first trial, and 22.2%, compared with 16.4%, in the second, and no serious drug-related adverse events were observed in either trial with the high dose of the drug," he said. The most common adverse events that occurred at least 5% more frequently in the high dose suvorexant group, compared with placebo, were sleepiness and headache, he noted.

There were no significant next-day objective residual effects associated with the study drug relative to placebo, as measured by the Digit Symbol Substitution Test, Dr. Krystal said. At 3 months, the incidence of next day sleepiness was about 10% in high-dose suvorexant patients and 3% among placebo patients.

While the drug was well tolerated in two short-term trials, "longer trials will be more telling," Dr. Thorpy said. "The orexin inhibitors were first investigated because of their effect on metabolism, so there is a possibility that, in the longer-term studies, we might see weight changes or other metabolic effects."

Although suvorexant, which has not yet been submitted to the Food and Drug Administration for approval, promises to be a valuable addition to the sleep therapy arsenal, "medications in the management of insomnia can only go so far," Dr. Thorpy stressed. "Some of the more important therapies are behavioral. No sleep pill will work with someone who has bad sleep hygiene or sleep/wake cycle issues. For optimal efficacy, all medications should be used in combination with behavioral interventions."

Dr. Krystal is a consultant to Merck, which funded both trials. Dr. Thorpy said that he had no relevant conflicts of interest.

* Correction, 6/21/12: An earlier version of this story implied that Dr. Andrew D. Krystal presented the results of the two trials described in the article. He was an investigator for the studies, but did not present them.

BOSTON – The promise of shorter time to sleep, longer sleep duration, and fewer side effects associated with the experimental sleep drug suvorexant has sleep medicine clinicians and their patients eagerly anticipating the approval of the first-in-class agent.

Suvorexant’s mechanism of action in targeting the orexin system, which promotes wakefulness, sets it apart from some of the currently available sleep medications, according to Dr. Michael Thorpy, director of the Sleep-Wake Disorders Center at the Montefiore Medical Center in New York. "The effects of the new drug are fairly localized because it targets a more specific receptor than the GABA agonists, which have a more generalized effect and thus more side effects." Importantly, suvorexant does not depress the central nervous system or respiratory function and thus may be a good option for patients with suspected sleep apnea, he noted.

Two pivotal phase III studies of the drug were presented at the meeting. Both randomized, double-blind, placebo-controlled trials were 3-month studies designed to confirm the safety and efficacy outcomes of an initial 4-week proof-of-concept study in patients with primary insomnia. Each trial evaluated two dose regimens: 40 mg for patients 18-64 years and 30 mg for those older than 65 years in the first trial; and 20 mg and 15 mg, respectively, in the second trial, explained Dr. Andrew D. Krystal, professor of psychiatry and behavioral sciences at Duke University Medical Center, Durham, N.C., and an investigator for both trials.*

Efficacy measures were patient self-reported time to sleep onset (sTSO), self-reported total sleep time (sTST), and self-reported wake after sleep onset (sWASO), as well as the polysomnographic end points of latency to onset of persistent sleep (LPS) and wake after persistent sleep onset (WASO), he said.

In the first trial, which randomized 1,021 patients, suvorexant at 40 mg and 30 mg was significantly better than placebo was in all end points at 1 and 3 months, Dr. Krystal reported. Specifically, at 3 months, the mean differences from placebo in change from baseline were an increase of 19.7 minutes for sTST, and decreases of 8.4 minutes for sTSO, 6.9 minutes for sWASO, 9.4 minutes for LPS, and 22.9 minutes for WASO.

Similarly, significant changes were observed in the second trial, with the exception of the drug’s effect on LPS at 3 months, which was not significant – a finding the investigators attributed to high placebo response, Dr. Krystal said. In this study, the mean differences from placebo in change from baseline at 3 months were an increase of 25.1 minutes for sTST and decreases of 13.2 minutes for sTSO, 8.9 minutes for sWASO, 3.6 minutes for LPS, and 29.4 minutes for WASO.

Both studies also measured the time it took patients to fall into continuous sleep and the time they spent awake during the first night of use, comparing the results with those reported before starting the drug, Dr. Krystal said. In the first trial, "patients [taking suvorexant] entered into continuous sleep 30.6 minutes faster and spent 58.0 fewer minutes awake during the night, compared to before they started taking the drug," he said. Similarly, in the second trial, the suvorexant patients entered into continuous sleep 34.7 minutes faster and spent 63.3 fewer minutes awake during the night, compared with before they started the drug. The respective placebo group improvements in the two trials were 13.0-20.3 minutes and 19.6-21.3 minutes, he said.

Both dose regimens of suvorexant in the trials were well tolerated with no evidence of clinically important rebound or withdrawal on discontinuation, Dr. Krystal reported. "Over the 3-month period, the overall incidence of adverse events in the higher-dose groups was 25.1%, compared with 13.8% for the placebo group in the first trial, and 22.2%, compared with 16.4%, in the second, and no serious drug-related adverse events were observed in either trial with the high dose of the drug," he said. The most common adverse events that occurred at least 5% more frequently in the high dose suvorexant group, compared with placebo, were sleepiness and headache, he noted.

There were no significant next-day objective residual effects associated with the study drug relative to placebo, as measured by the Digit Symbol Substitution Test, Dr. Krystal said. At 3 months, the incidence of next day sleepiness was about 10% in high-dose suvorexant patients and 3% among placebo patients.

While the drug was well tolerated in two short-term trials, "longer trials will be more telling," Dr. Thorpy said. "The orexin inhibitors were first investigated because of their effect on metabolism, so there is a possibility that, in the longer-term studies, we might see weight changes or other metabolic effects."

Although suvorexant, which has not yet been submitted to the Food and Drug Administration for approval, promises to be a valuable addition to the sleep therapy arsenal, "medications in the management of insomnia can only go so far," Dr. Thorpy stressed. "Some of the more important therapies are behavioral. No sleep pill will work with someone who has bad sleep hygiene or sleep/wake cycle issues. For optimal efficacy, all medications should be used in combination with behavioral interventions."

Dr. Krystal is a consultant to Merck, which funded both trials. Dr. Thorpy said that he had no relevant conflicts of interest.

* Correction, 6/21/12: An earlier version of this story implied that Dr. Andrew D. Krystal presented the results of the two trials described in the article. He was an investigator for the studies, but did not present them.

BOSTON – Consistently short sleep duration not only leaves otherwise healthy individuals tired, it also increases their risk of developing stroke, a study has shown.

Previous studies have linked self-reported sleep duration to incident stroke, but none have considered whether sleep-disordered breathing, which itself is associated with adverse cardiovascular outcomes, mediates that risk, said Megan Ruiter, Ph.D., of the University of Alabama at Birmingham. Dr. Ruiter and her colleagues used data from the national, population-based REGARDS (Reasons for Geographic and Racial Differences in Stroke) study to determine whether sleep duration predicts stroke risk among individuals at low risk for sleep apnea or hypopnea.

Funded by the National Institute of Neurological Disorders and Stroke, the ongoing REGARDS study enrolled more than 30,000 black and white volunteers, aged 45 years and older, to track stroke risk and cognitive health.

Based on self-reported stroke symptoms collected at 6-month intervals, Dr. Ruiter and her colleagues identified 5,666 participants who had been followed for up to 3 years without history of stroke, transient ischemic attack, stroke symptoms, or high risk for sleep-disordered breathing according to the Berlin Sleep Questionnaire. The researchers then conducted interval-censored, parametric survival models with exponential distributions to estimate the hazard ratios predicting time from measurement of sleep duration (less than 6 hours, 6-6.9 hours, 7-7.9 hours, 8-8.9 hours, and 9 or more hours) to first stroke symptoms. Data were adjusted for demographic information, cholesterol levels, hypertension, body mass index (BMI), sleep-disordered breathing, depressive symptoms, and anxiety.

"In people with a low risk for obstructive sleep apnea and a BMI in the optimal range of 18.5-24.99 kg/m², the risk of stroke symptoms was four times higher in those who had fewer than 6 hours of sleep per night, compared with participants in the same BMI range who reported 7-8 hours of sleep per night," Dr. Ruiter reported at the annual meeting of the Associated Professional Sleep Societies. Specifically, the hazard ratio for stroke symptoms among individuals within the normal BMI range who reported fewer than 6 hours of sleep nightly was 2.93, relative to the reference group. "We didn’t find any similar association between short sleep duration and stroke symptoms among overweight and obese individuals," she noted.

The association between shorter periods of sleep and stroke symptoms, including sudden body weakness, numbness, or vision deficits, remained significant after controlling for other known stroke risk factors, Dr. Ruiter said, acknowledging the possibility that "these participants may be late in the development of stroke."

The findings suggest that habitually short sleep duration may independently predispose middle-age adults to develop major stroke risk factors. "We speculate short sleep is precursor to other traditional risk factors and, once these traditional risk factors are present, they may become stronger risk factors than sleep duration alone," Dr. Ruiter hypothesized.

In a separate analysis, the investigators also evaluated the association between stroke symptoms and sleep duration by racial group and found a differential risk, according to Dr. Ruiter. "It is possible that sleep duration might partially explain the relationship between ethnic differences in stroke symptoms. For example, African Americans had a greater prevalence of short sleep and were more likely to have stroke symptoms," she said.

The study is limited by the reliance on self-reporting of stroke symptoms and the potential for recall inaccuracy, Dr. Ruiter said. Further studies are warranted to tease out the specific characteristics of sleep duration that are related to stroke symptoms, she said. For example, "Is it actually sleep fragmentation or one’s perception of sleep and factors that contribute to its quality rather than sleep duration itself?" she proposed. Additionally, "we need to see if sleep duration is related to actual stroke events." Many of these factors, she noted, are modifiable through behavioral treatment.

Dr. Ruiter had no relevant financial conflicts of interest to disclose.

BOSTON – Consistently short sleep duration not only leaves otherwise healthy individuals tired, it also increases their risk of developing stroke, a study has shown.

Previous studies have linked self-reported sleep duration to incident stroke, but none have considered whether sleep-disordered breathing, which itself is associated with adverse cardiovascular outcomes, mediates that risk, said Megan Ruiter, Ph.D., of the University of Alabama at Birmingham. Dr. Ruiter and her colleagues used data from the national, population-based REGARDS (Reasons for Geographic and Racial Differences in Stroke) study to determine whether sleep duration predicts stroke risk among individuals at low risk for sleep apnea or hypopnea.

Funded by the National Institute of Neurological Disorders and Stroke, the ongoing REGARDS study enrolled more than 30,000 black and white volunteers, aged 45 years and older, to track stroke risk and cognitive health.

Based on self-reported stroke symptoms collected at 6-month intervals, Dr. Ruiter and her colleagues identified 5,666 participants who had been followed for up to 3 years without history of stroke, transient ischemic attack, stroke symptoms, or high risk for sleep-disordered breathing according to the Berlin Sleep Questionnaire. The researchers then conducted interval-censored, parametric survival models with exponential distributions to estimate the hazard ratios predicting time from measurement of sleep duration (less than 6 hours, 6-6.9 hours, 7-7.9 hours, 8-8.9 hours, and 9 or more hours) to first stroke symptoms. Data were adjusted for demographic information, cholesterol levels, hypertension, body mass index (BMI), sleep-disordered breathing, depressive symptoms, and anxiety.

"In people with a low risk for obstructive sleep apnea and a BMI in the optimal range of 18.5-24.99 kg/m², the risk of stroke symptoms was four times higher in those who had fewer than 6 hours of sleep per night, compared with participants in the same BMI range who reported 7-8 hours of sleep per night," Dr. Ruiter reported at the annual meeting of the Associated Professional Sleep Societies. Specifically, the hazard ratio for stroke symptoms among individuals within the normal BMI range who reported fewer than 6 hours of sleep nightly was 2.93, relative to the reference group. "We didn’t find any similar association between short sleep duration and stroke symptoms among overweight and obese individuals," she noted.

The association between shorter periods of sleep and stroke symptoms, including sudden body weakness, numbness, or vision deficits, remained significant after controlling for other known stroke risk factors, Dr. Ruiter said, acknowledging the possibility that "these participants may be late in the development of stroke."

The findings suggest that habitually short sleep duration may independently predispose middle-age adults to develop major stroke risk factors. "We speculate short sleep is precursor to other traditional risk factors and, once these traditional risk factors are present, they may become stronger risk factors than sleep duration alone," Dr. Ruiter hypothesized.

In a separate analysis, the investigators also evaluated the association between stroke symptoms and sleep duration by racial group and found a differential risk, according to Dr. Ruiter. "It is possible that sleep duration might partially explain the relationship between ethnic differences in stroke symptoms. For example, African Americans had a greater prevalence of short sleep and were more likely to have stroke symptoms," she said.

The study is limited by the reliance on self-reporting of stroke symptoms and the potential for recall inaccuracy, Dr. Ruiter said. Further studies are warranted to tease out the specific characteristics of sleep duration that are related to stroke symptoms, she said. For example, "Is it actually sleep fragmentation or one’s perception of sleep and factors that contribute to its quality rather than sleep duration itself?" she proposed. Additionally, "we need to see if sleep duration is related to actual stroke events." Many of these factors, she noted, are modifiable through behavioral treatment.

Dr. Ruiter had no relevant financial conflicts of interest to disclose.

BOSTON – Consistently short sleep duration not only leaves otherwise healthy individuals tired, it also increases their risk of developing stroke, a study has shown.

Previous studies have linked self-reported sleep duration to incident stroke, but none have considered whether sleep-disordered breathing, which itself is associated with adverse cardiovascular outcomes, mediates that risk, said Megan Ruiter, Ph.D., of the University of Alabama at Birmingham. Dr. Ruiter and her colleagues used data from the national, population-based REGARDS (Reasons for Geographic and Racial Differences in Stroke) study to determine whether sleep duration predicts stroke risk among individuals at low risk for sleep apnea or hypopnea.

Funded by the National Institute of Neurological Disorders and Stroke, the ongoing REGARDS study enrolled more than 30,000 black and white volunteers, aged 45 years and older, to track stroke risk and cognitive health.

Based on self-reported stroke symptoms collected at 6-month intervals, Dr. Ruiter and her colleagues identified 5,666 participants who had been followed for up to 3 years without history of stroke, transient ischemic attack, stroke symptoms, or high risk for sleep-disordered breathing according to the Berlin Sleep Questionnaire. The researchers then conducted interval-censored, parametric survival models with exponential distributions to estimate the hazard ratios predicting time from measurement of sleep duration (less than 6 hours, 6-6.9 hours, 7-7.9 hours, 8-8.9 hours, and 9 or more hours) to first stroke symptoms. Data were adjusted for demographic information, cholesterol levels, hypertension, body mass index (BMI), sleep-disordered breathing, depressive symptoms, and anxiety.

"In people with a low risk for obstructive sleep apnea and a BMI in the optimal range of 18.5-24.99 kg/m², the risk of stroke symptoms was four times higher in those who had fewer than 6 hours of sleep per night, compared with participants in the same BMI range who reported 7-8 hours of sleep per night," Dr. Ruiter reported at the annual meeting of the Associated Professional Sleep Societies. Specifically, the hazard ratio for stroke symptoms among individuals within the normal BMI range who reported fewer than 6 hours of sleep nightly was 2.93, relative to the reference group. "We didn’t find any similar association between short sleep duration and stroke symptoms among overweight and obese individuals," she noted.

The association between shorter periods of sleep and stroke symptoms, including sudden body weakness, numbness, or vision deficits, remained significant after controlling for other known stroke risk factors, Dr. Ruiter said, acknowledging the possibility that "these participants may be late in the development of stroke."

The findings suggest that habitually short sleep duration may independently predispose middle-age adults to develop major stroke risk factors. "We speculate short sleep is precursor to other traditional risk factors and, once these traditional risk factors are present, they may become stronger risk factors than sleep duration alone," Dr. Ruiter hypothesized.

In a separate analysis, the investigators also evaluated the association between stroke symptoms and sleep duration by racial group and found a differential risk, according to Dr. Ruiter. "It is possible that sleep duration might partially explain the relationship between ethnic differences in stroke symptoms. For example, African Americans had a greater prevalence of short sleep and were more likely to have stroke symptoms," she said.

The study is limited by the reliance on self-reporting of stroke symptoms and the potential for recall inaccuracy, Dr. Ruiter said. Further studies are warranted to tease out the specific characteristics of sleep duration that are related to stroke symptoms, she said. For example, "Is it actually sleep fragmentation or one’s perception of sleep and factors that contribute to its quality rather than sleep duration itself?" she proposed. Additionally, "we need to see if sleep duration is related to actual stroke events." Many of these factors, she noted, are modifiable through behavioral treatment.

Dr. Ruiter had no relevant financial conflicts of interest to disclose.